UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
			WASHINGTON, D.C.  20460


							OFFICE OF CHEMICAL SAFETY 								AND POLLUTION PREVENTION



MEMORANDUM  

DATE:		September 16, 2019

SUBJECT:      IN-11069; 2-Phenoxyethanol: Human Health Risk and Ecological Effects 
		Assessment of a Food Use Pesticide Inert Ingredient 
 
		CAS Reg. No. 122-99-6; 	 
                  PC Code:  811513;     
                  Decision 532031

FROM:	Deirdre Sunderland, MHS, Industrial Hygienist
		Chemistry, Inerts & Toxicology Assessment Branch (CITAB)
		Registration Division (RD); 
	

TO:		Kerry B. Leifer, (Acting) Branch Chief
		CITAB/RD 


 EXECUTIVE SUMMARY

In July 2017, The Dow Chemical Company (herein referred to as "Dow"), submitted a petition (IN-11069) to the Environmental Protection Agency (herein referred to as EPA or the Agency) requesting an exemption from the requirement of tolerance for 2-phenoxyethanol (CAS Reg. No. 122-99-6) as an inert ingredient for use under 40 CFR § 180.910 as a solvent or co-solvent for use in pesticide formulations intended for use on crops pre- or post-harvest. 2-Phenoxyethanol is currently approved for use as an inert ingredient in nonfood use pesticide products including cleaning product and products applied to pets. It is also use in non-pesticidal paints and coatings, personal care/cosmetic products, and cleaning products. 2-Phenoxyethanol also has biocidal properties and therefore, the percent in formulation as an inert ingredient is limited to 0.2% by weight to ensure it is functioning as a solvent or co-solvent and not acting as a pesticide active ingredient. 

Various studies have been performed to characterize the pharmacokinetics of 2-phenoxyethanol. Single and repeat-dose studies in rats indicated that 2-phenoxyethanol is rapidly and nearly completely absorbed after oral administration and >90% of the administered dose is excreted in urine within 24 hours of exposure. Following oral and dermal exposure the terminal hydroxyl group of 2-phenoxyethanol is metabolized, mainly in the liver, by alcohol dehydrogenase (ADH) to 2-phenoxyacetaldehyde and then by aldehyde dehydrogenase (ALDH) to 2-phenoxyacetic acid (PhAA).

2-Phenoxyethanol exhibits low levels of acute toxicity. Acute studies in rats showed oral LD50 ranging from 1,260 to >2,500 mg/kg. The dermal LD50 in two rabbit studies were >2200 and >3653 mg/kg and 14391 mg/kg in a rat study. The inhalation LC50 in the rat was >1000 mg/m[3]. 2-Phenoxyethanol is considered to be an eye irritant and a mild skin irritant. However, it was not found to be a dermal sensitizer. 

Several repeat-dose oral, dermal, and inhalation toxicity studies have been conducted on rats, mice and rabbits. In a 10-day gavage study, rabbits received 2-phenoxyethanol at 100, 300, 600, or 1000 mg/kg/day. Signs of hematotoxicity and microscopic changes were observed in all dose groups. One animal died in the 300 mg/kg/day dose group and no animals survived in either of the high dose groups. The Lowest Observed Adverse Effect Level (LOAEL) of this study is 100 mg/kg/day as effects were seen at all dose levels. A No Observed Adverse Effect Level (NOAEL) was not determined. 

Two 14-day drinking water range finding studies were conducted in rats and mice. F344/DuCrj rats and BDF1 mice were exposed to concentrations of 0, 1600, 4000, 7000, 10000, 17500, and 25000 mg/L of 2-phenoxyethanol. In the rat study, significant changes in hematology (MCV and MCH) were observed in the higher dose groups (>= 10000 mg/L). Significant effects on clinical chemistry were observed in rats dosed with >= 17500 mg/L test substance. Kidney effects were seen at doses >= 17500 mg/L (i.e., increased kidney weight and increases in urea nitrogen values). Liver effects were also seen at doses of >= 17500 mg/L (i.e., increased liver weight and significant increases in AST at dose levels >= 17500 mg/L and increased ALT in females at 25000 mg/L). EPA conservatively estimates the NOAEL in this study to be 7000 mg/L (approximately 357 and 546 mg/kg/day for males and females, respectively) and the LOAEL to be 10000 mg/L (510 and 795 mg/kg/day for males and females, respectively) based on hematotoxicity.
In the other 14-day study in mice, no changes in hematology were observed. Significant increases in urea nitrogen values were observed in male rats dosed with 25000 mg/L. A significant increase in kidney weight to body weight ratio was observed in male and female mice dosed with 25000, 10000, and 7000 mg/L. No toxicologically relevant histopathological findings were observed during examination. EPA conservatively estimates the NOAEL from this study to be 10000 mg/L (approximately 898 and 1072 mg/kg/day for males and females, respectively) and the LOAEL to be 25000 mg/L (2340 and 2930 mg/kg/day for males and females, respectively) based on kidney effects (increased kidney weight and increases in urea nitrogen values).
Four 90-day oral studies were found in the database: a drinking water rat study, a drinking water mouse study, a gavage rat study, and a dietary study in rats. The two drinking water studies in rats and mice were conducted under the same set of conditions except for the dosing. In the 90-day drinking water study in rats, the dose levels were 0, 1250, 2500, 5000, 10,000 and 20,000 mg/L in drinking water. The critical effects in this study were the effects on red blood cell parameters and the histopathological changes in the kidney and urinary bladder occurring at doses >=10,000 mg/L (687 mg/kg/day in males and 1000 mg/kg/day in females). Therefore, the NOAEL was determined to be 5000 mg/L corresponding to 369 mg/kg/day in males and 652 mg/kg/day in females. 

In the 90-day drinking water study in mice, the dose levels were also 0, 1250, 2500, 5000, 10000 and 20000 mg/L in drinking water Changes in red blood cell parameters in females (hemoglobin, MCHC, and MCV) and males (reticulocytes) at 20000 mg/L suggest a slight hemolytic anemia at the high dose. Relative increases of kidney weight occurred in both sexes at higher dose levels (>=10000 mg/L) but no other effects on the kidney were noted. The NOAEL in this study of 2500 mg/L (390 mg/kg/day in males and 478 mg/kg/day in females) was based on the LOAEL of 5000 mg/L (765 mg/kg/day and 948 mg/kg/day in males and females, respectively) derived from liver effects.
Two more 90-day studies in rats were reported in the database. In the gavage study, there were several non-treatment related deaths in various dose groups indicating possible poor husbandry. There were no details provided on the purity of the test substance and therefore, this study is of limited value and not reliable. In the final 90-day study reviewed, 2-phenoxyethanol was administered in the diet to rats at dose levels up to and including, 697 and 939 mg/kg/day in male and females, respectively. No treatment related effects were observed. 
Two chronic/carcinogenicity drinking water studies were conducted, one in rats and one in mice. There was no evidence of carcinogenic activity in male or female rats dosed with 0, 2500, 5000, and 10000 mg/L and there were no clear treatment-related hematological effects. The kidney was a target organ in this study with an increased incidence of slight to moderate urothelial hyperplasia and slight papillary mineralization and necrosis observed in males at 10000 mg/L. Kidney weight were elevated in both male and females at 10000 mg/L. Based on the kidney effects, the NOAEL was established as 5000 mg/L (249 mg/kg/day in males and 380 mg/kg/day in females), with a LOAEL of 10000 mg/L (510 mg/kg/day in males and 795 mg/kg/day in females).
In the second chronic/carcinogenicity study, there was no evidence of carcinogenicity in male or female mice given 0, 5000, 10000 or 20000 mg/L. Significant effects on body weight gain (males and females) and subsequent changes in relative organ weights (males), indicate that the maximum tolerated dose was exceeded in males at 10000 mg/L (body weight 84% of controls) and in females at 20000 mg/L (body weight 79% of controls). Therefore, the NOAEL for 2-phenoxyethanol in this study was concluded to be 5000 mg/L, corresponding to an intake of 468 mg/kg/day in males and 586 mg/kg/day in females.
A 14-day inhalation study with rats was conducted with nominal concentrations of 0, 40, 200, and 1000 mg/m³. The animals were exposed 6 hours per day, 5 days a week. With the exception of decreased body weight gain (females only) and food consumption (males and females) at the highest concentration, treatment-related effects were restricted to irritation in nasal cavity, larynx and lung and increased lung weights in mid- and high-dose animals. Therefore, a NOAEC of 48.2 mg/m3 (~12.7 mg/kg/day) was determined based on respiratory tract effects at ~65 mg/kg/day. 

In a 90-day dermal study with rabbits at dose levels of 0, 50, 150 and 500 mg/kg/day, apart from sporadic and slight skin irritation, no other effects were observed including no signs of hematotoxicity. 

In a two-generation reproductive study with 2-phenoxyethanol there was an effect on fertility, but it was only seen at highest dose tested of 4000 mg/kg/day. Evidence of significant toxicity to the offspring was observed at the mid- and high-dose (i.e., 2000 mg/kg/day and 4000 mg/kg/day) level; however, it was seen in the presence of parental toxicity. Two developmental studies with 2-phenoxyethanol, one administered to the clipped skin of rabbits and the other by gavage to rats, showed no evidence of developmental toxicity. No effects on infants and children were seen in reproductive (oral) or developmental (oral and dermal) studies with 2-phenoxyethanol in the absence of maternal effects.
There is no evidence that exposure to 2-phenoxyethanol suppresses or otherwise harms immune function in humans. No signs of neurotoxicity were reported in acute or repeat-dose oral studies. There were also no signs of carcinogenicity in the database including the 2 year feeding studies. Similarly, all tests were negative for genotoxicity and mutagenicity. The available data suggests that 2-phenoxyethanol is not carcinogenic.
Studies on 2-phenoxyethanol show that the target organ in rats and mice is the kidney, most likely due to an extensive first-pass metabolism and formation of high amounts/concentrations of 2-phenoxyacetic acid in systemic circulation. Following oral and dermal exposure the terminal hydroxyl group of 2-phenoxyethanol is metabolized, mainly in the liver, to 2-phenoxyacetic acid (PhAA). Data suggest that mice are somewhat more resistant to the toxic effects of 2-phenoxyethanol and its main metabolite 2-phenoxyacetic acid than rats. 
In addition to the effects on the kidney, hematotoxicity was also observed. This appears to be the result of exposure to the parent compound. Although hematoxic effects of 2-phenoxyethanol were observed in repeat dose studies, the available repeat dose dataset indicates that the rabbit is the most sensitive species and that the hemolysis was less pronounced in rats and mice with humans as the least susceptible species to RBC hemolysis. 
The dose selections were different in the chronic and subchronic studies and these dose selections influenced the NOAELs identified in these studies. The most conservative NOAEL from the oral data set (i.e., 249 mg/kg/day) is from the chronic rat drinking water study with a corresponding LOAEL of 510 mg/kg/day based on kidney effects. Taking the database into consideration, the Agency feels that the NOAEL of 369 mg/kg/day from the subchronic 90-day drinking water study which lies between the LOAEL of 510 mg/kg/day and the NOAEL of 248 mg/kg/day of the chronic study is a more appropriate point of departure for all durations. This NOAEL would still be considered protective of all population subgroups for the following reasons.  

With the exception of the 10-day rabbit gavage study and a 90-day gavage study in rats which was determined to be unreliable, no adverse effects were seen at doses less than 510 mg/kg/day. The LOAEL in the 10-day rabbit study was 100 mg/kg/day based on hemolytic effects seen at all doses. Hematotoxicity in rabbits is caused by the parent compound when systemically available but not by the main metabolite 2-phenoxyacetic acid, which may be responsible for toxicity to the kidney. According to various studies/sources, humans are more resistant to lysis than rabbits, mice and rats. Given the much higher capacity of humans to metabolize 2-phenoxyethanol compared with rabbits (the most sensitive species), this study was considered less relevant to human exposure than rat and mice studies and subsequently, was not selected as the Point of Departure (POD) for oral exposure. 

The POD for dermal exposure is based on the finding in the 90-day dermal study and the developmental dermal study both done in rabbits. No adversed effects attributed to the test chemical were seen in the 90-day study. The NOAEL was 500 mg/kg/day (highest dose tested). Maternal toxicity was seen in the developmental dermal study in rabbits at 600 mg/kg/day and therefore, this was treated as the LOAEL for dermal exposure. 

The short-term inhalation POD of 48.2 mg/m3 (~12.7 mg/kg/day) is based on a 14-day inhalation study which showed respiratory effects at 246 mg/m3 (~65 mg/kg/day). The POD used for long-term inhalation exposure is also from the 14-day inhalation study with an additional 10x uncertainty factor for using a subchronic study for a chronic endpoint. 

Based on the proposed use as a solvent or co-solvent in pesticide formulations applied to crops pre- or post-harvest, dietary (oral) and residential (dermal and incidental oral in children) exposure is possible. The dietary assessment showed that children 1-2 years old would be the highest exposed subgroup at 0.00007% of the 3.69 mg/kg/day chronic Population Adjusted Dose (cPAD). Various residential uses were also evaluated such as pesticides applied to lawns and turf, use in paints, use in pet spot-on products, and use in household cleaning products. In addition, background exposure from use in cosmetics was also incorporated into the risk assessment. All exposure scenarios were within acceptable limits and were considered safe. 
When aggregating residential and dietary exposure EPA determines whether pesticide exposures are safe by comparing aggregate exposure estimates to the cPAD. Risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the Margin of Exposure (MOE) called for by the product of all applicable Uncertainty Factors (UFs) are not exceeded. The Agency is concerned with oral, dermal, and short-term inhalation MOEs <100 and a long-term inhalation MOE of 1000. The FQPA safety factor was reduced to 1X. 
The mode of action of the toxicological effect must be the same across routes of exposure in order to aggregate the exposure. In this case, however, the toxic effects are different by one route and duration from those produced by a different route and duration. To produce an aggregate risk estimate in situations in which it is NOT appropriate to aggregate exposures due to differing toxicological effects, risk measures are calculated separately for each route and duration for a given toxic effect. 
When combining similar routes of exposure, the estimated MOE for aggregate exposures in adults and children was above the Agency's level of concern of 100. Similarly, the Agency found that when used as proposed, the risk to occupational workers would not exceed the Agency's level of concern. 
2-Phenoxyethanol is characterized by high water solubility, low octanol-water partition coefficient, and low Henry's law constant. Based on the results of several screening studies, 2-phenoxyethanol is classified as readily biodegradable. Fugacity modeling predicts that 2-phenoxyethanol will reside mainly in the soil and water. Overall, 2-phenoxyethanol is considered to have low potential for environmental persistence.
Various ecotoxicity and environmental fate studies were conducted with 2-phenoxyethanol. Available data on the toxic effects of 2-phenoxyethanol on aquatic organisms, microorganisms, terrestrial plants, and soil microorganisms show low potential to cause harm to the environment. Therefore, at this time the Agency considered the risk for ecotoxicity and the risk to environmental systems acceptable. 
Based upon the factors summarized above, the Agency approves the use of 2-phenoxyethanol under 40 CFR § 180.910 as an inert ingredient in food use pesticide formulations at a maximum concentration of 0.2% by weight.

 BACKGROUND

In July 2017, The Dow Chemical Company (here in referred to as "Dow") submitted a petition (IN-11069) requesting an exemption from the requirement of tolerance for 2-phenoxyethanol (CAS Reg. No. 122-99-6) as an inert ingredient under 40 CFR § 180.910 for use as a solvent or co-solvent in pesticide formulations intended for use on crops pre- or post-harvest. 2-Phenoxyethanol is currently approved by the EPA for use as a nonfood inert ingredient. As a nonfood inert ingredient, 2-phenoxyethanol is used various pesticide products including cleaning products and products applied to pets. It is also currently used in non-pesticidal products such as paints and coatings, personal care/cosmetic products, and cleaning products. According to Dow, the use in latex paints and cosmetics are the most common and the ones most likely to result in the highest residential exposure.

2-Phenoxyethanol has antimicrobial properties and is used as a biocide in the European Union (EU). Dow submitted information to show that uses of 2- phenoxyethanol in concentrations greater than 0.2% would result in biocidal activity and therefore, a limitation of 0.2% by weight in pesticidal products is being applied.

Data on 2-phenoxyethanol has been submitted under the EU's Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) program and the toxicity of 2-phenoxyethanol has been previously evaluated by the EU European Commission's Scientific Committee on Consumer Safety (SCCS). This scientific committee, made up of high level independent global scientists, reviewed and evaluated relevant scientific data and assessed potential risks from 2-phenoxyethanol based on its use in cosmetics (maximum 1% in formulation). Toxicological relevant information from these reviews, which are publicly available, have been included in this document. 
         
 PHYSICAL/CHEMICAL PROPERTIES 

Below are the available physical and chemical properties of 2-phenoxyethanol:

           Table 1: Physical/Chemical Properties of 2-Phenoxyethanol
                                Characteristic
                                     Value
                                    Source
Chemical Names
2-Phenoxyethanol; 
Ethylene glycol monophenyl ether; Phenoxytol; Ethanol 2-phenoxy; 
1-Hydroxy-2-phenoxyethane; 
Phenoxyethanol


https://chem.nlm.nih.gov/chemidplus/rn/startswith/122-99-6
CAS Reg. No. 
122-99-6
https://chem.nlm.nih.gov/chemidplus/rn/startswith/122-99-6
Structure




MRID 50321636
Molecular Formula
C8H10O2
MRID 50321636
Molecular Weight 
138.17 g/mol
MRID 50321636
Density
1.11 g/mL at 20 °C
MRID 50321636
Vapor Pressure
0.0105 mmHg @ 20 °C  
0.0159 mmHg @ 25 °C
REACH
Melting point
9-11.8°C at 1013 hPa
REACH
Boiling point
245 °C at 760 mmHg
REACH
Flash Point 
126 °C at 760 mmHg
MRID 50321636
Water Solubility
 25 g/l at 20 °C, pH 7
26 g/l at 30 °C, pH 7
MRID 50321636
REACH
Octanol/Water Coefficient (Log Kow)
1.2 at 23 °C, pH 7
MRID 50321636

 METABOLISM
         
Various studies have been performed to characterize the pharmacokinetics of 2-phenoxyethanol. Single and repeat-dose studies in rats indicated that 2-phenoxyethanol is rapidly and near completely absorbed after oral administration and >90% of the administered dose is excreted in urine within 24 hours of exposure (MRID 50321613). Following oral and dermal exposure the terminal hydroxyl group of 2-phenoxyethanol is metabolized, mainly in the liver, by alcohol dehydrogenase (ADH) to 2-phenoxyacetaldehyde and then by aldehyde dehydrogenase (ALDH) to 2-phenoxyacetic acid (PhAA). (MRID 50321648)

According to Troutman et. al, (MRID 50321650) the metabolism of 2-phenoxyethanol "has been monitored in vitro by measuring the conversion of NAD[+] to NADH spectrophotometrically using rat liver and rat skin cytosolic fractions (internal citation Lockley et al., 2005). Based on definitive in vitro hepatic metabolism studies using liver S9, species differences in NAD[+]-dependent metabolism of 2-phenoxyethanol were noted and the rate of PhAA formation was found to be highest in the human > rat > mouse > rabbit (internal citation The Dow Chemical Company, 2007)." 
In one study (MRID 50321614) looking at the effects of 2-phenoxyethanol on the absorption, distribution, elimination and biokinetics of in male and female Wistar rats, rats were given 2-phenoxyethanol at dose levels of 30, 100, 300 and 1000 mg/kg for plasma kinetics and 40 and 400 mg/kg for mass balance, biliary excretion, and tissue distribution experiments. After a single oral administration of either 40 or 400 mg/kg, the mean total recoveries of radioactivity were > 90% in both sexes. In exhaled air, no relevant portions of the administered radioactivity were detected as CO2. Within 168 hours of being given 40 mg/kg, 94.0 and 92.9% of the administered radioactivity were excreted in the urine in male and female rats, respectively. For those given 400 mg/kg the results were similar (94.1% and 93.4%, respectively). After 168 hours the total amount of radioactivity excreted via feces in those rats receiving 40 mg/kg was found to be 2.2 % for males and 1.9 % for females. For the male and females given 400 mg/kg, 2.9 and 2.0% of the administered radioactivity were excreted via feces, respectively. 
In rats exposed to single oral doses of 30, 100, 300 and 1000 mg/kg, the maximum
plasma concentration of 13.66, 47.95, 82.78, and 415.04 μg Eq/g in males and14.26, 54.41, 127.26, and 487.73 μg Eq/g in females occurred 1 - 2 hours post-dosing, respectively.
Afterwards, plasma levels declined to 0.04, 0.08, .018, and 0.22 μg Eq/g in males and 0.04, 0.14, 0.38 and 0.85μg Eq/g in females at sacrifice after 96 hours, respectively. The initial half-lives were calculated to be 1.92 - 2.91 hours in males and 1.82 - 4.60 hours in females. Terminal half- lives were 33.1 0 - 54.05 hours for males and 27.99 - 60.45 hours for females.  

During the first two days post-dosing, lower concentrations of radioactivity were generally found in blood indicating that major parts of the radioactivity were in plasma and not bound to cellular blood constituents. Blood/plasma ratios >1 were not detected within the first 24 hours after dosing but were observed at 48 hours after dosing or later. Tissue radioactivity concentrations generally declined with time parallel to plasma concentrations. Throughout the time course of the experiments, the highest radioactivity concentrations were found in the gastrointestinal (GI) tract, kidney, pancreas, skin, and bone marrow for the high dose as well as GI tract, kidney, liver and skin for the low dose. Radioactivity levels were lowest in brain, muscle and heart for the high dose and brain, uterus, muscle and bone for the low dose.

The bioavailability of 2-phenoxyethanol was comparable between 400 and 40 mg/kg dose levels. The plasmakinetics demonstrated that an increase of the dose resulted in an over proportional increase of the AUC-values, indicating a saturation of excretion with increasing dose.
In a percutaneous penetration study (MRID 50321633), 2-phenoxyethanol was rapidly absorbed through rat skin mounted in both the static and flow-through diffusion cell. The stratum corneum did not appear to be a good barrier to 2-phenoxyethanol penetration. Covering increased the permeability coefficient of 2-phenoxyethanol in the static cell. The permeability profile and amount absorbed were similar for human and rat skin in the flow-through system with tissue culture medium. Other metabolism data in rats suggest higher systemic availability of 2-phenoxyethanol after dermal exposure than after oral exposure.

2-Phenoxyethanol, when applied in methanol, was absorbed (64 + 4.4% at 24 hr) through unoccluded rat skin in vitro in the static diffusion cell with ethanol/water as receptor fluid. In the flow-through diffusion system with tissue culture medium as receptor fluid (43 + 3.7% in 24 hr) was absorbed. 

In another study (MRID 50321636), male and female Wistar rats were treated topically with 2.8 or 3.7 mg 2-phenoxy[1-14C] ethanol dissolved in ethanol (corresponding to 20-25 mg/kg). Female rats were treated with one of two skin creams containing 1% 14C-2-phenoxyethanol (about 1 mg corresponding to about 7 mg/kg). Ethanol as a solvent is not ideal because it may interfere with oxidative metabolism, 2-phenoxyethanol was rapidly absorbed and mainly excreted in urine (55-60%). Proportions of 14C exhaled (1 - 1.5%) or found in tissues (1 - 2%) or feces (~2%) were similar to the gavage experiments. Recovery, however, was only around 70%, likely due to evaporation from skin when dissolved in ethanol and applied. Roughly 88% of the test substance applied in skin creams was absorbed and recoveries were >90%. 

 TOXICOLOGY
   
Available data for 2-phenoxyethanol are summarized from a variety of sources including published literature, proprietary studies, public domain sources (e.g., EU REACH, Cosmetic Ingredient Review (CIR), and "Opinion on Phenoxyethanol" by the European Commission's Scientific Committee on Consumer Safety (SCCS)). The data used in this risk assessment are summarized in the sections below and presented in Table 2: Repeat Dose Toxicology Profile for 2-Phenoxyethanol. 

 Acute Toxicity
        
 Acute Oral Toxicity 

Various acute oral studies have been conducted over the years on 2-phenoxyethanol. In one study, the acute oral toxicity of 2-phenoxyethanol was evaluated in Sprague-Dawley rats (5/sex/dose) treated with 625, 1250, 2500, and 5000 mg/kg of the test material (MRID 50321640). Survival was monitored for the next 14 days. Based on the moving average method, LD50 values of 2937 mg/kg and 4013 mg/kg were estimated for males and females, respectively.
In a second oral toxicity study on Wistar rats, animals were given 681, 1470, 3160, or 5000 mg/kg. LD50 values in female rats were approximately 1840 mg/kg whereas, males were generally less susceptible to 2-phenoxyethanol with an LD50 of 4070 mg/kg. The LD50 value for males and females combined was determined to be 2740 mg/kg. (ECHA, 2018)
In a much earlier acute oral study, 2-Phenoxyethanol was administered by gavage to groups of albino male Wistar rats. Mortality data were analyzed using the method of probits. The calculated oral LD50 for 2-phenoxyethanol in rats was 1,260 mg/kg. (MRID 50321638)

According to the 2004 SIDS Initial Assessment Profile (MRID 50321632) on 2-phenoxyethanol, "The most reliable LD50 values for the rat after oral administration are 1,386 and 2,563 mg/kg bw in fasted males and females (respectively), and 2,937 and 4,013 mg/kg bw in fed males and females, (respectively)." No further information was provided. 
 Acute Dermal Toxicity
    Rabbit
The acute dermal toxicity of 2-phenoxyethanol was determined following a single dermal administration (24-hr contact period) to the clipped skin of male Albino New Zealand rabbits. Thompson's method of calculating the LD50 was used. Under this study, the dermal LD50 for 2-phenoxyethanol in rabbits was > 3.3 mL/kg (3653 mg/kg based on the reported density of the study material of 1.107 g/mL). (MRID 50321640) Findings at autopsy included skin erythema or desquamation, lung congestion or hemorrhage, liver mottling (some areas were pale whereas others congested), kidney surfaces pitted, urine bloody and intestinal congestion or hemorrhage.
A second test on abraded skin of New Zealand White rabbits showed no mortality at the limit dose of 2.0 mL/kg (corresponding to 2214 mg/kg). The only effect observed in two rabbits was a local erythema and desquamation at the dosing site which was reversible within 3 days after dosing. Desquamation was observed in one rabbit from observation days 3-14. The acute dermal LD50 value in the rabbit was > 2214 mg/kg (MRID 50321636).
   Rat
In CFY rats, acute dermal toxicity was tested at concentrations of up to 24575 mg/kg (1-22.2 mL/kg) for 24 hours. Mortalities occurred 21 to 48-hours post-dosing. Hemorrhagic lungs were found at necropsy. No further details were provided. The LD50 in rat was determined to be 14391 mg/kg. (ECHA, 2018)

 Acute Inhalation Toxicity
Several acute Inhalation Risk Tests (IRT) of minor relevance were available for 2-phenoxyethanol in the REACH database; however, very few details were provided. Rats were exposed to saturated vapor for 7 or 8 hours and no deaths or clinical signs were observed. One guideline study, however, was considered reliable. No mortalities were seen in rats exposed nose-only up to 1000 mg/m³ for 14 days (6 hours per day, 5 days per week). No deaths were recorded, and no clinical signs of toxicity were observed throughout the study. Therefore, the LC50 was >= 1000 mg/m³.
 Skin Irritation (CIR, 1990)
Four New Zealand White rabbits were exposed to 2.0 ml/kg of undiluted 2-phenoxyethanol (cosmetic grade, minimum 92% 2-Phenoxyethanol, maximum 8% diethylene glycol monophenyl ether) applied to the shaved and abraded dorsal skin for 24 hours. The rabbits were observed for signs of systemic toxicity and dermal irritation and twice daily for 14 day following exposure to 2-phenoxyethanol. The rabbits were weighted on days 7 and 14. At bandage removal, two rabbits had erythema; the erythema persisted in one rabbit through day 3. The same rabbit also had desquamation on days 3-14. At the end of the observation period, the rabbits were necropsied. No other adverse effects were noted. 
In a second study, a single occlusive patch of 2% or 10% 2-phenoxyethanol in 10% acetone/90% water was applied to the clipped, intact or abraded skin on the flanks of six rabbits for 24 hours. The patch sites were examined upon patch removal and at 72 hours post-dosing. Slight transient erythema was observed in two of the rabbits at the 10% site at the 24-hour reading, and in one rabbit at the 2% site at 24 hours. 
2-Phenoxyethanol is considered a mild skin irritant. 
 Eye Irritation 
As described in the 1990 CIR review, a single application of 0.1 mL of undiluted 2-phenoxyethanol (cosmetic grade, minimum 92% 2-phenoxyethanol maximum 8% diethylene glycol monophenyl ether) was applied to the left eye of each of 12 New Zealand White rabbits. The eyes of six of the rabbits remained unrinsed, the eyes of three rabbits were rinsed after 4 seconds for 5 minutes with water, and the eyes of three rabbits were rinsed with water after 30 seconds for 5 minutes. The eyes were examined for irritation at 1, 24, 48, and 72 hours, and daily for additional 11 days. Irritation was scored according to the Draize method.
Of the six rabbits receiving no rinse, all had slight corneal opacity, minimal iritis, moderate to severe redness of the conjunctivae with blisters under the eyelids, and moderate swelling and discharge. The time required for the reactions to subside varied with the individual rabbits, the highest total Draize score was 46 at 1 hour. All rabbits had scores of 0 by day 14. The ocular reactions of the three rabbits receiving a rinse 4 seconds after 2-phenoxyethanol instillation had slight opacity of the cornea, slight iritis, and severe erythema with blisters under the lids in two of the rabbits. A score of 0 was noted on day 8 for two of the rabbits, and on day 11 for the third rabbit. The three rabbits which received a rinse 30 seconds after instillation had slight corneal opacity over varying areas of the cornea, slight iritis, and severe erythema with blisters under the eyelids, and swelling with minimal discharge. These reactions persisted for varying lengths of time, and all were cleared by day 12. The rabbits received scores of 0 on days 7, 8, and 12; no maximum score was >2 after 72 hours.  Undiluted 2-phenoxyethanol was an eye irritant under the conditions of the study.
In another study, 0.1 mL unchanged test material in the eye of each of three rabbits clearly induced signs of irritation in all three animals; the signs were of maximal severity between 48- and 72-hours following application. Thereafter, a tendency to reversibility was observed and after 15 days, only one animal still displayed slight corneal opacity affecting less than (1/4) of the corneal area of the treated eye. The test substance 2-phenoxyethanol was considered an eye irritant. (ECHA, 2018)
2-Phenoxyethanol is considered an eye irritant. 
 Skin Sensitization 
Ten animals received three pairs of 0.1 mL intradermal injections in the neck region (saline FCA alone, 0.1% 2-phenoxyethanol in olive oil, and 0.1% 2-phenoxyethanol in saline FCA). Epicutaneous induction was carried out one week later in the same region by applying 1 mL undiluted test substance to the skin, under occlusive dressing for 48 hours. Challenge was performed two weeks after epicutaneous induction under occlusive conditions, for 24 hours. The undiluted test substance (0.5 mL) was applied to the flank of each animal of the test group and the second control group; the animals of the first control group remained untreated. 

Animals were observed for signs of toxicity twice a day and daily on weekends and holidays. Skin reactions readings, assessed according to the grading scale of Magnusson and Kligman, were made 24 hours after intradermal induction, 48 hours after start of epicutaneous induction, and at 24 and 48 hours after removal of the challenge patch. The challenge with the undiluted test substance did not cause any skin reactions in the control group nor in the test group 24 and 48 hours after removal of the patches. Therefore, 2-phenoxyethanol is not considered a skin sensitizer. (MRID 5032618)

In study described in CIR, "The dermal sensitization potential of Phenoxyethanol was evaluated using six albino guinea pigs. The induction phase of the study consisted of five applications at 24 h intervals of 0.1 ml of 10% Phenoxyethanol to the outer surface of the ears. Five days after the last application to the ear, 0.2 ml of 0.1, 1.0, and 10% solutions of Phenoxyethanol were applied to the shaved flanks of the guinea pigs. No reactions were noted during either the induction or challenge phases of the study." No other details were given.

 Repeat Dose Toxicity
        
 Oral
           
   Sub-Acute: 10-day Oral Toxicity Study (rabbit):

Groups of three New Zealand White female rabbits were administered a single gavage dose of 100, 300, 600, or 1000 mg/kg/day 2-phenoxyethanol for 10 consecutive days. (MRID 50321636) During the 10-day treatment period, deaths occurred in all dose groups above 100 mg/kg/day or animals were sacrificed moribund. In the 300 mg/kg/day dose group, one animal was found dead on day 10 after dosing. No animals in the 600 and 1000 mg/kg/day dose group survived. Signs of toxicity included anorexia, lethargy and excretion of dark-red urine. On day 5, mean body weights of rabbits dosed with 100, 300, or 600 mg/kg/day had decreased approximately 8% from their pre-exposure weights and 10-14% from that of control animals. On day 10, rabbits in the 100 and 300 mg/kg/day dose groups continued to show similar decreases in body weight. Control rabbits exhibited a slight gain in mean body weight over the 10-day dosing period. 

In general, rabbits exposed to 2-phenoxyethanol had decreased red blood cell (RBC) count, hemoglobin (HGB) concentration and packed cell volume (PCV), with concurrent increases in nucleated and poly-chromatophilic red blood cells. Many animals exhibiting severe depressions in RBC numbers also showed concurrent increases in other blood parameters (i.e., MCH, MCHC, platelets and WBC). The values for MCH and MCHC were considered elevated due to free hemoglobin in plasma. 

Urine samples collected from rabbits in the 1000, 600 and 300 mg/kg/day dose groups exhibited decreased pH in combination with elevated levels of protein, bilirubin, urobilirubin and hemoglobin. Decreases in urinary pH and increases in urinary bilirubin and RBC were observed in at least one rabbit in the 100 mg/kg/day dose group. 

Most rabbits administered 600 or 1000 mg/kg/day exhibited gross pathological alterations consistent with hemolytic anemia including enlarged and dark kidneys and spleen, dark urine in the urinary bladder, and dark urine staining the perineal region. Conversely, rabbits gavaged with 100 or 300 mg/kg/day did not have treatment-related gross lesions. 

Treatment-related microscopic changes were observed in rabbits from all dose levels. Splenic microscopic changes included red pulp congestion and erythro-phagocytosis in most animals of both high dose groups. Treatment-related microscopic changes also occurred in the kidneys and stomach of both high-dose groups. The spleen of one rabbit in the 300 mg/kg/day dose group had thrombi in venous sinuses resulting in generalized splenic necrosis. This animal also had thrombi within pulmonary blood vessels. Two rabbits given 100 mg/kg/day had splenic extramedullary hematopoiesis. 

The Lowest Observed Adverse Effect Level (LOAEL) in this study is 100 mg/kg/day based on hematotoxicity and microscopic changes. The No Observed Adverse Effect Level (NOAEL) was 
undetermined.  
      
   Sub-Acute: 14-Day Drinking Water Toxicity Study (rat) 

This study is taken from the REACH dossier and conversion of the dose in mg/kg was not provided. However, this study is believed to be the range finding study for the chronic drinking water study in rats listed below. Therefore, these doses were extrapolated using the dosing information provide in that study.
A dose range finding 14-day drinking water study was conducted in rats. F344/DuCrj rats (5/sex/dose) were exposed to concentrations of 0, 1600, 4000, 7000, 10000, 17500, or 25000 mg/L (Males: 0, 82, 204, 357, 510, 892, or 1275 mg/kg/day, respectively; and Females 0, 124, 312, 546, 795, 1365, or 1950 mg/kg/day, respectively) 2-phenoxyethanol. Clinical signs, mortality, food consumption, water consumption and body weight were observed or measured on test days 3 and 7 of each week. After 14 days of exposure hematology, clinical chemistry and urinalysis were assessed, rats were sacrificed, and gross and histopathological examinations were conducted. No mortality was observed. 
Body weight gain, food intake and water intake were suppressed in both sexes in the higher dose groups. In the 17500 and 25000 mg/L dose group body weight gain was suppressed in both sexes. Terminal body weights were 90% and 78% for males and 89% and 73% for females, respectively. 
Food intake was suppressed in the higher dose groups as well as water intake (>=10000 mg/L). Male water consumption in the 10000, 17500, and 25000 mg/L dose groups differed significantly from the control group. The average group intake was 69-80%, 59-92%, and 33-90% in the 10000, 17500, and 25000 mg/L dose groups, respectively. Female water consumption was significantly decreased in the 10000, 17500, and 25000 mg/L dose groups. The average group intake was 67-78%, 48-78%, and 32-83% in the 10000, 17500, and 25000 mg/L dose groups, respectively.
Food consumption in males was suppressed in the 10000, 17500, and 25000 mg/L dose groups. Group average food intake was 86-92%, 71-89%, and 49-82% in the 10000, 17500 and 25000 mg/L dose groups, respectively. Female food consumption was significantly suppressed in the 17500 and 25000 mg/L dose groups. The average group food intake ranged from 70-86% and 38-85% in the 17500 and 25000 mg/L dose groups, respectively. In female rats a significant decrease in glucose was seen in the 25000 mg/L dose group.
MCV concentrations were significantly increased in males at >=10000 mg/L. A significant increase in MCH concentration was found in male rats after dosing with >= 4000 mg/L. Other minor changes occurred in blood parameters but did not appear to be statically significant. 
Relative organ weights (liver and kidneys) were increased in the higher dose groups. Relative to body weight a significant increase in kidney weight was observed in males dosed with 25000 mg/L and females dosed with 25000 and 17500 mg/L 2-phenoxyethanol. Significant increases in urea nitrogen values were observed in male rats dosed with >= 17500 mg/L and females dosed with 25000 mg/L.
A relative increase in liver weight was observed in males dosed with 10000 and 25000 mg/L, showing a lack of dose response as there was no effect at 17500 mg/L. Females dosed with 17500 and 25000 mg/L also showed a relative increase in liver weight; however, AST and ALT were not significantly elevated except in females in the 25000 mg/L group. 
This summary was drafted from information provided in the REACH dossier for 2-phenoxyethanol. No other pertinent information was provided for this study. Based on the limited information provided, the EPA conservatively estimates the NOAEL to be 7000 mg/L (approximately 357 and 546 mg/kg/day for males and females, respectively) and the LOAEL to be 10000 mg/L (510 and 795 mg/kg/day for males and females, respectively) based on hematotoxicity. 
   Sub-Acute: 14-Day Drinking Water Toxicity Study (mice) 
This study is taken from the REACH dossier and conversion of the dose in mg/kg was not provided. However, this study is believed to be the range finding study for the chronic drinking water study in mice listed below. Therefore, doses were extrapolated using the dosing information provide in that study.
A dose range finding 14-day drinking water study was conducted in DBF1 mice. Mice (5/sex/dose) were exposed to concentrations of 0, 1600, 4000, 7000, 10000, and 25000 mg/L (0, 150, 375, 655, 898, and 2340 mg/kg/day in males, respectively; and 0, 187, 468, 820, 1072, and 2930 mg/kg/day in females, respectively). Clinical signs, mortality, food consumption, water consumption and body weight were observed or measured on test days 3 and 7 of each week. After 14 days of exposure hematology, clinical chemistry and urinalysis were assessed, rats were sacrificed, and gross and histopathological examinations were conducted. No mortality was observed. 
Body weight gain, food intake and water intake were suppressed in both sexes in the higher dose groups. In the 25000 mg/L dose group terminal body weights were 84% for males and 90% for females compared to controls. Food consumption in males was suppressed in the 10000 and 25000 mg/L dose groups during the first week of treatment but only significant in the highest dose group. Group average food intake was 23 to 58% in the 25000 mg/L dose group. Female food consumption was significantly suppressed in the 25000 mg/L dose group. The average group food intake ranged from 61-91% compared to controls. 
Male water consumption in the 25000 mg/L dose group was significantly lower compared to controls. Average group intake was 23 to 58 % compared to the control group during the study. Female water consumption was significantly decreased in the 7000, 10000, and 25000 mg/L dose groups. The average group intakes were 74-82%, 63-73 % and 27-53 %, respectively.
No significant hematological changes were observed. Significant increases in urea nitrogen values were observed in male rats dosed with 25000 mg/L. In males a significant increase in phospholipids concentrations were seen in the 10000 mg/L dose group.  
Relative to body weight, a significant increase in kidney weight was observed in male and female mice dosed with 25000, 10000, and 7000 mg/L 2-phenoxyethanol. No toxicologically relevant histopathological findings were observed during examination. 
This summary was drafted from information provided in the REACH dossier for 2-phenoxyethanol. No other pertinent information was provided for this study. The information provided limits our ability to determine a NOAEL and LOAEL but based on the limited data provide it appears the NOAEL would be 10000 mg/L and the LOAEL would be 25000 mg/L based on the increased kidney weight coupled with the increase in urea nitrogen. 

   Subchronic: 13-Week Drinking Water (rat)
Two repeated dose drinking water studies were conducted and summarized by the European Commission's Scientific Committee on Consumer Safety (SCCS) (MRID 50321636). The first 13-week drinking water study was conducted with F344/DuCrj rats (10/sex/dose) were exposed to 0, 1250, 2500, 5000, 10000 or 20000 mg/L. Based on chemical intake data, the mean intake of test substance across the duration of the study was estimated to be 0, 96, 185, 369, 687, and 1514 mg/kg/day in males and 0, 163, 313, 652, 1000, and 1702 mg/kg/day in females. Food intake, water intake, and body weight were determined weekly. Food consumptions and body weight values were significantly decreased females at >=10000 mg/L and >=20000 mg/L in males. 
After 13 weeks urinalysis, hematology, blood chemistry, gross pathology, organ weights and histopathology were examined. Effects on the red blood cell parameters (i.e., statistically significant (SS) reduction in RBC, hemoglobin, and platelets at >=10000). Platelets were SS at >=5000 mg/L in males, however, the decrease at 5000 mg/L was <10% change from controls and the decreased platelets were not accompanied by evidence of a functional effect since no changes were observed in coagulation parameters (prothrombin and APPT). 
At the end of the treatment period, various changes in clinical chemistries were seen; however, with the exception of urea nitrogen in both sexes and ALP in females, these statistically significant differences in relation to controls were slight (generally less than 10%). The ALP elevation was observed only at the highest dose level in females and was not accompanied by other changes in liver enzymes or histopathological findings in liver or bone.
Although there was a dose-related increase in relative liver weight in both sexes at 10000 and 20000 mg/L there was no increase in absolute liver weight in either sex and biochemical changes in the serum were slight and did not provide a clear pattern of toxicity. In addition, no treatment-related histopathological findings were reported in the liver. 
Changes in histopathology of the kidney and bladder were observed in rats dosed with 10000 mg/L and above. An increase in relative kidney weight of 10% was seen in females at doses of >= 10000 mg/L and in both sexes up to 27% at 20000 mg/L. Absolute kidney weights were not significantly increased in either males or females. 
Slight to moderate urothelial hyperplasia of the renal pelvis was observed at 10000 mg/L in 2 of 10 males and 1 of 10 females and at 20000 mg/L in males (6 of 10 animals). Slight to moderate urinary bladder transitional epithelial hyperplasia was observed at 10000 mg/L in 2 of 10 females and at 20000 mg/L in 7 of 10 females. As mentioned above, urea nitrogen was increased in both sexes at 20000 mg/L and at 10000 mg/L in females. These observations are all considered treatment-related. 
Based on these results, the study NOAEL was determined to be 5000 mg/L (369 mg/kg/day in males and 652 mg/kg/day in females). The LOAEL was 10000 mg/L (687 mg/kg/day and 1000 mg/kg/day in males and females, respectively), based on kidney and bladder effects and effects on blood parameters (i.e., statistically significant reductions in RBC, hemoglobin, and platelets). 
   Subchronic: 13-Week Drinking Water (mouse)
The second study (MRID 50321636) was conducted with Cru: BDF1 mice. The study design, examination, and observations were similar to the study above in rats. Based on the information available, it appears the only difference was the dose levels which were 0, 1250, 2500, 5000, 10000 and 20000 mg/L with the mean intake of test substances estimated to be 0, 182, 390, 765, 1178, and 2135 mg/kg/day in males and 0, 236, 478, 948, 1514, and 2483 mg/kg/day in females. Effects on red blood cell parameters (females: hemoglobin, MCHC, MCV; males:  reticulocytes) were found in mice dosed with 20000 mg/L. In males dosed with >=5000 mg/L, changes in blood chemistry parameters (decreases in cholesterol and phospholipids) were measured; however, no histopathological changes were observed in the liver. 
As summarized in the SCCS report (MRID 50321636), 
      Changes in red blood cell parameters in females (haemoglobin, MCHC, and MCV) and males (reticulocytes) at 20,000 ppm suggest a slight haemolytic anaemia at the high dose but no effect at lower doses. Changes in clinical chemistry parameters that may suggest a treatment-related effect on the liver including decreases in cholesterol and phospholipid at doses of > 5,000 ppm in males, although there was no evidence of any histopathology in the liver and no increase in liver enzymes (GPT, GOT). Relative increases of kidney weight occurred in both sexes at higher dose levels (>= 10000 ppm). While it is possible that the liver-related changes in cholesterol and phospholipid are not adverse, these findings in males were very conservatively used as the basis for establishing the NOAEL. 
Based on these effects, the study NOAEL was determined to be 2500 mg/L (390 mg/kg/day in males and 478 mg/kg/day in females). The LOAEL was 5000 mg/L (765 mg/kg/day and 948 mg/kg/day in males and females, respectively), based on liver effects. 
   Subchronic: 13-Week Gavage (rat) 
In another study (pre-GLP), 2-phenoxyethanol was administered via gavage for 13 weeks to CD rats (15/sex/dose) at doses of 0, 80, 400, and 2000 mg/kg/day (Ben-Dyke et.al, 1977 and MRID 50321636). At 2000 mg/kg/day clinical signs included occasional episodes of prostration and lethargy shortly following 2-phenoxyethanol dosing. Females were more affected than males. These episodes occurred as isolated or low incidence events when dosing was initiated and resolved with continued dosing. Nine animals (4 male and 5 female) died or were killed in extremis during the treatment period. Four of high-dose females which died during the treatment period were considered treatment related, although no gross or histopathological changes were identified (one died of bronchopneumonia). 
After four weeks of treatment at 2000 mg/kg/day, the alkaline phosphatase and serum glutamate-pyruvate transaminase activities and glucose and urea concentrations of males were significantly greater than those of the controls. Males receiving 400 mg/kg/day were similarly affected in respect to alkaline phosphatase (ALP) activities only. Females in the highest dosage showed high glucose concentrations but were unaffected in all other respects. At termination the ALP activities of males receiving 2000 mg/kg/day remained elevated. 
At 2000 mg/kg/day clinical chemistry data showed toxicity to red blood cells (i.e., decreased erythrocyte number, decreased packed cell volume and decreased hemoglobin concentration) and kidney inflammation with epithelial cells and polymorphonuclear leukocytes in the urinary sediment. Liver, kidney and thyroid weigh were increased at 2000 mg/kg/day. Inflammation of the kidneys also was seen in males at 400 mg/kg/day. 
In a proportion of male animals receiving 400 mg/kg/day and in both males and females receiving 2000 mg/kg/day, the occurrence of chronic inflammatory cell infiltration and of tubules characterized by the basophilic staining of the cells of the epithelium was seen to be more frequent than in other groups and was associated with an increase in the degree of change in some instances. In addition, distension of the tubules up to a moderate degree was noted, particularly in male animals receiving 2000 mg/kg/day. These changes were considered to represent evidence of a response to treatment at these dose levels.
Minor testicular changes were noted in a few high-dose male rats, but these changes were considered to be of equivocal toxicological significance. 
The NOAEL in this study was 80 mg/kg/day. The LOAEL of 400 mg/kg/day was based on the kidney effect in males. As observed by the SCCS, there were several non-treatment related deaths in various dose groups indicating possible poor husbandry. In addition, no information was given on the purity of the substance and therefore, this study is of limited value and not reliable. 
   Subchronic: 13-Week Dietary (rat)
2-Phenoxyethanol was administered via the diet to SPF-bred Wistar rats (Hsd Cpb: WU, 10/sex/dose) in doses of 0, 500, 2500 and 10000 ppm for a period of 13 weeks (MRID 50321647). Based on the average test compound consumption the dose levels were determined to be 34, 169 and 697 mg/kg/day in males and 50.2, 233.8 and 938.8 mg/kg/day in females.
In addition, groups of 10 rats per sex were treated with 0 and 10000 ppm followed by a 4-week recovery period. Satellite groups of 5 rats per sex were treated for 13-14 weeks with the same doses of the main groups. Additional satellite recovery groups were treated with 0 and 10000 ppm over 13 weeks followed by a 4 to nearly 5-week recovery period. Animals of all satellite groups were subjected to whole-body- perfusion during necropsy for possible neuropathological investigations.

A statistically significant reduction in the mean corpuscular hemoglobin concentration (MCHC) was observed in males at 10000 ppm and at all doses in females of the main group at week 13. These changes were marginal (<3% relative to controls) and not dose-related and were therefore, not considered treatment-related. No difference in MCHC was observed in animals in the recovery groups. No changes were observed in any of the other red blood cell parameters in either males or females. Slight increases were observed in mean corpuscular volume (MCV) but were not considered treatment related. 

No indication of treatment related effects were seen in the follow parameters: general behavior; mortality; ophthalmological investigations, food intake; water consumption; body weights; clinical chemistry; urinalysis; and gross and histopathological investigations. In addition, functional observational battery data, motor activity, reflex testing, and grip strength measurements revealed no signs of neurotoxicity. 
Based on the results of this study the NOAEL was 10000 ppm 2-phenoxyethanol (697 mg/kg/day male and 939 mg/kg/day female), the highest dose tested.

   Chronic: Drinking Water (rat)
Two chronic drinking water studies (104 weeks) were conducted with 2-phenoxyethanol in rats and mice (MRID 50321625 and 50321636). One study, conducted with F344/DuCrlCrlj rats (50/sex/dose), exposed animals to nominal concentrations of 0, 2500, 5000, and 10000 ppm. Analytical concentrations in drinking water were determined based on chemical intake data. The mean intake of test substance across the duration of the study was estimated to be 124, 249, and 510 mg/kg/day in males and 191, 380, and 795 mg/kg/day in females.
Mortality and clinical signs were investigated. Food intake, water intake and body weight were determined weekly during the first 13 weeks followed by measurements once every 4 weeks until study termination. After 104 weeks urinalysis, hematology, blood chemistry, gross pathology at necropsy, organ weights and histopathology (both non-neoplastic and neoplastic lesions) were examined. 
There was no significant difference in survival rate between any of the treated or control groups. Soiled fur around genitalia was observed in males given 10000 mg/L and in all treated female groups. Growth rates of 10000 mg/L treated males and all treated female groups were suppressed. Terminal body weights of animals given 2500, 5000 and 10000 mg/L were 98%, 98% and 94% for males, and 95%, 96% and 89% for females, respectively. Food consumption was decreased in 10000 mg/L treated males and in all treated female groups during the study period. Water consumption was decreased in males in the 5000 and 10000 mg/L dose groups and in all treated female groups during the early half of the study period.
Slight changes in MCV and MCHC were noted in females given 10000 mg/L. While plasma levels of AST and ALT were increased in males in the 10000 mg/L dose group, no corresponding histopathological changes in the liver were found. Total protein and creatinine were slightly decreased in males administered 10000 mg/L. Blood urea nitrogen was slightly increased, and total bilirubin and triglyceride were slightly decreased in females given 10000 mg/L. Lowered urinary pH, decreases in urinary protein, and the incidence of positive ketone body in urine were noted in the 10000 mg/L females; the lowered urinary pH might be caused by the acidic PhAA metabolite. 
The kidney was the target organ in this study. The increased kidney weight and the increased incidences of urothelial hyperplasia of the pelvis, and papillary mineralization and necrosis were noted in the 10000 mg/L males, while the increased kidney weight was observed in the females treated with 10000 mg/L.
Based on these results the systemic toxicity NOAEL in rats was determined to be 5000 mg/L or 249 mg/kg/day males and 380 mg/kg/day in females based on kidney effects at the LOAEL of 10000 mg/L (510 mg/kg/day and 795 mg/kg/day for males and females, respectively). There was no evidence of carcinogenicity in male and female rats. 
   Chronic: Drinking Water (mouse) 
In the chronic drinking water study in mice (MRIDs 50321626 and 50321636), groups of 50 B6D2F1/Crlj were dosed with 0, 5000, 10000 or 20000 mg/L. Based on chemical intake data the mean intake of test substance across the duration of the study was estimated to be 468, 898, and 1701 mg/kg/day for males and 586, 1072, and 2058 mg/kg/day for females. The study design was similar to the rat study with the only difference being the dosing. 
There was no significant difference in survival rate between any treated or control groups. No clinical signs were observed in any treated group. Growth rates of the males and females administered >=10000 mg/L were suppressed in a dose-related manner. Terminal body weights of the animals receiving 10000 and 20000 mg/L were 84% and 73% for males, and 92% and 79% for females, respectively. Food consumption was decreased in both males and females administered >=10000 mg/L. A dose-dependent decrease in water consumption was noted in all treated groups of both sexes.
Hematological (i.e., MCV and MCHC) and biochemical parameters were slightly changed in the 2-phenoxyethanol treated male and females, but these changes were considered not to be clearly related to the test material. Lowered urinary pH was observed in both the males and females administered >=10000 mg/L 2-phenoxyethanol; the lowered urinary pH might be caused by the acidic PhAA metabolite.
No treatment-related histopathological findings were observed in any of the tissues evaluated in either males or females. Changes in clinical chemistry parameters included decreases in cholesterol and phospholipids at >= 10000 mg/L and a decrease in triglycerides at 20000 mg/L in males; however, there was no evidence of any histopathology in the liver. 
No statistically significant changes of organ weights or biochemistry parameters were observed at the low dose (5000 mg/L). Statistically significant increases in relative organ weights at 10000 mg/L in males were observed in testes (+31%), lungs (+25%), kidneys (+16%) and brain (+16%) compared with controls. Comparable or higher increases at 20000 mg/L indicate that these increases were dose-dependent. These changes are likely to be related to the decrease in body weight observed in both sexes in this study. No increase in absolute organ weights was observed for adrenal or testis. Absolute organ weights were statistically significantly decreased in the heart and brain in males. Kidney weights were statistically significantly increased in males at >= 10000 mg/L but decreased in females at 20000 mg/L.  
No treatment related neoplastic or non-neoplastic lesions were found in either sex. 
The NOAEL for this study was 5000 mg/L, corresponding to an intake of 468 mg/kg/day in males and 586 mg/kg/day in females. The LOAEL of 10000 mg/L (i.e., 898 mg/kg/day in males and 1072 mg/kg/day in females) was based on decreased body weight and subsequent changes in relative organ weights. 
 Dermal
           
 Subchronic: 13-week Dermal (rabbit)
Groups of New Zealand White rabbits (10/sex/dose) received daily dermal applications of 50, 150, or 500 mg/kg/day of undiluted 2-phenoxyethanol. (MRIDs 50321636 and 50321642) The test material was applied 5 days/week, 6 hours/day for 13 weeks excluding holidays. All animals survived the 13-week treatment period with no signs of systemic toxicity. 
Results of dermal irritation scores revealed sporadic observations of erythema and very slight scaling in male and female rabbits of the 500 mg/kg/day dose group. These effects were not associated with gross or histopathologic changes and were not considered toxicologically significant. There were no treatment-related effects observed in body weights, organ weights, hematologic and clinical chemistry determinations, or gross and histopathologic examinations. 
A statistically significant decrease in AST activity in the 150 mg/kg/day dose group of female rabbits was observed after 4 weeks of treatment, and ALT activity was increased prior to necropsy in male rabbits dosed with 50 mg/kg/day. There was no dose-response relationship for these differences, and similar changes were not identified at any other sampling periods. Therefore, the statistical differences identified in AST and ALT were not considered treatment related.
No toxicologically significant changes were observed in terminal body weights or absolute and relative organ weights. A statistical decrease in absolute liver weight was identified in female rabbits administered 50 mg/kg/day but there was no dose-response relationship. Therefore, the statistically identified difference in liver weight was not considered to be treatment related.
Based on the lack of effect seen, the NOAEL for this study was 500 mg/kg/day, the highest dose tested.
 Inhalation
                                                                               
 Sub-Acute: 2-Week Inhalation (rat)
                                                                               
An inhalation study (MRIDs 50321613 and MRID 50321636) was performed to characterize the toxicity of 2-phenoxyethanol to Wistar Crl:WI(Han) rats (5/sex/dose) after 2 weeks exposure (6 hours/day, 5 days/week) to liquid 2-phenoxyethanol aerosols. Rats were exposed to target concentrations of 0, 40, 200, or 1000 mg/m[3]. Measured concentrations were 48.2, 246, or 1070 mg/m[3], respectively. 
At termination of the study, clinical pathological examinations of the blood, gross necropsy, measurement of selected organ weights (i.e., liver, kidney, adrenals, testes, thymus, spleen, and lung) and histopathological examinations of selected organs were carried out. No deaths occurred. Clinical pathological examinations revealed no treatment-related changes in either males or females. 
Animals dosed with 246 mg/m[3] or 1070 mg/m[3] showed respiratory tract effects: degeneration/squamous metaplasia of respiratory epithelium in the nasal cavity, hyperplasia of the respiratory epithelium in the nasal cavity of all males and females, inflammatory cell infiltrates in the nasal cavity, and statistically significant increased absolute lung weights in males. Morphological changes indicating irritation potential of the test compound were found in nasal cavity, larynx and lung of male and female mid- and high concentration animals.
Animals exposed to 1070 mg/m[3] also showed statically significant decreased body weight change in females (- 48.2 %) on Day 7 but did not show a statically significant change on Day 13. Statically significant decreased food consumption in males (- 5.8 %) and females (-10.6 %) was seen in animals exposed to 1070 mg/m[3] on Day7 but not Day 13. 

Respiratory tract affects were seen in animals treated with >=246 mg/m[3]. Therefore, the No Observed Adverse Effect Concentration (NOAEC) for male and female rats, after 2-weeks exposure to liquid aerosols, was determined to be 48.2 mg/m[3]. 
Aerosol concentrations were converted to an animal equivalent dose in mg/kg/day using the EPA's 2018 RDDR HEC Spreadsheet for inhalation calculation conversion. When assuming a 6-hour period of inhalation the following equivalent values were determined:
      48.2 mg/m[3] = 12.72 mg/kg/day
      246 mg/m[3] = 64.94 mg/kg/day
       1070 mg/m[3] = 282.48 mg/kg/day
 Reproductive and Developmental Toxicity
 Oral
 Two Generation Dietary Toxicity Study (mouse)
A two-generation feeding study (MRID 50321632) to determine the reproductive and fertility effects of 2-phenoxyethanol using was performed by the National Toxicology Program (NTP) and reported in Fundamental and Applied Toxicology by Heindel et al., (MRID 50321623). This multi-generation reproduction study was conducted according to the Reproductive Assessment by Continuous Breeding (RACB) Protocol. CD-l mice (40/sex/dose) were given 0.25, 1.25, and 2.5 % 2-phenoxyethanol in the diet, approximately equivalent to 0, 400, 2000 or 4000 mg/kg/day. 
Mice were administered the test substance in feed for 7 days prior to mating, and throughout the remainder of the study. Pairs of mice were then housed together for 98 days. For the following 21 days, the mice were separated and housed individually; the mice of the litters prior to this 21-day period were sacrificed; eight to ten of the litters (depending on survival to weaning) were further randomly selected for rearing and breeding.
Exposure to 2-phenoxyethanol had no effect on the number of mouse pairs that produced at least one litter and no effect on the number of male pups per total number of pups born alive. There were no effects seen in the lowest dose group and the only effect observed at the mid-dose level was a lower pup body weight. Mice in the high-dose group produced fewer litters per pair, had smaller litters, and produced fewer live pups per litter. The decrease in weight of live pups in this dose group indicated that the effect was dose-dependent. 
By Day 21 there were only 8 out of 40 litters in the mid- and high dose groups which had at least one male and female/litter indicating neonatal toxicity. Second generation reproductive performance of the mid-dose group (1.25%) was unaffected except for a small decrease in live pup weight.
Because of 2-phenoxyethanol effects on reproductive performance the study authors decided to conduct a crossover mating trial with the control and high dose F0 mice. This crossover mating trial, with a seven-day mating period, was performed to determine which sex was affected by the administration of 2-phenoxyethanol. This phase of the study was a continuation of the previous phase, using control males and females, control females and high-dose males, and control males and high dose females as the 20 mating pairs. The crossover mating trial demonstrated no effects on mating or fertility; however, pup body weights of females given 2.5% of the test substance were lower than the controls. 
Mice involved in the crossover mating test were necropsied 3 weeks after their 7-day mating period. No significant differences were found in the sperm viability and in brain, pituitary, left testis/epididymis, right testis, and prostate weights. Body and seminal vesicle weights were significantly lower and liver weights were significantly increased in the high-dose males compared with control males. The differences in seminal vesicle weights were not significant when adjusted for body weights and then compared with the seminal vesicle weight for the combined controls. The only significant difference noted in the female mice in the crossover trial was an increased liver weight in the high-dose females.
As stated in the NTP study:
      Under the conditions of this reproductive toxicity study EGMPE* (2.5% in the diet) was a reproductive toxicant in breeding pairs of F0 mice as evidenced by a reduced number of litters per pair, a decreased average litter size, and a lower proportion of pups born alive versus control and 0.25% and 1.25% EGMPE-exposed F0 breeding pairs. In addition, there was a significant (p<0.01) dose-related decrease in live pup weight during the 18-week dietary exposure of F0 pairs to EGMPE. A crossover mating trial with the control and high dose F0 pairs revealed that EGMPE (2.5% in the diet) exerted a selective fetotoxic effect in the F0 females as indicated by decreased live pup weights. Continuous exposure of the Fl generation mice to EGMPE resulted in a dose-related decrease in body weight from birth to 74 +- 10 days of age and was lethal to 39% of a sample of mice (33/84) in the 1.25% EGMPE group and 87% of a sample of mice (66/76) in the 2.5% EGMPE group. Live pup weights at birth also were diminished in a dose-dependent manner for offspring (F2 generation) produced by F1 breeding pairs. The effects on the F1 generation and its offspring demonstrated the clear-cut toxicity of EGMPE in newborn and young growing mice. Further, seminal vesicle weights tended to be selectively decreased in F0 and F1 males fed 2.5% and 1.25% EGMPE in the diet, respectively. Pituitary weights adjusted for body weight were increased significantly (p<0.01) in F1 males continuously exposed to dietary levels of 1.25% EGMPE. Finally, EGMPE had generalized toxic effects in the F0 and F1 mice as indicated by significantly decreased body weights and increased liver weights. It should be emphasized, however, that reproductive effects were not observed in the F0 pairs fed 0.25 or 1.25% EGMPE in the diet and that body weight gain was not adversely affected in these two dose groups. Thus, it is possible that some or all of the adverse effects on reproductive performance may have been secondary to the generalized toxicity of EGMPE.
      *EGMPE=ethylene glycol monophenyl ether

According to the SIDS Initial Assessment Profile (MRID 50321633), "EGPhE* was associated with decreased body weight (in males at 4000 mg/kg/day and in both males and females at 2000 mg/kg/day) and increased liver weight (males and females at both 2000 and 4000 mg/kg/day). Decreased absolute weight of seminal vesicles was noted in males treated with 2,000 mg/kg bw/day, but not 4,000 mg/kg bw/day." *Ethylene glycol pheny ether (EGPhE)

In summary, fertility was decreased at the high dose group (4000 mg/kg/day) in the presence of parental toxicity. There was evidence of toxicity in infants and young seen in mid- and high-dose groups.
Maternal NOAEL = 400 mg/kg/day  
Maternal LOAEL = 2000 mg/kg/day based on decreased body weight and increased liver weight
Developmental/Offspring NOAEL = 400 mg/kg/day
Developmental/Offspring LOAEL = 2000 mg/kg/day based on decreased live pup weights
Reproductive NOAEL = 2000 mg/kg/day 
Reproductive LOAEL = 4000 mg/kg/day as evidenced by a reduced number of litters per pair, a decreased average litter size, and a lower proportion of pups born alive
    Developmental Gavage Toxicity Study (rat) 
The SCCS review (MRID 50321636) of 2-phenoxyethanol outlines an unpublished prenatal developmental toxicity study in rats. Wistar rats were gavaged at levels of 0, 100, 300 and 1000 mg/kg/day on days 6-19 of gestation. One animal in the high-dose group was prematurely sacrificed in a moribund state. Clinical signs of maternal toxicity were observed at 1000 mg/kg/day. One dam at this dose was sacrificed in treatment related moribund condition on day 14 p.c. All dams showed unsteady gait and transient salivation for a time of up to 3.5 hours after dosing at least once during the treatment period. A few times, high-dose rats were found in lateral position shortly after treatment, had vaginal hemorrhage and/or urine smeared fur. At this dose level, food consumption as well as gross and net body weight gain were affected by treatment. There were no clinical signs of test substance-related maternal toxicity in the mid- or low-dose dams. 

No treatment-related changes were noted in hematology or serum enzymes. Clinical chemistry for animals receiving 1000 mg/kg/say, showed statistically significant differences in the following parameters: decreased concentrations in total bilirubin (-31%), total protein (-7%), albumin (-6%) and globulin (-8%) as well as increased triglyceride values (+50%). Somewhat lower but also statistically significant changes were noted in the mid-dose animals (300 mg/kg/day): total bilirubin (-21%), total protein (-2%), albumin (-4%) as well as increased triglyceride values (+40%). The total protein (sum parameter including globulin) results were slightly below the lower limit of historical controls. Whereas liver enzymes in serum were not influenced, it is believed that all of these findings were related to adaptational metabolic changes of liver functions rather than to particular organ toxicity. Although these effects were likely to be caused by the test material, they were not considered as adverse per se.  

There were no toxicological relevant differences between the control and the test groups in conception rate, mean number of corpora lutea, total implantations, resorptions and live fetuses, fetal sex ratio, or in calculated pre- and post-implantation losses. No test substance-related differences were recorded for placental and fetal body weights. In addition, the external and soft tissue and/or skeletal examinations of the fetuses revealed no toxicologically relevant effects.  

Based on the effects (i.e., unsteady gait, transient salivation, lateral positioning, vaginal hemorrhage and/or urine smeared fur, as well as effects on food consumption and body weight gain) in the dams at the LOAEL of 1000 mg/kg/day, the NOAEL for maternal toxicity was 300 mg/kg/day. 2-Phenoxyethanol had no effect on gestational parameters and induced no signs of developmental toxicity up to and including the high dose of 1000 mg/kg/day. Therefore, the NOAEL for developmental toxicity was 1000 mg/kg/day, the highest dose tested.
	
 Dermal 
           
   Developmental Toxicity Study (rabbit) 

2-Phenoxyethanol was applied to the clipped skin of pregnant rabbits (25/dose) on days 6 through 18 of gestation in order to assess the fetotoxic and teratogenic potential of dermally applied 2-phenoxyethanol (MRID 50321642). Groups of breed rabbits were treated with 0, 300, 600 or 1000 mg/kg/day and the 28-day fetuses were examined for external, soft tissue and skeletal alterations. Dermal application of 1000 mg/kg/day produced maternal toxicity as evidenced by intravascular hemolysis of red blood cells and death. Because of the morbidity and mortality seen at 1000 mg/kg/day, the remaining animals in that dose group were terminated.  

Maternal toxicity was observed in rabbits treated with 600 mg/kg/day, but at a lower incidence than observed at 1000 mg/kg/day. Rabbits in the two highest dose groups which survived until day 28 of gestation showed no evidence of treatment-related effects. No signs of maternal toxicity were seen at 300 mg/kg/day. 
Throughout the dosing period, slight to moderate reddening of the skin at the application site was seen in some animals at all treatment levels. Four rabbits in the 600 mg/kg/day dose group and three rabbits at 1000 mg/kg /day were observed to have darkened areas of skin at the application site. Several animals in the middle and high dose groups were observed to exhibit blood in the perineal region and/or the pan underneath the cage.
During the course of the study, five rabbits in the 600 mg/kg/day dose group and nine rabbits in the 1000 mg/kg/day dose group died or were sacrificed in extremis.  Most deaths occurred between gestation days 11 and 18. The pathologic finding in most of these animals was the presence of dark-colored urine in the bladder. In addition to the dark urine, the animals were jaundiced, and the kidneys were also darkened in color. The gross necropsy observation of dark urine was interpreted to be due to hemoglobinuria. Intravascular hemolysis was diagnosed in moribund animals based on changes in hematology including severely depressed RBC counts and PCV values as well as elevated reticulocytes and increased red blood cell fragility. In general, the rabbits showed evidence of anorexia as indicated by the presence of a hairball in the stomach. Also associated with the anorexia were superficial erosions, ulcers, and/or hemorrhages in the gastric mucosa with a decrease in feed and fecal material in the intestines. 
In general, no treatment-related effects were observed in either absolute body weights or body weight gains at 300 or 600 mg/kg/day.  No differences in absolute and relative liver weights were seen between control and treated rabbits.
No adverse effects on implantations resorbed, pre- implantation loss, sex ratio or fetal body measurements were observed among rabbits dosed with 300 or 600 mg/kg/day. No significant differences in the incidences of either malformations or alterations were observed in the treated groups as compared to controls. In the control group, one case of microphthalmia and one of annoychia occurred. 
A total of five rabbits at 1000 mg/kg/day completed the dosing regimen and were sacrificed on day 28 of gestation. Due to the excessive lethality seen at this dose, the remaining animals in that dose group were terminated with no further observations. Fetuses from these animals which survived to day 28 did not exhibit external, visceral or skeletal alterations. No statistical evaluations were performed on these data, but there was no evidence of adverse effects in the five rabbits or their fetus. 
Maternal toxicity, including dose-related intravascular hemolysis and death, was observed in dams dosed with 600 and 1000 mg/kg/day. The NOAEL for maternal toxicity was 300 mg/kg/day. Dermal application of 2-phenoxyethanol produced no evidence of teratogenicity, fetotoxicity or embryotoxicity under the conditions of this study. The NOAEL for developmental toxicity was concluded to be 600 mg/kg/day because of maternal deaths at 1000 mg/kg/day precluded a full evaluation of developmental toxicity in the highest dose group. 
 Carcinogenicity
The carcinogenicity of 2-phenoxyethanol was examined in two chronic drinking water studies (MRIDs 50321636, 50321625, and 50321626) in F344/DuCrlCrlj rats and B6D2F1/Crlj mice. Details of these studies are provided in sections 5.2.1.8 and 5.2.1.9 above. No significant increase in the incidence of neoplastic lesions was found in any group of either sex as compared with the respective control. Overall, there was no evidence of carcinogenic activity in male or female rats and mice.
 Genotoxicity and Mutagenicity
        
 Bacterial Reverse Mutation Test (Copied from CIR, 1990)
                                                                               
2-Phenoxyethanol was evaluated for mutagenicity (Ames test) at concentrations of 50, 150, 500, 1500, and 5000 ug/plate in Salmonella typhimurium strains TA 1535, TA 1537, TA 1538, TA 98, and TA100. No significant increases in the numbers of revertants were found in any of the test strains at any concentrations, with or without metabolic activation.
 Bacterial gene mutation test 
2-Phenoxyethanol was evaluated for its potential to induce gene mutations at concentrations of 0, 20, 100, 500, 2500, and 5000 ug/plate in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and E. coli WP2 uvr A with and without S9 mix activation (MRID 50321636). No biologically relevant increase in revertant colony numbers of any of the five tester strains was observed following treatment with 2-phenoxyethanol at any concentration level, either in the presence or in the absence of metabolic activation (S9-mix). Under the experimental conditions used, 2-phenoxyethanol was considered not genotoxic (mutagenic) in bacteria. 
 Mammalian cell gene mutation assay 

2-Phenoxyethanol was evaluated in an in vitro gene mutation test utilizing cultured mammalian Chinese hamster ovary cells and hypoxanthine-guanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay. (MRID 50321644) Concentrations of 2500, 3000, 3250, 3375 and 3500 micrograms/ml (ug/mL) in the absence of metabolic S9 activation and 2000, 2500, 3000, 3250 and 3500 ug/ml in the presence of S9 were administered. Cultures were also treated with 621 ug/ml ethyl methanesulfonate (EMS) and 4.03 ug/ml 20- methylcholanthrene (20-MCA) to serve as positive controls for non-activation and activation assays, respectively. There were no significant increases in mutation frequencies in cultures treated with 2-phenoxyethanol in either the absence or presence of S9. Therefore, 2-phenoxyethanol was considered negative for genotoxicity.

 In vivo chromosomal aberration assay 

2-Phenoxyethanol was evaluated in a rat bone marrow chromosomal aberration assay. (MRID 50321645) The test chemical was administered to Sprague-Dawley rats in a single oral gavage dose of the test chemical in mixed with corn oil, of 280, 933 and 2800 mg/kg.  Groups of animals (5/sex/dose) were sacrificed at 6, 24 and 48 hours after treatment. Fifty metaphases were examined from each surviving animal in the negative control, positive control and the two high dose groups of the test chemical (933 and 2800 mg/kg) for the presence of various cytogenetic anomalies. There were no significant increases in the incidence of cytogenetic anomalies in groups treated with the test material as compared to the controls. Positive control rats showed significant increases in cytogenetic anomalies. Therefore, under the experimental conditions of this study, 2-phenoxyethanol was not cytotoxic.

 Micronucleus test
Although the full study report is not available, according to the 1990 CIR review, 
      Phenoxyethanol was tested for mutagenicity in a micronucleus test using Swiss CD-1 mice. The mice were administered two equal doses of 2-phenoxyethanol in a methylcellulose vehicle at 24-h intervals for total doses of 300, 600, or 1200 mg/kg. The methylcellulose vehicle was used as a negative control and mitomycin C was used as a positive control. The mice were observed for either 24 or 48 hours, after which time, five mice of each sex from each dosage group were sacrificed and bone marrow cells were removed. The cells were examined for the number of micronucleated cells per 1000 polychromatic erythrocytes per mouse and for the ratio of normochromatic to polychromatic erythrocytes. The numbers of micronucleated cells and the ratio of normochromatic to polychromatic cells were comparable for both the 2-phenoxyethanol-treated mice and the control mice. 2-phenoxyethanol was nonmutagenic under the conditions of the study.
 Neurotoxicity

No neurotoxicity studies are available for 2-phenoxyethanol; however, evidence from short- and long-term studies showed no indication that 2-phenoxyethanol is neurotoxic. In the subchronic 13-week rat study (MRID 50321647) there were no indications of treatment-related effects in the functional observational battery data, motor activity, reflex testing and grip strength measurements as well as neuropathological investigations at the highest dose tested: 697 mg/kg/day in males and 938 mg/kg/day in females. 
To further evaluate the neurotoxic potential of 2-phenoxyethanol, quantitative structure activity relationships (QSAR) using Derek Nexus (v. 5.0.2) was performed and submitted by the petitioner. There were no alerts for neurotoxicity or cholinesterase activity.
 Immunotoxicity
No specific immunotoxicity studies have been carried out with 2-phenoxyethanol. 2-phenoxyethanol was shown to cause acute-onset red blood cell (RBC) hemolysis typically at high doses with regenerative anemia. Significant effects were not observed in the long-term rodent studies potentially due to adaptation mechanism over time.
An in vitro study showed that rabbits are highly sensitive for hemolysis when compared to other species. According to Starek (MRID 50321639), "The mechanism is at least partially due to the rate of the oxidative metabolism to PhAA, a detoxification mechanism that limits hemolysis at high doses; the highest PhAA metabolite formation was shown in liver S9 homogenates from humans, followed by rat, mouse and rabbit ...". Human RBCs were 1.9 - 3.1 times more resistant to the hemolytic activity of AAAs [alkoxyacetic acids] than rat erythrocytes.  
Based on these parameters, the Agency does not feel that 2-phenoxyethanol would cause immunotoxicity in humans. 
 Toxicology Summary Profile
         Table 2:  Repeat Dose Toxicology Profile for 2-Phenoxyethanol
                                  Study Type
                                     Doses
                                    Results
                                     Oral
10-Day Gavage Toxicity (rabbit)
0, 100, 300, 600, or 1000 mg/kg/day
NOAEL = none determined
LOAEL = 100 mg/kg/day based on hemolytic effects
14-Day Drinking Water Toxicity (rat)

0, 1600, 4000, 7000, 17500, or 25000 mg/L/day
NOAEL = 7000 mg/L (357 and 546 mg/kg/day for male and females, respectively)
LOAEL= 10000 mg/L (510 and 795 mg/kg/day for male and females, respectively) based on hemolytic effects (increase in MCV and MCH)
14-Day Drinking Water Toxicity (mice)

0, 1600, 4000, 7000, or 25000 mg/L/day
NOAEL = 10000 mg/L (898 and 1072 mg/kg/day for male and females, respectively)
LOAEL= 25000 mg/L (2340 and 2930 mg/kg/day for male and females, respectively) based on kidney effect
90-Day Drinking Water Toxicity (rat)

0, 1250, 2500, 5000, 10000 or 20000 mg/L.
NOAEL = 5000 mg/L (369 mg/kg/day in males and 652 mg/kg/day in females)
LOAEL = 10000 mg/L (687 mg/kg/day in males and 1000 mg/kg/day in females) based on hematotoxicity and histopathological changes in the kidney and bladder
90-Day Drinking Water Toxicity (mice)

0, 1250, 2500, 5000, 10000 or 20000 mg/L.
NOAEL = 2500 mg/L (390 mg/kg/day in males and 478 mg/kg/day in females)
LOAEL = 5000 mg/L (765 mg/kg/day in males and 948 mg/kg/day in females) based on liver effects
90-Day Feeding Toxicity(rat)
0, 500, 2500 or 10000 ppm
NOAEL = 10000 ppm (697 mg/kg/day in males and 938 mg/kg/day in females (highest dose tested)
Chronic Toxicity/Carcinogenicity-Drinking Water (rat)

0, 2500, 5000, or 10000 mg/L
NOAEL = 5000 mg/L (249 mg/kg/day in males and 380 mg/kg/day in females)
LOAEL = 10000 mg/L (510 mg/kg/day in males and 795 mg/kg/day in females) based on increased kidney weight and the increased incidences of urothelial hyperplasia of the pelvis, and papillary mineralization and necrosis

No evidence of carcinogenicity was seen.

Chronic Toxicity/Carcinogenicity-Drinking Water (mice)

0, 5000, 10000 or 25000 mg/L
NOAEL = 5000 mg/L (468 mg/kg/day in males and 586 mg/kg/day in females)
LOAEL = 10000 mg/L (898 mg/kg/day in males and 1072 mg/kg/day in females) based on effects on body weight gain.  

No evidence of carcinogenicity was seen.

                                    Dermal
90-Day Dermal Toxicity Study (rabbit)

0, 50, 150, or 500 mg/kg/day
(5 days/week)
NOAEL = 500 mg/kg/day (highest dose tested)
                                  Inhalation
14-Day Inhalation Toxicity-rat

0, 48.2, 246, or 1070 mg/m[3]
(5 days/week)
NOAEC = 48.2 mg/m[3] (~12.7 mg/kg/day)
LOAEC = 246 mg/m[3] (~65 mg/kg/day) based on respiratory tract effects (degeneration/squamous metaplasia of respiratory epithelium in the nasal cavity, hyperplasia of the respiratory epithelium in the nasal cavity of all males and females, inflammatory cell infiltrates in the nasal cavity, and statistically significant increased absolute lung weights in males)

                          Reproductive/Developmental
Reproductive Toxicity- Feeding 2-Generation (mice)


0, 0.25, 1.25, and 2.5 % in the diet, approximately equivalent to 0, 400, 2000 or 4000 mg/kg/day 
Maternal NOAEL = 400 mg/kg/day  
Maternal LOAEL = 2000 mg/kg/day based on decreased body weight and increased liver weight
Developmental/Offspring NOAEL = 400 mg/kg/day
Developmental/Offspring LOAEL = 2000 mg/kg/day based on decreased live pup weights
Reproductive NOAEL = 2000 mg/kg/day 
Reproductive LOAEL = 4000 mg/kg/day as evidenced by a reduced number of litters per pair, a decreased average litter size, and a lower proportion of pups born alive

Developmental Toxicity-Gavage (rat)

0, 100, 300 and 1000 mg/kg/day on days 6-19 of gestation
Maternal NOAEL = 300 mg/kg/day
Maternal LOAEL = 1000 mg/kg/day based on unsteady gait, transient salivation, lateral positioning, vaginal hemorrhage and/or urine smeared fur, as well as effects on food consumption and body weight gain. 
Developmental/Offspring NOAEL = 1000 mg/kg/day (highest dose tested)
Developmental/Offspring LOAEL = not determined, no effects on development

Developmental Toxicity-Dermal (rabbit)

0, 300, 600 or 1000 mg/kg/day
Maternal NOAEL = 300 mg/kg/day 
Maternal LOAEL = 600 mg/kg/day based on hemolysis and death.  
Developmental/Offspring NOAEL = 600 mg/kg/day 
Developmental/Offspring LOAEL 1000 mg/kg/day; no evidence of fetal toxicity was observed; however, maternal deaths at 1000 mg/kg/day precluded a full evaluation of developmental toxicity in the highest dose group, therefore the conservative NOAEL is 600 mg/kg/day



 TOXICITY ENDPOINT SELECTION

Several oral studies have been conducted on 2-phenoxyethanol in rabbits, rats, and mice. Dermal studies in rabbits have also been carried out as well as one inhalation study in rats. Result indicate that rabbit is the most sensitive species due mainly to its susceptibility to hemotoxic effects. Target organs in rats and mice were the kidney and liver, most likely due to an extensive first-pass metabolism and formation of high amounts/concentrations of 2-phenoxyacetic acid in the systemic circulation. Hematotoxicity in rats and mice was less pronounced than in rabbits and was not seen to be an adverse effect in long-term studies, potentially due to adaptation over time. Data suggest that mice are somewhat more resistant to the toxic effects of 2-phenoxyethanol and its main metabolite 2-phenoxyacetic acid than rats. 
Due to the complexity of the data set including varying effects across species and exposure scenarios, physiologically-based pharmacokinetic (PBPK) modeling was employed by Troutman et al. (MRID 50321650) to facilitate a more direct comparison of the internal dose associated with the toxicology findings across the data set and to facilitate the interspecies extrapolation in the human health risk assessment. The PBPK model incorporated key kinetic processes describing the absorption, distribution, metabolism and excretion of 2-phenoxyethanol and the major metabolite PhAA following oral and dermal exposures from multiple species, including human data.  
In the article, a dose response analysis was conducted using U.S. EPA Benchmark Dose (BMD) Software ver. 2.2. BMD modeling resulting in an identified BMD10 of 487 mg/ kg/day and BMDL of 369 mg/kg/day with a interspecies uncertainty factor (UF) of 2.5X. The Agency is not currently using PBPK modeling to evaluate exposure to pesticide chemicals, however, the Agency does agree that dose selections were different in the chronic and sub-chronic studies and that these dose selections influenced the NOAELs identified in these studies. 

With the exception of the 10-day rabbit study and a 90-day gavage study in rats (determined to not be reliable), no adverse effects were seen at doses less than 510 mg/kg/day. The LOAEL in the 10-day rabbit study was 100 mg/kg/day based on hemolytic effects seen at all doses. Hematotoxicity in rabbits is believed to be caused by the parent compound when systemically available but not by the main metabolite 2-phenoxy acetic acid, which may be responsible for toxicity to the kidney. According to various studies/sources, humans are more resistant to lysis than rabbits, mice and rats. Given the much higher capacity of humans to metabolize 2-phenoxyethanol compared with rabbits (the most sensitive species), this study was considered less relevant to human exposure than rat and mice studies. In addition, it was only 10 days in duration. Subsequently, it was not selected as the POD for oral exposure. 

The most appropriate conservative NOAEL from the data set (i.e., 249 mg/kg/day) is from the chronic rat drinking water study with a corresponding LOAEL of 510 mg/kg/day based on kidney effects. Taking the database into consideration, the Agency feels that the NOAEL of 369 mg/kg/day from the subchronic drinking water study in rats, which lies between the LOAEL of 510 mg/kg/day and the NOAEL of 248 mg/kg/day of the chronic study, is a more appropriate point of departure for all durations. The 14-day drinking water study in rats shows a slightly lower NOAEL of 357 mg/kg/day for males. This value is almost identical to the NOAEL found in the 90-day drinking water study in rats; however, this range finding study was only 14 days in duration and only limited information was provided. Subsequently, it was not chosen as the endpoint. The Agency feels that the 90-day drinking water study in rats is the most appropriate endpoint and it takes into account the large dosing gap in the chronic study. This NOAEL would still be considered protective of all population subgroup. 

The POD for dermal exposure is based on the finding in the 90-day dermal study and the developmental dermal study both done in rabbits. No adversed effects attributed to the test chemical were seen in the 90-day study. The NOAEL was 500 mg/kg/day (highest dose tested). Maternal toxicity was seen in the developmental dermal study at 600 mg/kg/day and therefore, this was treated as the LOAEL for dermal exposure. 

The short-term inhalation POD of 48.2 mg/m3 (~12.7 mg/kg/day) is based on a 14-day inhalation study which showed respiratory effects at 246 mg/m3 (~65 mg/kg/day). The POD used for long-term inhalation exposure is also from the 14-day inhalation study with an additional 10x uncertainty factor for using a subchronic study for a chronic endpoint. 

The Agency used an uncertainty factor of 100 (i.e., 10X for interspecies extrapolation, 10X for intraspecies variability, and 1X FQPA safety factor (SF)). The FQPA SF is reduced to 1X because the reproductive and developmental toxicity database is complete and there is no evidence of increased risk to infants and children in the absence of maternal toxicity. See Section 7 below for more information on the FQPA SF. 
When the 100X uncertainty or safety factor is applied, the chronic reference dose (cPAD) is 3.69 mg/kg/day. EPA determines whether acute and chronic pesticide exposures are safe by comparing exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safety factors (SFs). No acute endpoint was determined therefore, an acute assessment was not done. EPA calculates the cPAD by dividing the Point of Departure (POD) by all applicable UFs. Risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the Margin of Exposures (MOE) called for by the product of all applicable UFs is not exceeded.  

The residential and aggregate level of concern (LOC) is for MOEs that are less than 100 and is based on 10X interspecies extrapolation, 10X for intraspecies variability and 1X FQPA factor.


Table 3: Summary of Toxicological Doses and Endpoints for 2-Phenoxyethanol for Use in Human Risk Assessment
                               Exposure/Scenario
               Point of Departure and Uncertainty/Safety Factors
                                RfD, PAD, LOC 
                        Study and Toxicological Effects
Chronic dietary 
(All populations)
NOAEL= 369 mg/kg/day  
UFA = 10x
UFH = 10x
FQPA SF = 1x
Chronic RfD = 3.69 mg/kg/day

cPAD = 3.69 mg/kg/day
90-Day Drinking Water Toxicity (rat)
LOAEL = 10000 mg/L (687 mg/kg/day in males and 1000 mg/kg/day in females) based on hematotoxicity and histopathological changes in the kidney and bladder.
Incidental oral short-term 
(1 to 30 days)
NOAEL= 369 mg/kg/day  
UFA = 10x
UFH = 10x
FQPA SF = 1x
LOC for MOE =100
90-Day Drinking Water Toxicity (rat)
LOAEL = 10000 mg/L (687 mg/kg/day in males and 1000 mg/kg/day in females) based on hematotoxicity and histopathological changes in the kidney and bladder.
Dermal short-term 
(1 to 30 days)
Dermal study NOAEL = 500 mg/kg/day 
UFA = 10x
UFH = 10x
FQPA SF = 1x
LOC for MOE = 100
NOEAL from 90-Day Dermal Toxicity Study (rabbit) 
LOAEL = 600 mg/kg/day from hemolysis and death seen in the Developmental Toxicity-Dermal (rabbit)

Dermal intermediate-term
(1 to 6 months)
Dermal study NOAEL = 500 mg/kg/day
UFA = 10x
UFH = 10x
FQPA SF = 1x
LOC for MOE = 100
NOEAL from 90-Day Dermal Toxicity Study (rabbit) 
LOAEL = 600 mg/kg/day from hemolysis and death seen in the Developmental Toxicity-Dermal (rabbit)

Inhalation short-term 
(1 to 30 days)
Inhalation study NOAEL = ~12.7 mg/kg/day (inhalation absorption rate = 100%)
UFA = 10x
UFH = 10x
FQPA SF = 1x
LOC for MOE = 100
14-Day Inhalation Toxicity Study (rat) 
LOAEL = ~65 mg/kg/day based on respiratory effects (i.e., degeneration/squamous metaplasia of respiratory epithelium in the nasal cavity, hyperplasia of the respiratory epithelium in the nasal cavity of all males and females, inflammatory cell infiltrates in the nasal cavity, and statistically significant increased absolute lung weights in males)
Inhalation 
(1 to 6 months)
Oral study NOAEL = 12.7 mg/kg/day (inhalation absorption rate = 100%)
UFA = 10x
UFH = 10x
UFS = 10x

FQPA SF = 1x
LOC for MOE = 1000
14-Day Inhalation Toxicity Study (rat) 
LOAEL = ~65 mg/kg/day based on respiratory effects (i.e., degeneration/squamous metaplasia of respiratory epithelium in the nasal cavity, hyperplasia of the respiratory epithelium in the nasal cavity of all males and females, inflammatory cell infiltrates in the nasal cavity, and statistically significant increased absolute lung weights in males)
Cancer (Oral, dermal, inhalation)
Based on 2 chronic drinking water studies in mice and rats along with negative genotoxicity studies, risk for cancer is not expected to be of concern, therefore a cancer endpoint is not necessary. 

FQPA SF = Food Quality Protection Act Safety Factor. LOAEL = lowest-observed-adverse-effect-level. LOC = level of concern. mg/kg/day (= milligram/kilogram/day). MOE = margin of exposure. NOAEL = no-observed-adverse-effect-level. PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). UFS = use of a short-term study for long-term risk assessment

 SPECIAL CONSIDERATION for INFANTS and CHILDREN

FFDCA Section 408(b)(2)(c) provides that EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines based on reliable data that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA safety factor (SF). In applying this provision, EPA either retains the default value of 10X, or uses a different additional safety factor when reliable data available to EPA support the choice of a different factor. Based on the reasons listed below the Agency has used a FQPA SF of 1X. 

 The database for 2-phenoxyethanol is considered adequate for FQPA assessment. There are several subacute, subchronic, and chronic studies, as well as two oral and one dermal developmental/reproductive toxicity study, and mutagenicity studies.
 Two developmental studies showed no effect on offspring at the limit dose of 1000 mg/kg/day. 
 A reproductive study showed effect on reproductive parameters of fertility at doses of 4000 mg/kg/day. These effects were not seen in animals dosed with 2000 mg/kg/day which is above the limit dose of 1000 mg/kg/day. Although evidence of adverse effects were observed on the offspring (e.g., decreased pup weight), this effect was observed in the presence of maternal toxicity. 
 Although no neurotoxicity studies are available, no clinical signs of neurotoxicity were observed in the available subchronic and chronic studies. Therefore, there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity.
 Immunotoxicity studies were not available. Hemolytic effects were seen in some studies; however, it was determined that the test species was much more susceptible to these effects than humans based on the metabolism of the chemical by each species. It is, therefore, less likely for these blood effects to be seen in humans. These effects were not seen in long-term rodent studies potentially due to adaptation mechanism over time.
   
Taking into consideration all available information including potential exposure, there is no concern, at this time, for increased sensitivity to infants and children to 2-phenoxyethanol when used as inert ingredient in pesticides formulations. Therefore, it is appropriate to reduce the FQPA SF to 1X as this will not underestimate the risk to infants and children. 

 EXPOSURE

2-Phenoxyethanol will be used as a food use inert ingredient, solvent or co-solvent, in pesticide formulations intended for use on crops pre- or post-harvest. 2-Phenoxyethanol is currently approved by the EPA for use as a nonfood inert ingredient in pesticide products. As a nonfood inert ingredient, 2-phenoxyethanol is used various products including residential pet products and cleaning solutions. As a result, dietary and residential exposure from pesticidal use is expected. 
2-Phenoxyethanol is also used in non-pesticidal products. The primary consumer products containing 2-phenoxyethanol were identified as paints and coatings, personal care/cosmetic products, and cleaning products. The current exposure assessment incorporates both pesticidal and non-pesticidal uses. When available, actual values were used for known pesticide products. The maximum concentration of 3% in paint was provided by the submitter and is "based on end-use information collected for REACH and this maximum worst-case concentration was used". The submitter also states, "The maximum allowable concentration in cosmetic products as a preservative is based on the (EC) No. 1223/2009 cosmetic regulation and on the conclusions of CIR and SCCS bodies stating that EPh [2-phenoxyethanol] is safe for cosmetic use as a preservative in cosmetic products at up to 1%."  Subsequently, these values were used as the maximum concentration in this risk assessment for those exposure scenarios. 
The endpoint used for oral exposure was 369 mg/kg/day based on the 90-day drinking water study in rats. The inhalation POD of 48.2 mg/m3 (~12.7 mg/kg/day) was based on a 14-day inhalation study which showed respiratory effects at 246 mg/m3 (~65 mg/kg/day). The dermal endpoint is from the 90-day dermal study in which no effects were seen in rabbits at 500 mg/kg/day. An effect was seen, however, in the dermal developmental study in rabbits at 600 mg/kg/day and this was used to represent the LOAEL for dermal exposure. The effects for each route of exposure are not the same, therefore, only route specific daily doses were combined. 
 Dietary Exposure
A dietary exposure assessment (including drinking water) was conducted using the Dietary Exposure Evaluation Model-DEEM-FCID[TM], Version 3.16, which uses food consumption information from the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, "What we eat in America", (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. A complete description of the general approach taken to assess inert ingredient risks in the absence of residue data is contained in the memorandum entitled "Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the Inerts." (D361707, S. Piper, 2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA-HQ-OPP-2008-0738.

In the absence of actual residue data, the highly conservative inert ingredient dietary exposure model assumes that the residue level of the inert ingredient would be no higher than the highest established tolerance for an active ingredient on a given commodity. In the case of 2-phenoxyethanol, food use applications will be limited to 0.2% by weight in pesticide formulations. This limitation was incorporated into the DEEM model. For drinking water, the default of 100 ppb is assumed. Although sufficient information to quantify actual residue levels in food is not available, the compounding of the conservative assumptions will lead to a significant exaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data. The results of the dietary exposure assessment have been summarized in Table 4. The full DEEM report can be found in Appendix A. 

Table 4. Summary of Chronic Dietary Exposure and Risk of 2-Phenoxyethanol
                              Population Subgroup
                               cPAD (mg/kg/day)
                             Exposure (mg/kg/day)
                                     %cPAD
General U.S. Population
                                       
                                     3.69
                                       
                                   0.000076
                                    0.00002
All Infants (<1 year old)

                                   0.000158
                                    0.00004
Children 1-2 years old

                                   0.000283
                                    0.00007
Children 3-5 years old

                                   0.000194
                                    0.00005
Children 6-12 years old

                                    0.0001
                                    0.00003
Youth 13-19 years old

                                   0.000054
                                    0.00001
Adults 20-49 years old

                                   0.000058
                                    0.00002
Adults 55+ years old

                                   0.000061
                                    0.00002
Females 13-19 years old

                                   0.000054
                                    0.00001

The chronic dietary exposure estimates for 2-phenoxyethanol are below the Agency's level of concern for the general U.S. population and various population subgroups. The highest exposed population subgroup, children 1-2 years old, is 0.00007% of the chronic population adjusted dose (cPAD). The chronic dietary exposure estimate for the general U.S. population is 0.00002 % of the cPAD.

 Residential Exposure

The term "residential exposure" is used in this document to refer to non-occupational, non-dietary exposure. 2-Phenoxyethanol is currently approved as a nonfood use inert ingredient. A review of residential products containing this inert ingredient revealed that it is currently used in antimicrobial cleaning products and in pet spot-on treatment products. 

In addition to the current uses, there is a potential for outdoor uses in pesticides applied to residential lawns and turf as stated by the submitter. In a conservative effort to assess exposure, the EPA has conducted a screening level assessment using high-end exposure scenarios for pesticidal use on lawns/turf, in antimicrobial spray cleaning products, and in pet spot-on application. When available, the Agency used actual data from current products containing the inert ingredient along with default assumptions from EPA's Office of Pesticide Programs (OPP), Health Effect Division (HED) 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, herein referred to as HED's 2012 Residential SOP. With regards to the antimicrobial cleaning products, default assumptions from OPP's Antimicrobial Division were used. 

In addition to the proposed and current uses in pesticide formulations, 2-phenoxyethanol is also used in various non-pesticidal products. The submitter states that a search of US EPA's Chemical and Product Categories (CPCat) database, the NIH Household Products Database, the ECHA REACH database and the Dow Technical Data Sheet were reviewed for relevant consumer applications. According to the submitter:
      Based on this search and review the primary consumer products containing 2-phenoxyethanol were identified as paints and coatings, personal care/cosmetic products, and cleaning products. Of these, the use in latex paints and in consumer cosmetics are by far the most common and the ones likely to result in the highest residential exposure estimates. 

Of the three non-pesticidal uses mentioned above, the risk assessment already incorporates the use of this chemical in antimicrobial cleaning products. Therefore, known non-pesticidal exposure to latex paint and cosmetic products were incorporated into this risk assessment.

 Pesticides
                                                                               
 Lawn and Turf
                  
The Agency conducted an assessment to represent worse-case residential exposure by assessing residential handler/applicator and post-application exposures and risk from 2-phenoxyethanol in pesticide formulations applied to lawn/turf. The three exposure scenarios: Hose-End Sprayer, Manually-Pressurized Handwand, and Backpack Sprayer were selected from Section 3 (Lawn/Turf) of HED's 2012 Residential SOP. Although food use of this inert ingredient will be limited to 0.2% in pesticide formulations, potential nonfood uses may exceed this value as the limitation only applies to the exemption from the requirement of tolerance. Therefore, a 5% concertation (default) in pesticide formulations was used to evaluate this inert ingredient in pesticides applied to lawns/turf. This more conservative value for exposure is expected to be protective of potential uses of this inert ingredient in pesticide products applied to lawns and turf.  

 Handler 
Consumer pesticide handlers are assumed to wear short-pants, short-sleeved shirts and shoes plus socks but no protective gloves. As stated in HED's 2012 Residential SOP, this activity is generally considered to be short-term in duration and therefore, only short-term applicator exposure is assessed. Because there is no specific product label associated with this inert ingredient, the application rate is based on default assumption based on a review of various product labels and supplemental information provided by the submitter. 
In addition to HED's 2012 Residential SOP, further details of the assumptions used in the residential exposure and risk analysis can be found in the memorandum entitled ``JITF Inert Ingredients. Residential and Occupational Exposure Assessment Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations D364751", (5/7/09, Lloyd/LaMay in docket ID number EPA - HQ - OPP - 2008 - 0710) found at http://www.regulations.gov. The Agency believes that the handler scenarios assessed represent worse-case short-term exposures and risks. The results of these model predictions are provided in Table 5.  
   Table 5: Short-term Exposure and Risks for Residential Handlers Applying
                      2-Phenoxyethanol to Lawns and Turf
                 Exposure Scenario (Formulation/ Application)
                              Application Rate1 
                     Quantity Handled/ Treated per day[2]
                     Dermal Unit Exposure[3] (mg/lb inert)
                 Inhalation Unit Exposure[3] (mg/ lb inert)[3]
                         Dermal Dose[4] (mg/kg/day)[2]
                      Inhalation Dose[4] (mg/kg/ day)[2]
                                 Dermal MOE[5]
 Inhalation MOE[5]
Liquids/ Manually-Pressurized Handwand 
                                 0.0105 lb/gal
                                   5 gallons
                                      63
                                     0.018
                                    0.0415
                                   0.000012
                                    12,000
                                   1,058,000
Liquids/ 
Hose End Sprayer

                              0.45 lb/half acre**
                                   0.5 acre
                                     13.4
                                     0.022
                                    0.0753
                                   0.000124
                                     6,600
                                    102,000
Liquids/ Backpack Sprayer

                                 0.0105 lb/gal
                                   5 gallons
                                      130
                                     0.14
                                    0.0857
                                   0.000092
                                     5,800
                                    138,000
1 Application rate (AR) Hand-wand and Backpack= Product Density (PD) * % in Formulation (%) * Dilution Factor (DF)
      PD= 9 lbs/gallon (Assumed, 2009 JITF Inert Ingredients. Residential and Occupational Exposure Assessment and Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations D364751)
      %= 5% max expected in formulation 
      DF= Assumed 0.0234 (3 oz product in 1 gallon (128 oz) of water), From Benzyl Acetate www.regulations.gov (Docket # EPA-HQ-OPP-2014-0783-004)
[1]Application rate (AR) Hose-End= Product Density (PD) * 1 gallon** * % in Formulation (%) 
** Based on reviews of currently available pesticide products, the expected use rate is 32 fl oz of product to cover approximately 5000 sq ft. A residential user is expected to use 4 x 32oz bottles (128 fl oz or 1 gallon) to treat (1/2) acre (21780 sq ft) based on the approximated used rate of 32 fl oz per 5000 sq ft. 
[2] Default Assumption from HED's 2012 Residential SOP Table 3-2
[3] From HED's 2012 Residential SOP Table 3-1
[4] Average Daily Dose (HED's 2012 Residential SOP Equation 3.2) = Daily exposure (=Application rate * Quantity Treated) * Unit Exposure * Absorption Factor / Body Weight (80 kg).  A Dermal Study was provided therefore, dermal absorption factor was not necessary. 
[5]MOE = PoD (NOAEL mg/kg/day)/ Daily dose (mg/kg/day); 
      NOAELs: Dermal = 500 mg/kg/day, Inhalation = 12.7 mg/kg/day

Risks were calculated using the Margin of Exposure (MOE) approach. This is a ratio of the body burden to the toxicological Point of Departure (PoD). For these chemicals a MOE greater than 100 indicates that the exposure scenario does not demonstrate a risk of concern. For all residential handler scenarios regarding application of pesticides containing this inert ingredient to lawns and turf, risk estimates are not of concern for both the dermal and inhalation assessment. These exposure models are highly conservative and therefore, the true risk of the anticipated exposure to these chemicals is believed to be less than what is illustrated in Table 5. 
 Post-application
Product specific data was not available; therefore, default assumptions were used to assess risk. Post-application exposure to 2-phenoxyethanol was calculated using the scenarios outlined in HED's 2012 Residential SOP. As stated in the 2012 SOP "Post-application inhalation exposure while engaged in activities on or around previously treated turf is generally not assessed and should be handled on a case-by-case basis." The Agency did not assess post-application inhalation exposure to treated lawn and turf for 2-phenoxyethanol. 

Pesticide residues can be transferred to the skin of adults and children who enter treated lawns for play, recreation, yardwork, or other home activities on the day the pesticide is applied. Dermal exposure to treated lawns were calculated for adults and children (1-2 yrs). It is assumed that individuals come in contact with treated lawns/turf the same day the pesticide is applied. Post-application dermal exposure following applications to lawns and turf is generally considered short-term in duration therefore, only short-term exposure was assessed. 
      Table 6: Short-term Post-Application Dermal Exposure and Risks from
                 2-Phenoxyethanol from Treated Lawns and Turf
                               Exposure Scenario
                              Application Rate[1]
                                       
                         Turf Transferable Residue[2]
                       Transfer Coefficients[3] (cm2/hr)
                                       
                               Exposure Time[3]
                               Dose (mg/kg/day)
                                      MOE
                                       
                                      AR
                                      TTR
                                      TC
                                      ET
                                       
                                       
Adults
                             0.9 (lbs inert/acre)
                               0.1018(ug/cm[2])
                                    180000
                                      1.5
                                     0.344
                                     1,450
Children (1-2 years)
                                       
                                       
                                     49000
                                      1.5
                                     0.656
                                      760

1 AR= 0.9 lbs inert ingredient/acre (Hose-end sprayer-Table 5) 
[2]TTR=AR * F* (1-FD)t *CF2 *CF3   
Using the Default Values from HED's 2012 Residential SOP: 
      F= Fraction of Transferable Residue (0.01); 
      FD=Fraction of Residue that Dissipates per Day (0.1); 
      t= Post-Application Day (0) EPA assessed exposure on the day of application 
      CF2 4.58 x 108 ug/lb; 
      CF3 2.47 x 10[-][8] acre/cm[2]
[3]Default HED's 2012 Residential SOP
[4]Dose= TTR * CF1 * TC *ET * Dermal Adsorption Factor / BW; 
      CF1= 0.001 mg/ ug, Dermal Absorption not used, Dermal Study provided. BW adult 80 kg, BW child 11.4 kg
[5]MOE = PoD (NOAEL 500 mg/kg/day)/ Daily dose (mg/kg/day)

In addition, post-application oral exposure (i.e., hand-to-mouth (HTM)) for children 1-2 years old was also determined and use in the risk assessment. While post-application exposure to children exposed to treated lawns is possible via object-to-mouth (OTM) transfer and soil ingestion, based on the conservatisms of all post-application exposure scenarios for exposure to treated lawns/turf, the Agency typically combines dermal and hand-to-mouth post-application exposure. This combination is considered a protective estimate of children's exposure to pesticides use on turf. However, the toxic effect seen in the dermal toxicity study and the oral toxicity study are not the same and so doses were not combined.

  Table 7: Short-term Post-Application Hand-to-Mouth Exposure and Risks from
                 2-Phenoxyethanol from Treated Lawns and Turf
                           Hand Residue[1] (mg/cm2)
                                     (HR)
                            Area Mouthed/Event[2] 
                                     (cm2/
                                    event)
                                     (AM)
                          Exposure time[3] (hrs/day)
                                     (ET)
                           Replenishment Interval[3]
                                (intervals/hr)
                                  (N-Replen)
                          Saliva Extraction Factor[3]
                                     (SE)
                                 Frequency[3]
                                  (events/hr)
                                    (Freq)
                                    Dose[4]
                                  (mg/kg/day)
                                    MOE[5]
                                    Rounded
                                    0.00013
                                     19.05
                                      1.5
                                       4
                                     0.48
                                     13.9
                                    0.0012
307,000
[1] HR=Fraction on Hand * Dermal Exposure / (2 * Surface Area of 1 hand)
      Defaults from HEDs 2012 Residential SOP, Dermal exposure based on Table 4
      Fraction on Hand = 0.06
      Dermal Exposure= 0.656 mg from Table 4
      Surface Area of 1 hand= 150 cm[2]
[2] AM=fraction hand surface mouthed (0.127) *surface area of one hand (150 cm2); Defaults from HED 2012 Residential SOP
[3] Default HED 2012 Residential SOP
[4] Dose = [HR * (AM) * (ET * N_Replen) * (1- (1- SE)[(][Freq_HtM][/N-][Replen][)])]/BW 11.4kg
[5] MOE = PoD (ORAL NOAEL 369 mg/kg/day)/ Daily dose (mg/kg/day)

All MOEs for residential dermal and hand-to-mouth post-application exposures to treated lawns for both adults and children were greater than or equal to 760. The level of concern is for MOEs that are lower than 100, therefore, post-application exposure to treated lawn in each scenario are not of concern.

   Cleaning Products 

2-Phenoxyethanol is currently used as a nonfood inert ingredient in antimicrobial trigger pump spray cleaning products. Based on a review of currently registered cleaning products containing 2-phenoxyethanol, a concentration of 0.5% in formulation was used to assess exposure. Dermal and inhalation exposure to 2-phenoxyethanol was assessed for adult applicators/handlers. 

     Table 8: Short-term Exposure and Risks for Residential Handlers from 
           Exposure to Cleaning Products Containing 2-Phenoxyethanol
                 Exposure Scenario (Formulation/ Application)
                     Application Rate1 (lb inert/ gallon)
                     Quantity Handled/ Treated per day[2]
                     Dermal Unit Exposure (mg/lb inert)[3]
                  Inhalation Unit Exposure (mg/ lb inert)[3]
                          Dermal Dose (mg/kg/day)[4]
                        Inhalation Dose (mg/kg/ day)[4]
                                 Dermal MOE[5]
 Inhalation MOE[5]
New UE
Trigger pump and wipe
                                 0.0417 lb/gal
                                 0.06 gallons
                                     1740
                                     24.9
                                     0.054
                                    0.00078
                                     9200
                                    16,000
1 Application rate = Density of product (8.34 lbs/gal-assumed to be equal to the density of water) * % in Formulation (0.5%) 
[2] Default EPA assumption from OPP's Antimicrobials Division from personal email from Tim Dole as derived from MRID 46799302)
[3]Unit Exposures from OPP's Antimicrobials Division (Derived from Antimicrobial Exposure Assessment Task Force II (AEATF II) Data)
[4]Average Daily Dose = Application rate * Quantity Treated * Unit Exposure * Absorption Factor / Body Weight (80 kg). Absorption Factor was not use because a dermal study was provided.
[3] MOE = POD (NOAEL mg/kg/day)/ Daily dose (mg/kg/day); Dermal NOAEL 500 mg/kg/day, Inhalation NOAEL 12.7 mg/kg/day

The MOE for dermal exposure to antimicrobial cleaning products for adult residential handlers is 9200. The level of concern is for MOEs that are lower than 100, therefore, exposure to antimicrobial cleaning products is not of concern.

While it is possible that these spray products could be applied to floors, a review of labels for trigger pump spray antimicrobial cleaning products indicates that it is unlikely as no instructions are given for floor moping. The Agency assesses post-application exposure to indoor cleaning products based on exposure to treated floors; therefore, a post-application exposure assessment was not necessary. 

   Pet Products

2-Phenoxyethanol is currently used as an inert ingredient in pet spot-on products. Dermal exposure to 2-phenoxyethanol was assessed for adult applicators as it is assumed that adults will apply these products. According to HED's 2012 Residential SOP, inhalation exposure from spot-on pet treatments is considered negligible. Post-application exposure is anticipated to occur from dermal (adults and children) and hand-to-mouth (children only) exposure to treated pets.  Based on a review of the current spot on products containing 2-phenoxyethanol, a value of 15% in formulation was used to assess exposure to pet products with an application volume of 0.135 fl oz for the largest dog treated. 

 Applicator/Handler

   Table 9: Pet Spot-On Applicator Dermal Exposure to 2-Phenoxyethanol
Application Rate
(lbs/pet)[1]
 Dermal Unit Exposure
 (mg/lb ai)[2]
 Number of Animal Treated per Day[2]
  Dose (mg/kg/day)[3]
   MOE[4]
   (Rounded) 
 0.00127
 120
             2
 0.0038
    131,000
[1]Application Rate (AR)= Application Volume (0.135 oz) * Conversion Factor (1lb/16 oz) * % in formulation (15%)
2 Default value from HED's 2012 Residential SOP
[3]Dose= AR * Dermal Unit Exposure * Animals Treated * Absorption Factor (AF) AF not used, dermal study provided
			Body Weight (80 kg)	
[5]MOE=POD (Dermal NOAEL 500mg/kg/day)/Dose

The level of concern is for MOEs that are lower than 100; therefore, based on the MOE for residential handlers of 131000, exposure from applying spot-on pet treatments is not of concern. 

 Post-application 
                                                                               
Post-application exposure can result from physical activities such as petting or otherwise interacting with pets following pesticide applications. This includes dermal exposure to adults and children and oral hand-to-mouth (HTM) exposure in children. Like handlers/applicators, post-application inhalation exposure is expected to be negligible; therefore, inhalation exposure was not assessed. 
	
In order to estimate post-application dermal exposure a transferable residue (TR) was calculated using the same values used for applicator/handler (i.e., 15% in formulation with an application volume of 0.135 fl oz). All other parameters were based on default assumption values in HED's 2012 Residential SOP. 

    Table 10: Post-application Dermal Exposure from Pet Spot-on Treatments
                                  Population
                                 Transferable
                                  Residue[1]
                                   (mg/cm2)
                            Transfer Coefficient[2]
                                   (cm2/hr)
                          Exposure time[2] (hrs/day)
                                    Dose[3]
                                  (mg/kg/day)
                                    MOE[4]
                                   (Rounded)
Adults 
                                    0.00105
                                     5200
                                     0.77
                                     0.053
                                     9,400
Children (1<2 years)
                                    0.00105
                                     1400
                                      1.0
                                     0.129
                                     3,800
[1] Transferable Residue = Application Rate (AR) * Fraction available as transferable residue (FAR)
			Surface Area of Pet (SA) 
	AR= 576 mg/pet; converted from 0.00127 lbs/pet in Table 9)
	FAR = 0.02 (Default from HED's 2012 Residential SOP)
	SA = 11000 cm[2] (Default for "Large" Dog from HED's 2012 Residential SOP)
[2] Default value for liquids from HED's 2012 Residential SOP. 
[3] Dose= Transfer Coefficient * Transferable Residue * Exposure Time
		Body Weight (Adult 80 kg, Child 11.4 k)
[4] MOE=POD (Dermal NOAEL 500 mg/kg/day)/Dose

To estimate post-application HTM exposure in children (1<2 years) a hand residue loading value was calculated using values from Table 10 along with default assumptions. All other parameters were based on default assumption values in HED's 2012 Residential SOP. 

Table 11: Post-application Hand-to-Mouth Exposure to Children from Pet Spot-on Treatments
                          Hand Residue[1] (mg/cm[2])
                                     (HR)
                            Area Mouthed/Event[2] 
                                    (cm[2]/
                                    event)
                                     (AM)
                          Exposure time[3] (hrs/day)
                                     (ET)
                             Replenish Interval[3]
                                (intervals/hr)
                                  (N-Replen)
                          Saliva Extraction Factor[3]
                                     (SE)
                                   Freq.[3]
                                  (event/hr)
                                    (Freq)
                                    Dose[4]
                                  (mg/kg/day)
                                    MOE[5]
                                   (Rounded)
                                    0.00019
                                     19.5
                                       1
                                       4
                                     0.48
                                      20
                                    0.0013
                                    283,000
[1] Hand Residue Loading= [Dermal Exposure (DE)] * [Fraction on hands (Faihands)] 
			2* [Surface Area of One Child Hand (SAH )]
	DE = 1.47 mg (i.e., Transfer Coefficient * Transferable Residue * Exposure Time); See Table 10
	Faihands) = 0.04 (Default HED's 2012 Residential SOP)
	SAH = 150 cm2 (Default HED's 2012 Residential SOP)
[2] Area Mouthed/event = [Surface area of one child's hand (SAH)] * [Fraction of hand surface mouthed/event (FM )]	
	SAH = 150 cm2 (Default HED's 2012 Residential SOP)
 	FM = 0.13 (Default HED's 2012 Residential SOP)
3 Default HED's 2012 Residential SOP Values
[4] Dose = [HR * AM * (ET * N_Replen) * (1- (1- SE) [(][Freq][/N-][Replen][)])]/11.4 kg Body Weight (Values listed in table)
[5] MOE = POD (Oral NOAEL 369 mg/kg/day)/Dose

The MOEs for all post-application exposures scenarios list in Table 10 and 11 are above the level of concern (i.e., MOEs that are lower than 100), therefore, post-application exposure to pet spot-on products containing the inert ingredient are not of concern. 

 Non-pesticidal
            
In addition to the current and proposed pesticidal uses of 2-phenoxyethanol, non-pesticidal products (e.g., paints and coatings, cosmetics, and cleaning agents) are available for consumer usage which could contribute to aggregate exposures to 2-phenoxyethanol. According to the submitter, the use in latex paints and in consumer cosmetics are the ones most likely to result in the highest residential exposure estimates. Pesticidal cleaning product containing 2-phenoxyethanol have already been included in the risk assessment; therefore, 2-phenoxyethanol in non-pesticidal cleaning products have not been doubly assessed. 
   Paint
 Handler/Applicator
In the absence of actual exposure data for the use of 2-phenoxyethanol in non-pesticidal paint, EPA's exposure methodology for residential uses of treated paints and preservatives from the HED's 2012 Residential SOP was used to estimate consumer exposures. Some of the values in HED's 2012 Residential SOP were based on information on the use of non-treated paint. Exposures to residential handlers from mixing and applying paint containing to 2-phenoxyethanol can occur through inhalation and dermal exposure during mixing and applying paint (residential handler), or as post-application exposures relating to contact with dried paint. Typically, residential painters are assessed using the short pants, short-sleeved shirt, no gloves scenario. The maximum paint concentration of 3% was provided by the submitter and is based on end-use information collected from REACH. 
       Table12: Residential Handler Exposure to 2-Phenoxyethanol in Paint
                                       
                               Application Method
                                       
                              Application Rate[1] 
                                       
                            Amount Handled Daily[2]
                                        
                            Unit Exposure[3] (mg/lb)
                          Dermal  Dose[4] (mg/kg/day)
                                   (Rounded)
                         Inhalation Dose[4] (mg/kg/day)
                                   (Rounded)
                                       
                                 Dermal MOE[5]
                                   (Rounded)
                                         
                                Inhalation MOE[5]
                                   (Rounded)
                                       
                                       
                                       
                                     Dermal
                                     Inhal
                                        
                                        
                                       
                                         
 Aerosol
 Can

                                     0.018
                                 lbs/12 oz can

                                      3  
                                 (12 oz cans)
                                       
                                      370
                                       
                                       3

                                      0.25

                                                                         0.0020
                                       
                                                                          1,400

                                     6,350
 Airless Sprayer

                                      0.29
                                  (lb /gallon)

                                       5
                                    Gallons

                                       
                                      160
                                       
                                     0.56

                                      2.9


                                                                         0.0102
                                                                               
                                                                               

                                                                            170


                                     1,200
                                        
 Brush/
 Roller

                                      0.31
                                  (lb /gallon)

                                       2
                                    gallons
                                       
                                      144

                                       
                                    0.0077

                                      1.11

                                                                        0.00006


                                                                            450


                                    212,000

Manually Pressurized Hand-wand

                                      0.31
                                  (lb /gallon)

                                       3
                                    gallons
                                       
                                      63
                                       
                                     0.018

                                      0.73

                                                                         0.0002

                                                                            685

                                     63,500

1 Application Rate=Volume paint in each can (V) * Paint Density (ρ) * Weight Fraction (WF) * Conversion Factor (CF). 
Note: Airless sprayer has been diluted to (1/2) pint water per gallon of paint so 8 fl oz in 128 oz = 0.94 or 94% paint to water ratio, (This value is taken from a review of various MSDSs related to applying paint via airless sprayer). 
	V= Liquid paint = 3785 mL/can (i.e., 1 gallon); Aerosol = 355 ml/can (i.e., 12oz can)
      ρ = Liquid paint = 1.24 g/mL (i.e., Default 10.34 lbs/gallon); Aerosol = 0.779 g/mL (i.e., Relative Density 0.78 = 8.34 lbs/gal (density of water) * 0.78 = 6.5 lbs/gal, converted to g/mL)
	WF = 3% inert ingredient (max permitted in paints)
	CF = 0.0022 lbs/g
[2] Default HED's 2012 Residential SOP Values. Note: Aerosol Can (3* 12oz cans) has been converted to gallons. 
[3] With the exception of the brush/roller scenario all values are Default HED's 2012 Residential SOP Values. The brush roller Unit Exposure is from the Antimicrobial Division's  Science Review of the AEATF II Brush/Roller Painting Human Exposure Monitoring Study (AEATF II Project ID AEA09; MRID 50521701).
4 Dose= Application Rate * Amount Handled * Unit Exposure * Dermal Absorption (Not used, Dermal study provided)
					BW
[5] MOE = POD (NOAEL mg/kg/day)/ Daily dose (mg/kg/day); 
      Dermal NOAEL 500 mg/kg/day, Inhalation NOAEL 12.7 mg/kg/day
The highest estimated exposure was from dermal exposure to paint application using a Airless Sprayer. This highly conservative model resulted in a Margin of Exposure (MOE) of 170. This is considered an acceptable level of risk as it exceeds the MOE of concern of 100.  
 Post-Application 
Post-application exposures to paints may occur to adults and children via the inhalation and dermal routes of exposure or via incidental oral exposure due to hand-to-mouth activity in children. These exposures are considered short-term in duration. Post-application exposures related to paints containing 2-phenoxyethanol were calculated for adults and children 1-2 years of age using the calculations and default assumptions in HED's 2012 Residential SOP with the exception of the transfer efficiency (TE) value as described below. 
			Dermal
HED's 2012 Residential SOP estimates the dermal transfer efficiency for treated paints and preservatives based on the worst-case scenario of exposure for aresenic from copper arsenate treated wood. However, for this assessment, in place of the default dermal transfer efficiency of 14% (based on a study of arsenic exposures from chromated copper arsenate treated wood) an alternative transfer efficiency identified for dried paint was used. Dow submitted a publication from The European Institute for Health and Consumer Protection with a transfer efficiency of 3% for dried fluid residues from painted wood (MRID 50321624). This transfer efficiency is based on studies conducted by the United Kingdom's Health & Safety Laboratory on dislodgeable residues from hard surfaces. For this scenario a 3% transfer efficiently was considered appropriate. 
   Table 13: Dermal Post-Application Exposure from Paint containing 2- Phenoxyethanol



Population
 Surface
 Residue Concentration[1] (mg /cm2)
 Total body surface area to body weight ratio[2] (cm2/kg)
 Fraction of body exposed2 (Unitless)
 Daily Material- to-Skin Transfer Efficiency[3] (Fraction/Day)
  Dose[4] (mg/kg/day)
   MOE[5] (Rounded) (Unitless Fraction)

    SR
 SA/BW
    FBody
                                                                             TE
D
    MOE
 Adults (16<81 years)
    0.3784
 280
    0.31
                                                                           0.03
                                                                               
                                                                               
 0.9854
 
 
       500


 Children (1 <2 years)
    0.3784
 640
    0.31
                                                                           0.03
                                                                               
                                                                               
 2.252
 
 
    220
    
    
[1]SR = Volume of paint used (ml) * Density of paint (mg/ml) * % in Formulation  
      Surface Area of painted room 
      Volume of paint used = 3785.41 mL (i.e., 1 gallon)
      Density of paint 1239 mg/mL (i.e., converted from 10.34 lbs/gallon, Default assumption) 
      % in Formulation = 3% (product specific date)
      Surface area of painted room= 371612 cm[2] (i.e., 1 gallon is expected to cover a 400 ft[2] room * conversion factor of 929.03 cm[2]/ft[2])
[2] Default HED's 2012 Residential SOP Values.
3 European Institute for Health and Consumer Protection published a transfer efficiency for paint of 3%
[4]Dose= SR * SA/BW *Fbody * TE *AF; 
(*Dermal endpoint was used to determine the Dermal MOE therefore, a dermal absorption factor (AF) was not used)
[5] MOE = POD (Dermal NOAEL 500 mg/kg/day)/ Dose (mg/kg/day)

Estimated dermal exposures were calculated as 0.95 mg/kg/day for adults with a MOE of 500 and 2.25 mg/kg/day for children 1-2 years of age with a MOE of 220. These are considered acceptable as they are great than 100. 
			Inhalation
As stated in HED's 2012 Residential SOP:
      In many cases, inhalation exposure from impregnated paints is expected to be negligible, since many non-preservative pesticides have low vapor pressures and would be designed to be incorporated into the treated surface. When treated paints/wood preservatives contain more volatile pesticide chemicals, however, it may be necessary to assess post-application inhalation exposures.  
Based on the chemical characteristics of 2-phenoxyethanol (e.g., vapor pressure), post-application inhalation exposure is possible; however, the dose from inhalation exposure to dried paint is not expected to exceed the inhalation exposure assessment for handlers/applicators which was within acceptable limits. Therefore, the risk from inhalation post-application exposure to paints was also considered to be within acceptable limits. 
In regard to post-application exposure to children, an estimate was made based on Section 10.2.3 of HED's 2012 Residential SOP. The SOP incorporates the use of the EPA's Wall Paint Exposure Model (WPEM) to estimate the air concentration. Unfortunately, the model was not available and therefore, the Agency estimated a worst-case air concentration for this semivolatile compound at 1 mg/m[3] based on measured air VOC concentrations following application of paint with an airless sprayer. Tests conducted at EPA's Indoor Air Quality Research House (EPA, 2000) showed air concertation ranging from 5,500 to 13,000 ug/m[3] for VOCs in paint 4-8 hours post application. These tests were conducted in a closed room without ventilation. Concentrations of semivolatile compounds, such as 2-phenoxyethanol, would be expected to be much less; therefore, a concertation of 1000 ug/m[3] (i.e., 1 mg/m[3]) was assumed as a worst-case concentration for 2-phenoxyethanol. This value was then used to calculate the daily dose using the equation on pg 10-13.
      D = C*IR*ET*AF
          			 BW

      D	= Potential Daily Dose 
      C	= 4-Hour Average Air concentration 
      IR	= Inhalation rate 
      ET	= Exposure time 
      AF	= Absorption Factor (Not Used, Inhalation study provided)
      BW	= Bodyweight (11.4 kg).

 Table 14: Post-application Inhalation Exposure in Children 1-2 years of age.
                           Concentration[1] (mg/m3)
                              Inhalation Rate[1]
                                   (m[3]/hr)
                           Exposure Time[2] (Hours/
                                     Day)
                               BW[2] (Events/hr)
                              Dose[3] (mg/kg/day)
                               MOE[4] (Rounded)
                                       C
                                      IR
                                      ET
                                      BW
                                       D
                                      MOE
                                       1
                                     0.33
                                       4
                                     11.4
                                     0.11
                                      115
[1] From Chapter 6 of the EPA's Exposures Factors Handbook (https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=236252)

		Hand-to-mouth

Post-application oral exposures could also occur in children from hand-to-mouth behaviors which are common in young children. Hand-to-mouth (HTM) exposures were assessed for children 1-2 years of age using the Calculation 10.6 of HED's 2012 Residential SOP. Assumptions were similar to those used for the dermal exposure assessment, using the same parameters to determine surface residues of 2-phenoxyethanol and the same 3% TE for dried fluid residues from painted wood. Hand-to-mouth exposure was estimated as 0.29 mg/kg/day (MOE 1270). 
Table 15: Post-application Hand-to-Mouth Exposure in Children 1-2 years of age.
                           Hand Residue[1] (mg/cm2)
               Fraction of hand mouthed per event[2] (Fraction/
                                    Event)
               Typical Surface area of one toddler hand[2] (cm2)
                   Replenishment Intervals[2] (Intervals/hr)
                           Exposure Time[2] (Hours/
                                     Day)
                    Saliva Extraction Factor[2] (Unitless)
                              HTM[2] (Events/hr)
                              Dose[3] (mg/kg/day)
                               MOE[4] (Rounded)
                                      HR
                                      FM
                                      SAH
                                   N_Replen
                                      ET
                                      SE
                                     Freq
                                       D
                                      MOE
0.011
0.13
150
4
4
0.48
20
0.29
1,270
[1]HR=Surface Residue * Transfer Efficiency 
      Surface Residue 0.3784 mg/cm[2] from Table 13
      Transfer Efficiency = 3% based on European Institute for Health and Consumer Protection 
[2] Default HED's 2012 Residential SOP Values.
3 Dose= [HR * (FM * SAH) * (ET * N_Replen) * (1- (1- SE) [(Freq/N-][Replen][)])]/11.4 kg Body Weight
[4] MOE = POD (Oral NOAEL 369 mg/kg/day)/ Dose (mg/kg/day)

These results are highly conservative as they assume 100% contact of the exposed skin with the painted surface each day which likely overestimates post-application exposures from treated paints. Actual residential exposures following application of paint containing 2-phenoxyethanol are expected to be substantially lower than those predicted above.
   Cosmetic Exposure 
According to the EU European Commission's Scientific Committee on Consumer Safety (SCCS), the maximum allowable concentration in cosmetic products, as a preservative, is 1% and is based on the (EC) No. 1223/2009 cosmetic regulation (MRID 50321636). Exposure values for consumers using cosmetic products containing 2-phenoxyethanol have been presented in the SCCS document. The estimations are extremely conservative in that they assumed that all of the products contained 2-phenoxyethanol are at the maximum concentration of 1%. However, "a survey of 43 cosmetic products including leave-on and rinse-off products demonstrated that only 25% of the products had levels of PhE at 0.60% and the mean concentration of PhE in the cosmetic products was 0.46% (ANSM, 2009)" (MRID 50321650). 

The SCCS estimate also assumed that all 15 dermally applied cosmetic products and 2 oral products are used every day. Cosmetics containing 1% 2-phenoxyethanol as a preservative account for a dose of 2.69 mg/kg/day, whereas the inhalation route (shower scenario) may contribute an additional 0.02 mg/kg/day. 2-Phenoxyethanol when used as a fragrance in fragrance mixtures in cosmetics may account for around 0.05 mg/kg/day. Taken together, according to the SCCS report, the aggregate adult exposure to 2-phenoxyethanol in cosmetics may sum up to 2.76 mg/kg/day. 

Daily cosmetic exposures to babies/toddlers were calculated as described for adults with the exception that only those products that are used on babies/toddlers were included in the calculations. The SCCS also calculated a reasonable worst-case value of 61.2 mg per day as an external aggregate exposure to age-specific cosmetic products. The report used a low body weight (i.e., 7 kg, 5-percentile for toddlers/infants <=3 years, and 9 kg) and the daily dose was 6.8 mg/kg/day. If this dose was divided by the body weight used in this risk assessment for children 1-2 years old (i.e., 11.4 kg), it would result in a daily dose of 5.4 mg/kg/day. 
The Agency believes that the compounding nature of the cosmetic exposure assessment would result in an over estimation of exposure. Based on the review of cosmetic products, the Agency feels that a concentration of 0.5% would more accurately represent the concentration of 2-phenoxyethanol in cosmetics. Therefore, the Agency used a dose of 1.38 mg/kg/day for adults and 2.7 mg/kg/day for children.  

 Occupational Exposure/Risk
The representative occupational scenarios selected by the Agency for assessment incorporate the likely maximum application rates for products which may contain the inert ingredient for the short-term exposure assessment, and average application rates for products likely to contain the inert ingredient for the intermediate-term exposure durations. Active ingredient application rates are corrected for the maximum amount of inert ingredient likely to be in the final formulations to determine exposure and risk from exposure to the inert ingredient by fungicide/insecticide or herbicide. These models use high exposure scenarios and would likely overestimate risk; however, they have been chosen to represent a worst-case scenario for the potential use of this inert ingredients.

The Agency considers a level of concern (LOC) for these risk assessments to be a dermal MOE of 100 based on the standard 10X inter- and 10X intra- species extrapolation safety factors and an inhalation MOE of 1000 based on 10X inter- and 10X intra- species extrapolation safety factors and 10X for using a short-term study as a chronic endpoint.  
 Occupational Handler Risk
Dermal and inhalation exposure are estimated using the Pesticide Handlers Exposure Database (PHED) and Outdoor Residential Exposure Task Force (ORETF) data. The analytical techniques were developed by the Science Policy Council on Exposure (ExpoSAC), Heath Effects Division, Office of Pesticide Programs, US Environmental Protection Agency. The quantitative exposure assessment developed for occupational handlers exposed to the inert ingredient is based on scenarios that represent the highest potential exposure. 

Occupational exposures are presented for aerial applicators, ground applicators and for mixer/loaders preparing and applying liquid formulations diluted for use in applications. These are the occupational activities believed to be associated with the highest exposures use patterns. The occupation exposure assessment utilized the values for the highest exposure herbicide, insecticide and fungicide, however, only the herbicide data is provided below because, in general, it provided the lowest and most conservative MOEs. Although food use of this inert ingredient will be limited to 0.2% in pesticide formulations, potential nonfood uses may exceed this value as the limitation only applies to the exemption from the requirement of tolerance. Therefore, 5% in pesticide formulations was used as this is a more appropriate value for occupational exposure to pesticides. 
      
Table 16: Exposure and Risks for Occupational Handlers at Baseline* Dermal and Inhalation PPE
              Exposure Scenario (Formulation/ Application/ Crop)
                        Application Rate1 (lb inert/ A)
                          Area Treated Daily2 (acres)
                     Dermal Unit Exposure[3] (mg/lb inert)
                  Inhalation Unit Exposure[3] (ug/ lb inert)
                                       
                      Baseline Dermal Dose4 (mg/kg /day)
                                       
                    Baseline Inhalation Dose4 (mg/kg/ day)
                            Baseline Dermal MOE[5]
                          Baseline Inhalation MOE[5]
                            Mixer/Loader Scenarios
             Liquids/ Aerial Application/ High Acreage Crops (ST)
                                     0.52
                                     1200
                                     0.22
                                     0.219
                                     1.716
                                    0.00171
                                      290
                                     7,400
             Liquids/ Aerial Application/ High Acreage Crops (IT)
                                      0.1
                                       
                                       
                                       
                                     0.330
                                    0.00033
                                     1500
                                    42,000
                 Liquids/ Groundboom/ High Acreage Crops (ST)
                                     0.52
                                      200
                                       
                                       
                                     0.286
                                    0.00028
                                     1700
                                    45,000
                 Liquids/ Groundboom/ High Acreage Crops (IT)
                                      0.1
                                       
                                       
                                       
                                     0055
                                    0.00005
                                     9100
                                    250,000
             Wettable Powder/ Groundboom/ High Acreage Crops (ST)
                                     0.08
                                      200
                                    0.0777
                                     2.75
                                    0.01554
                                    0.00055
                                     32000
                                    23,000
             Wettable Powder/ Groundboom/ High Acreage Crops (IT)
                                     0.05
                                       
                                       
                                       
                                    0.00971
                                    0.00034
                                     51000
                                    37,000
                             Applicator Scenarios
            Liquid/ Aerial Application/ High Acreage Crops (ST)[9]
                                     0.52
                                     1200
                           Eng control only: 0.0028
                           Eng control only: 0.0049
                                    0.0162
                                   0.000038
                                     31000
                                    334,000
            Liquid/ Aerial Application/ High Acreage Crops (IT)[9]
                                      0.1
                                       
                                       
                                       
                                    0.0031
                                   0.000007
                                    160000
                                   1,814,000
                      Groundboom/ High Acreage Crops (ST)
                                     0.52
                                      200
                                    0.0786
                                     0.34
                                    0.1022
                                    0.00044
                                     4900
                                    29,000
                      Groundboom/ High Acreage Crops (IT)
                                      0.1
                                       
                                       
                                       
                                    0.0197
                                    0.00009
                                     25000
                                    141,000
                       Mixer/Loader/Applicator Scenarios
                Liquid/ Low Pressure Handwand/ Ornamentals (ST)
                                     0.36
                                       5
                                      100
                                      30
                                     2.25
                                    0.00068
                                      220
                                    19,000
                Liquid/ Low Pressure Handwand/ Ornamentals (IT)
                                     0.36
                                       
                                       
                                       
                                     2.25
                                    0.00068
                                      220
                                    19,000
                               Flagger Scenarios
                   Liquid/ Flagger/ High Acreage Crops (ST)
                                     0.52
                                     1200
                                     0.011
                                     0.35
                                    0.0858
                                    0.00273
                                     5800
                                     4,650
                   Liquid/ Flagger/ High Acreage Crops (IT)
                                      0.1
                                       
                                       
                                       
                                    0.0165
                                    0.00053
                                     30000
                                    24,000
* Baseline Dermal PPE = single layer clothing, no gloves. Baseline Inhalation PPE= no respirator. 
[1].Default maximum application rates from Table 3.1.2 "JITF Inert Ingredients. Residential and Occupational Exposure Assessment Algorithms and Assumptions Appendix for the Human Health Risk Assessments to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations,'' (D364751, 5/7/09, Lloyd/LaMay in docket ID number EPA - HQ - OPP - 2008 - 0710 and adjusted for 5 % inert ingredient in formulation. Application rates for Short-term (ST) exposure risk estimates are based on maximum application rates.  Application rates for Intermediate-term (IT) exposures are based on average application rates.  
[2]Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of concern.
[3]Unit Exposure values are reported in EPA's Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHUE) dated June 2018.  All exposure scenarios assess baseline dermal PPE plus baseline inhalation exposure except for aerial applicator scenarios, which assess inhalation and dermal exposures with engineering controls.
4 Average Daily Exposure (**) = Unit Exposure * Application Rate * Units Treated * Absorption Rate (dermal study provided)
                        80 kg Body Weight
      (** = Conversion Factor (1 mg /1000 ug) for inhalation exposure calculations)
[5] Margin of Exposure = POD (Dermal NOAEL: 500mg/kg/day, Inhalation NOAEL from 90-day oral: 12.7 mg/kg/day) / Dose

The assessment for occupational handlers was conducted assuming baseline personal protective equipment (PPE) (i.e., long pants, a long-sleeved shirt, shoes, socks, no chemical-resistant gloves, and no respiratory protection). In the absence of additional dermal or inhalation PPE, all exposure scenarios indicated an acceptable level of risk (i.e., MOEs greater than 100 for dermal exposure and MOEs greater than 1,000 for inhalation exposure). Therefore, the Agency believes occupational handler risk is acceptable. 

 Post-application Exposure Scenarios
           
Post-application exposures occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions such as scouting for pests or harvesting. Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure. Inhalation exposures are also not typically calculated for occupational post-application scenarios because inhalation exposures generally account for a negligible percentage of the overall body burden for most pesticide chemicals. 
      
The Agency expects post-application agricultural exposures to workers would typically be short-term (1-30 days for 8 hrs/day). Therefore, only short-term post-application exposure was assessed for the day of treatment (Day 0). Risks were calculated using the Margin of Exposure (MOE) approach, which is a ratio of the body burden to the toxicological PoD. The three occupational scenarios assessed are for post-application activities associated with:

 Tall field/row crops (including scouting, weeding, hand harvesting sweet corn)
 Turf (golf course/sod farm) (including mowing, transplanting, hand weeding)
 Vine/Trellis crops (including scouting, training, tying, thinning, and grape girding and cane turning)
Table 17.  Summary of Exposure & Risk from Occupational Post-Application Exposure to 2-Phenoxyethanol
                              Exposure Potential
                           Transfer Coefficients[1]
                                   cm[2]/hr
                              Application Rate[1]
                                 lb inert/Acre
                                 DFR Levels[2]
                                   ug/cm[2]
                              Short-term Dose[3]
                               mg inert/kg /day
                                    MOE[4]
                                       
                      Herbicide Short-term Tall Field Row
Low: scouting, weeding immature/low foliage plants
                                      100
                                0.52 lb inert/A
                                     1.167
                                    0.0117
                                     43000
Medium: scouting, weeding more mature/foliaged plants
                                      400
                                       
                                       
                                    0.0467
                                     11000
High: scouting, irrigation, weeding mature/full foliage plants
                                     1000
                                       
                                       
                                    0.1167
                                     4300
Very high: hand harvest or detasseling
                                     17000
                                       
                                       
                                    1.9835
                                      250
                           Herbicide Short-term Turf
Low: mowing
                                      500
                                0.52 lb inert/A
                                     0.292
                                     0.015
                                     34000
High: transplanting, hand weeding
                                     6800
                                       
                                       
                                     0.198
                                     2500
                      Insecticide Short-term Vinetrellis
Low: hedging, irrigation, scouting, hand weeding, training/tying blueberries
                                      500
                                0.35 lb inert/A
                                     0.785
                                    0.0393
                                     13000
Medium: scouting, training, tying
                                     1000
                                       
                                       
                                    0.0785
                                     6400
High: hand harvest, leaf pulling, thinning, pruning, training/tying grapes
                                     5000
                                       
                                       
                                    0.3927
                                     1300
Very high: grape girdling and cane turning
                                     10000
                                       
                                       
                                    0.7853
                                      640

[1.] Default values are taken from Occupational Post-application Risk Assessment Calculator Version 2 (12/2008). 
[2.] Dislodgeable Foliar Residue = AR * F * (1-D)[t] * CF2 * CF3 
		AR = Application rate (lb inert/A)
      F = fraction of inert retained on foliage (unitless) (default 20%)
      D = fraction of residue that dissipates daily (unitless) (default 10%)
      t = post application day on which exposure is being assessed (day 0)
      CF2 = weight unit conversion factor to convert the lbs inert in the application rate to ug for the DFR value (4.54E8 ug/lb)
      CF3 = Area unit conversion factor to convert the surface area units (ft[2]) in the application rate to cm[2] for the DFR value (1.08E-3 ft[2]/cm[2] or 2.47E-8 acre/cm[2])
[3]. Average Daily Dose (ADD) = DFR * TC * hours of daily exposure (8 hrs/day) * CF (0.001 mg/ug)
							80 kg body weight
[4.] Margin of Exposure = POD (Dermal NOAEL 500mg/kg/day) / Dose

A dermal study was provided therefore a dermal absorption factor was not used. The post application occupational MOEs for all scenarios were above 100. As the level of concern is for MOEs that are lower than 100, post-application occupational worker exposure is not of concern.

 AGGREGATE EXPOSURE

EPA determines whether acute and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safety factors (SFs). No acute endpoint was identified in the database; therefore, EPA did not conduct an acute aggregate assessment. EPA calculates the cPAD by dividing the Point of Departure (POD) by all applicable UFs. Risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the MOE called for by the product of all applicable UFs is not exceeded.  

Consumer exposure to 2-phenoxyethanol could occur through dietary exposures to 2-phenoxyethanol in food and drinking water resulting from the proposed pesticidal uses, from direct-use consumer products such as latex paints, cosmetics, DIY pesticides for lawn/turf, and from post application exposure to these scenarios. Tables 18 and 19 lists the various potential exposure scenarios, gives the dose and corresponding cPAD or MOE for each and provides the aggregate exposure values. A POD of 369 mg/kg/day for oral exposure and 500 mg/kg/day for dermal exposure was used. The inhalation POD of 48.2 mg/m3 (~12.7 mg/kg/day) was based on an inhalation study which showed respiratory effects at 246 mg/m3 (~65 mg/kg/day). 
The mode of action of the toxicological effect must be the same across routes of exposure in order to aggregate the exposure. In this case, however, the toxic effects are different by one route and duration from those produced by a different route and duration. To produce an aggregate risk estimate in situations in which it is NOT appropriate to aggregate exposures due to differing toxicological effects, risk measures are calculated separately for each route and duration for a given toxic effect for each hypothetical "individual,". In these situations, multiple aggregate assessments are performed for a single chemical of interest if the relevant toxicological endpoints for all routes/pathways are not the same. When that is the case, a separate aggregate assessment is then performed for each toxic effect of concern.
It is unlikely that one person would paint their house, treat their pet and lawn, and eat all treated foods and apply all cosmetics containing this chemical in one day. The Agency feels a more realistic approach for aggregate exposure, based on the already conservative nature of the exposure assessment, would be to consider the greatest exposure scenario (i.e., paint), along with exposure to lawn and pet products. While someone could also use cosmetics and cleaning products, the highly conservative paint exposure scenario would be protective of exposure to cosmetics and cleaning products.  For these reasons the Agency aggregated these exposures and risk in Table 18 below. 
Table 18: Dietary and Residential Exposure Values for Adults Exposed to 2-Phenoxyethanol

                                     Oral
                                    Dermal
                                  Inhalation

                                     Dose
                                     %CPAD
                                     Dose
                                      MOE
                                     Dose
                                      MOE
Dietary (Food and Water)
                                    0.00076
                                    0.00005
                                       
                                       
                                       
                                       
Lawn
       (H/A) backpack sprayer
                                      N/A
                                      N/A
                                    0.0857
                                     5,800
                                   0.000092
                                    148,000
                                                               Post-app Lawn   
                                      N/A
                                      N/A
                                     0.344
                                     1,450
                                      N/A
                                      N/A
                                                                          Total


                                    0.4297
                                     1,160
                                   0.000092
                                    148,000
Pet Products 
                        (H/A) Spot-On
                                      N/A
                                      N/A
                                    0.0038
                                    131,000
                                      N/A
                                      N/A
                                                           Post-app Pet Spot-On
                                      N/A
                                      N/A
                                     0.053
                                     9,400
                                      N/A
                                      N/A
                                                                          Total


                                    0.0568
                                     8,800
                                      N/A
                                      N/A
Paint
            (H/A) Airless Sprayer
                                      N/A
                                      N/A
                                      2.9
                                      170
                                     0.03
                                      450
                                                               Post-app Paint  
                                      N/A
                                      N/A
                                    0.9854
                                      500
                             0.03 (est. from H/A)
                              450 (est. from H/A)
                                                                          Total
                                       
                                       
                                     3.885
                                      128
                                     0.06
                                      210
Cleaning Product
     (H/A) trigger pump sprayer
                                      N/A
                                      N/A
                                     0.054
                                     9,200
                                    0.00078
                                    16,300
Cosmetic        
                                      N/A
                                      N/A
                                     1.38
                                      360
                                     0.01
                                     1,270
Aggregate 
(Dietary, Cosmetic, Cleaning, and Paint)
                                    0.00076
                                    0.00005
                                    4.3715
                                      114
                                     0.07
                                      180
Bold= values that were used to arrive at the aggregate total
Similarly, not all potential exposures to children are expected to co-occur in the dame day. The aggregate assessment in children (Table 19) combined the same scenarios as adults. Note: The cosmetic value was not broken down by route and so all of the dose has been included as dermal as this is the most likely pathway. 
Table 19: Dietary and Residential Exposure Values for Children Exposed to 2-Phenoxyethanol

                             Oral/Incidental Oral
                                    Dermal
                                  Inhalation

                                     Dose
                                   %CPAD/MOE
                                     Dose
                                      MOE
                                     Dose
                                      MOE
Dietary (Food and Water)           
                                                                    (child 1-2)
                                    0.0028
                                    0.0002
                                      N/A
                                      N/A
                                      N/A
                                      N/A
Lawn 
                                                           Post-app (child 1-2)
                                    0.0012
                                    307000
                                     0.656
                                      760
                                      N/A
                                      N/A
Pet Spot-On 
                                                           Post-app (child 1-2)
                                    0.0013
                                    283000
                                     0.129
                                     3800
                                      N/A
                                      N/A
Paint
                                                           Post-app (child 1-2)
                                     0.29
                                     1270
                                     2.251
                                      220
                                     0.11
                                      130
Cosmetic           
                                                              (child <= 3 yrs)
                                       
                                       
                                      2.7
                                      185
                                       
                                       
Aggregate (Dietary, Cosmetic, and Paint)
                                    0.2928
                                     1260
                                     3.036
                                      165
                                     0.11
                                      130
Bold= values that were used to arrive at the aggregate total
This aggregate risk assessment is based on highly conservative assumptions that would likely over estimate exposure to 2-phenoxyethanol. The aggregate MOEs for both adults and children are greater than 100 and therefore, the Agency believes the levels of concern are not exceeded for aggregate risk for persons involved in consuming and handling pesticide products containing 2-phenoxyethanol at maximum of 0.2 % by weight in pesticide formulations.  

    CUMULATIVE EXPOSURE

Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity."

EPA has not found 2-phenoxyethanol to share a common mechanism of toxicity with any other substances, and 2-phenoxyethanol does do not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that 2-phenoxyethanol does not have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative.

    ENVIRONMENTAL FATE & EFFECTS 
                                                                               
 Environmental Fate

Based on the vapor pressure of 2-phenoxyethanol it is expected to volatilize; it is highly soluble in water, has a low octanol-water partition coefficient, and a low Henry's law constant (Table 20). For equal and continuous emissions to air, water, and soil, the fugacity modeling predicts that 83% of 2-phenoxyethanol will be removed from the environment by reaction, and the remaining 17% removed by advection, with an overall persistence time of 472 hours (19.7 days). The non-degraded fraction is expected to reside mainly in the air (70%) and water (29%) compartments. 
Based on the measured Koc (40.74 L/mg), 2-phenoxyethanol is expected to have very strong sorption to soil and sediment and the migration potential to groundwater is negligible. Therefore, it is unlikely that the chemical will leach into groundwater from use as a pesticide inert ingredient, Fugacity modeling predicts that 2-phenoxyethanol will exist mainly in the soil (70%) and water (29%). The Henry's law constant indicates that 2-phenoxyethanol is unlikely to evaporate from water.   
The atmospheric oxidation half-life (7.86 hour) indicates that any 2-phenoxyethanol that enters the atmosphere is expected to be degraded and not persist. 2-Phenoxyethanol was evaluated for ready biodegradability under OECD Method 301F, Manometric Respirometry. 2-Phenoxyethanol exhibited an average of 90% biodegradation after 28 days. (MRID 50321646) 2-Phenoxyethanol is classified as readily biodegradable. 
Table 20: Environmental Fate Characteristics of 2-Phenoxyethanol
Characteristic
Value
Physical state
Liquid at 20 °C and 760 mmHg
Henry's Law Constant
(VP/WSol calc)
7.64E-008 atm-m3/mol at 20 °C
1.13E-007 atm-m3/mol at 25 °C
Koc
40.74 L/kg measured
Atmospheric Oxidation
Half-life 
Half-life = 7.86 hr (AOPWIN in EPISUITE)
BCF 
1.5-2.4 L/kg w/w


Level III Fugacity Model (US EPA, 2017a)
                    Mass Amount	Half-Life	Emissions (percent)		(hr)		(kg/hr)
Air                 0.596                 7.86	1000
Water	29.3	360	1000
Soil	70.0	720	1000
Sediment       0.103	 3240                          0


 Ecotoxicity Data
                                                                               
    Fish
                                                                               
 Fathead Minnow
 
Fathead minnows (Pimephales promelas) were tested in a flow-through system at nominal concentrations of 0, 68, 113, 188, 313 and 522 mg/L (MRID 50321615). The 96 h LC50 value was 344 mg/L (mean measured concentration). Symptoms of toxicity occurred from a measured concentration of 270 mg/L. Affected fish stopped schooling, became hypoactive on the tank bottom and lost equilibrium prior to death.
In a second study (ECHA, 2018), early life-stage toxicity of 2-phenoxyethanol to embryos, larvae and juvenile fathead minnow (Pimephales promelas) were examined according to OECD Test Guideline 210. Fertilized eggs were exposed to nominal concentrations (0, 10, 23, 50, 110 and 220 mg/L) of 2-phenoxyethanol under flow-through conditions for 34 days. Parameters tested included: mortality of embryos, number of surviving larvae, survival of young fish, time to hatch and swim-up, toxic sign (symptoms) and abnormalities, and weight and total length of surviving fish. 
The NOEC for survival was 23 mg/L (nominal concentration) and 24 mg/L (based on the mean analytically determined concentration), and the LOEC was 50 mg/L (nominal concentration) and 51.3 mg/L (analytical concentration). For sublethal effects, the NOEC was 110 mg/L and 106 mg/L for nominal and analytical concentrations, respectively, while the LOEC was 220 mg/L and 215 mg/L for nominal and analytical concentration, respectively. For the development of body weight, the NOEC was 50 mg/L and 51.3 mg/L for nominal and analytical concentration, respectively, and the LOEC was 110 mg/L (nominal) and 106 mg/L (analytical). For development of body length of the surviving fish at the end of the exposure period, the NOEC and LOEC values equal those from development of body weight.
 Golden Orfe
The acute toxicity (ECHA, 2018) of pure 2-phenoxyethanol to the golden orfe (Leuciscus idus L., golden variety) was determined in a static system at nominal concentrations of 0, 100, 215, 464 and 1000 mg/L. The 96 h LC50 was determined to be in the range of > 220 mg/L and < 464 mg/L (nominal concentrations). Fish exposed to a concentration of 215 mg/L showed symptoms of toxicity (apathy, tumbling, gasping and narcotic-like state) at all exposure times.
 Fish 
The acute toxicity of 2-phenoxyethanol (purity only 85.7% with 12% 2-phenoxyethanol) to the zebra fish (Danio rerio) was tested in a semi-static system at nominal concentrations of 0, 100, 180, 300, 520 and 900 mg/L. (ECHA, 2018) The 96h LC50 was determined as 154 mg/L (mean measured concentration). Further supporting studies reported endpoints for Ptychocheilus oregonensis in a semi-static saltwater system with an LC50 (48 h) of 135 mg/L (nominal), an LC50 (96 h) of 366 mg/L (nominal) for fathead minnows in a static freshwater system, an LC50  (96 h) of 478 mg/L (nominal) for fathead minnows in a static freshwater system, a LOEC (96 h) of 370 mg/L (nominal) for Lepomis macrocirus in a freshwater flow-through system and an LC50 (8 h) of 333 mg/L (nominal) for Oncorhynchus nerka in a freshwater system. 
    Aquatic Invertebrates
 Water Flea
Daphnia magna were evaluated for acute toxicity to 2-phenoxyethanol. (MRID 50321641) Daphnids were exposed to nominal test concentrations of 100, 320, or 750 mg/L. The 48 hr EC50 for immobility was calculated to be 460 mg/L (95% confidence interval of 394 to 538 mg/L).
A second acute study (ECHA, 2018) on daphnia magna was performed under static conditions for 48 hours, testing the immobility of daphnids at nominal concentrations of 0, 31.3, 62.5, 125, 250, 500 mg/L. No immobility was observed for any of the tested concentrations. The EC50 after 48 hours was > 500 mg/L. 
The chronic toxicity of 2-phenoxyethanol on the reproduction of the water flea Daphnia magna was determined in a semi-static test (ECHA, 2018). Daphnids were exposed to nominal concentrations (0, 10, 23, 50, 110 and 220 mg/L) of 2-phenoxyethanol for 21 days. Reproduction (young animals), swimming ability, length and weight of the parent animals were measured. The 21-day NOEC values for 2-phenoxyethanol in the reproduction test were (nominal and measured concentrations) 10 mg/L for reproduction (9.43 mg/L measured), and 50 mg/L for weight and for length (49.2 mg/L measured). The LOEC values were 23 mg/L for reproduction (22.5 mg/L measured), and 110 mg/L for weight and length (nominal and measured), the LC0 value for swimming ability of the adult animals was >= 220 mg/L (>= 221 mg/L measured).

 Crustacea
The acute toxicity of 2-phenoxyethanol to the marine species Chaetogammarus marinus was determined in a saltwater static system. The resulting 48 h and 96 h LC50 values were 941 mg/L (nominal) and 357 mg/L (nominal), respectively.

    Algae (ECHA, 2018)

An algal growth inhibition test was performed on the toxicity of 2-phenoxyethanol to the freshwater algae Scenedesmus subspicatus. The toxicity was determined in a static system at the nominal concentrations 0, 7.81, 15.6, 31.3, 62.5, 125, 250 and 500 mg/L resulting in an ErC50 for growth after 72 hours of > 500 mg/L and a NOEC of >= 500 mg/L.

Another study examined the inhibitory effects of 2-phenoxyethanol on biomass yield and growth rate of Scenedesmus subspicatus. The toxicity was determined in a static system at nominal concentrations of 0, 70, 120, 200, 360, 600 and 1000 mg/L resulting in a 72-hr EyC50 for biomass of 443 mg/L and a 72-hr EyC10 of NOEC of 159 mg/L. The 72-hr ErC50 based on growth rate was 625 mg/L and the 72-hr ErC10 was 333 mg/L. The 72-hr NOEC based on growth rate was 70 mg/L.

    Soil organisms
                                                                               
 Earthworm (ECHA, 2018)
                  
The key study investigated the acute toxicity of 2-phenoxyethanol (purity 99.9%) to earthworms (Eisenia fetida) according to OECD Test Guideline 207. The clitellated adult earthworms were exposed to test substance treated artificial soil for 14 days. The 14 d LC50 based on mortality was determined to be >1000 mg/kg soil (dried weight-dw).

In a supporting study, the toxicity of 2-phenoxyethanol to earthworms was tested according to EU Method C.8. In a limit test, Eisenia fetida were exposed to 1170 mg/kg test substance (purity 85.7%, contaminated with phenoxydiethanol) in waterfree substrate. The LC0 based on mortality was reported as > 1170 mg/kg soil dw.

 Micro-organisms (ECHA, 2018)
A test on long-term potential effects of 2-phenoxyethanol on nitrogen transformation was conducted according to OECD Test Guideline 216. Soil samples mixed with lucerne meal as source of nitrogen and placed in test vessels were exposed to 2-phenoxyethanol (purity 99.9%) at the following concentrations 0, 62.5, 125, 250, 500 and 1000 mg/kg soil dw in the dark for 28 days. The results were a 28-day long-term EC10 of 951 mg/kg soil dw, with a corresponding EC50 of >1000 mg/kg soil, based on nitrate formation.
Another test on short- and long-term potential effects of single exposure to 2-phenoxyethanol on carbon transformation activity of soil microorganisms was conducted according to OECD Test Guideline 217. Soil samples were exposed to the test substance at the following (nominal) concentrations: 0, 62.5, 125, 250, 500 and 1000 mg/kg soil dw. Glucose-induced respiration rates were measured for 12 hours by measuring negative pressure (Oxi-Top) at 20°C in darkness. The effect on carbon dioxide evolution resulted in a 28-day long-term EC10 (and EC50) of > 1000 mg/kg soil dw, and a 7-day short-term EC10 of 147 mg/kg soil dw (with 95% confidence limit of 41 to 529 mg/kg soil dw).
    Terrestrial Plants (ECHA, 2018)

The effects of 2-phenoxyethanol on Brassica napus, Avena sativa and Vicia sativa were investigated according to OECD Test Guideline 208 under GLP. Soil samples were exposed to 2-phenoxyethanol at nominal concentrations of 0, 62.5, 125, 250, 500 and 1000 mg/kg soil dw. Five days after exposure, the seeds were sown and the emerging seedlings were recorded as well as 14 days after emergence of all seedlings, the dry weight, fresh weight and shoot length were determined. The NOEC values based on emergence rate, dry weight, fresh weight and shoot height were:  Avena sativa-250, 63, <63 and <63 mg/kg soil dw, respectively; 250, <63, <63 and <63 mg/kg soil dw, respectively, for Brassica napus; and 63, <63, <63 and <63 mg/kg soil dw, respectively, for Vicia sativa (most sensitive species). The EC50 values based on emergence rate, dry weight, fresh weight and shoot height were 466, 235, 166 and 203 mg/kg soil dw, respectively, for Avena sativa; 361, 37, 34 and 40 mg/kg soil dw, respectively, for Brassica napus (most sensitive species); and 64, 107, 83 and >251 mg/kg soil dw, respectively, for Vicia sativa.

In a supporting study, the inhibiting effect of 2-phenoxyethanol on seedling emergence and growth was investigated for three terrestrial plants according to OECD Test Guideline 208. Seeds were planted in soil having test substance (purity 85.7%, contaminated with phenoxydiethanol) concentrations of 0, 1, 10 and 100 mg/kg soil dw. The NOEC was based on seedling emergence while the EC50 value was based on growth inhibition. For Brassica alba, a NOEC (17d) of 100 mg/kg soil dw and an EC50 (17d) of 40 mg/kg soil dw were reported. For Lepidum sativum, a NOEC (17d) of >100 mg/kg soil dw and an EC50 (17d) of 38 mg/kg soil dw were reported; and for Triticum aestivum, a NOEC (17d) of >100 mg/kg soil dw and an EC50 (17d) of 73 mg/kg soil dw were reported.

    RISK CHARACTERIZATION

2-Phenoxyethanol is rapidly and extensively absorbed in animals and humans after oral administration with >90% of the administered dose excreted in urine within 24 hours of exposure. Following oral and dermal exposure the terminal hydroxyl group of 2-phenoxyethanol is metabolized, mainly in the liver, by alcohol dehydrogenase (ADH) to 2-phenoxyacetaldehyde and then by aldehyde dehydrogenase (ALDH) to 2-phenoxyacetic acid (PhAA).

2-Phenoxyethanol exhibits low levels of acute toxicity. Acute studies in rats showed oral LD50 ranging from 1,260 to >2,500 mg/kg. The dermal LD50 in two rabbit studies were >2200 and >3653 mg/kg. A third dermal study in rats determined the LD50 to be 14391 mg/kg. The inhalation LC50 in the rat was >1000 mg/m[3]. 2-Phenoxyethanol is considered to be an eye irritant and a mild skin irritant. However, it was not found to be a dermal sensitizer. 

Several repeat-dose oral, dermal, and inhalation toxicity studies have been conducted on rats, mice, and rabbits. Hemolysis was seen in both the 10-day rabbit gavage study at doses of 100 mg/kg/day and the 14-day rat drinking water study at doses of 510 and 795 mg/kg/day for males and females, respectively. There were no hemolytic effects seen in mice treated for 14 days with drinking water at dose up to and including 2340 and 2930 mg/kg/day for males and females, respectively. 
Two 90-day drinking water studies were conducted in rats and mice. Changes in histopathology of the kidney and bladder (i.e., urothelial hyperplasia of the renal pelvis and urinary bladder transitional epithelial hyperplasia) were observed in rats dosed with 10000 mg/L and above. Urea nitrogen was increased in both sexes at 20000 mg/L and at 10000 mg/L in females. In addition, statistically significant reductions in RBC, hemoglobin, and platelets were observed at >=10000 mg/L. 
In mice, changes in red blood cell parameters in females (hemoglobin, MCHC, and MCV) and males (reticulocytes) treated with 20000 mg/L suggest a slight hemolytic anemia at the high dose. Changes in clinical chemistry parameters (i.e., decreases in cholesterol and phospholipid at doses of > 5,000 ppm in males) may suggest a treatment-related effect on the liver including, although there was no evidence of any histopathology in the liver and no increase in liver enzymes (GPT, GOT). Relative increases of kidney weight occurred in both sexes at higher dose levels (>= 10000 mg/L). While it is possible that the liver-related changes in cholesterol and phospholipid are not adverse, these findings in males were very conservatively treated as an effect. 
Two more 90-day studies in rats were reported in the database. In the gavage study, there were several non-treatment related deaths in various dose groups indicating possible poor husbandry. There were no details provided on the purity of the test substance and therefore, this study is of limited value and not reliable. In the final 90-day study reviewed, 2-phenoxyethanol was administered in the diet to rats at dose levels up to and including, 697 and 939 mg/kg/day in male and females, respectively. No treatment related effects were observed. 
Two chronic (104 weeks) drinking water studies were conducted in rats and mice. There was no evidence of carcinogenicity in either study. The rat study indicated that the kidney was the target organ. The increased kidney weight and the increased incidences of urothelial hyperplasia of the pelvis, and papillary mineralization and necrosis were noted in the 10000 mg/L (510 mg/kg/day) males, while the increased kidney weight was observed in the females treated with 10000 mg/L (795 mg/kg/day). 
In the second chronic/carcinogenicity study, significant effects on body weight gain indicate that the maximum tolerated dose was exceeded in male mice at 10,000 mg/L (body weight 84% of controls) and in females at 20,000 mg/L (body weight 79% of controls). 
A 90-day dermal study in rabbits was also conducted. No effects of treatment were observed at the highest dose tested, 500 mg/kg/day. A 2-week inhalation study in rats showed respiratory tract effects in animals dosed with 246 mg/m[3] or 1070 mg/m[3]. Morphological changes indicating irritation potential of the test compound were found in nasal cavity, larynx, and lung of male and female mid- and high concentration animals. 

No effects on infants and children were seen in reproductive (oral) or developmental (oral and dermal) studies in the absence of maternal effects at the limit dose of 1000 mg/kg/day. In a two-generation reproductive study there was slight effect on fertility, but this was seen at very high doses (4000 mg/kg/day). Evidence of significant toxicity to the offspring was observed when 2-phenoxyethanol was administered at the mid- and high-dose level (i.e., 2000 mg/kg/day and 4000 mg/kg/day). Parental toxicity was also reported at the mid- and high-dose level. In the two developmental studies, 2-phenoxyethanol was administered to the clipped skin of rabbits and by gavage in rats. No evidence of developmental toxicity was observed. 
There is no evidence that exposure to 2-phenoxyethanol suppresses or otherwise harms immune function in humans. No signs of neurotoxicity were reported in acute or repeat-dose oral studies. There were also no signs of carcinogenicity in the database including the 2 year feeding studies. Similarly, all tests were negative for genotoxicity and mutagenicity. The available data suggests that 2-phenoxyethanol is not carcinogenic.
Result indicate that rabbit is the most sensitive species due mainly to its susceptibility to hematoxic effects. Target organs in rats and mice were the kidney and liver, most likely due to an extensive first-pass metabolism and formation of high amounts/concentrations of 2-phenoxyacetic acid in the systemic circulation. Hematotoxicity in rats and mice was less pronounced than in rabbits and was not seen to be an adverse effect in long-term studies, potentially due to adaptation over time.
The proposed use pattern for 2-phenoxyethanol is as a food use pesticide inert ingredient used pre- and post- harvest when ready for use, the end-use concentration is not to exceed 0.2% by weight. Therefore, dietary (oral) and residential (dermal) exposure is possible. The dietary assessment for 2-phenoxyethanol showed that children 1-2 years old would be the highest exposed subgroup with 0.00007% of the cRfD. 

2-Phenoxyethanol is approved for use as a nonfood inert ingredient. Residential pesticide products currently containing 2-phenoxyethanol include antimicrobial cleaning products and pet products. 2-Phenoxyethanol is also found in non-pesticidal residential products such as paints and cosmetic. Therefore, the Agency assessed these scenarios to determine exposure and to assess aggregate exposure to 2-phenoxyethanol. The submitter mentioned the potential use of this inert ingredient in residential turf products; therefore, the Agency also assessed the use of 2-phenoxyethanol in residential turf products.  

The endpoint used for oral exposure was 369 mg/kg/day based on the 90-day drinking water study in rats. The short- and long- term inhalation POD of 48.2 mg/m3 (~12.7 mg/kg/day) was based on a 14-day inhalation study which showed respiratory effects at 246 mg/m3 (~70 mg/kg/day). The dermal endpoint, on the other hand, is from a dermal study. The effects for each route of exposure are not the same, therefore, the route specific daily doses were not combined. 

Modeling scenarios showed the lowest MOE was for residential handler exposure to paint at 3% in formulation applied via an airless sprayer. This conservative exposure scenario resulted in a dermal MOE of 170. As the Agency is concerned with MOEs below 100 (i.e., intraspecies uncertainty factor of 10X and the interspecies uncertainty factor of 10X); therefore, the Agency does not have concern for residential exposure to 2-phenoxyethanol at this time. 
When aggregating residential and dietary exposure to 2-phenoxyethanol, EPA determines whether pesticide exposures are safe by comparing aggregate exposure estimates to the PAD. Risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the MOE called for by the product of all applicable UFs is not exceeded. The estimated MOE for aggregate exposure to 2-phenoxyethanol was above the Agency level of concern of 100 for adults and children; therefore, the Agency does not feel that the use of 2-phenyoxyethanol at 0.02% in pesticide products poses a safety risk to adults or children and it is subsequently, considered safe when used under the conditions in this risk assessment. 
Results of the worker exposure assessment indicate acceptable level of risk for applicator scenarios as well as for mixer/loaders. Post-application exposure assessments also indicate acceptable MOEs at all re-entry intervals. The results of the risk assessments coupled with the other information contained within this petition is sufficient to demonstrate that proposed use of 2-phenoxyethanol as an inert ingredient in pesticide formulations will not result in unreasonable adverse effects to humans.
2-Phenoxyethanol is characterized by high water solubility, low octanol-water partition coefficient, and low Henry's law constant. Based on the results of several screening studies, 2-phenoxyethanol is classified as readily biodegradable. Fugacity modeling predicts that 2-phenoxyethanol will reside mainly in the soil and water. Overall, 2-phenoxyethanol is considered to have low potential for environmental persistence.
Various ecotoxicity and environmental fate studies were conducted with 2-phenoxyethanol. Available data on the toxic effects of 2-phenoxyethanol on aquatic organisms, microorganisms, terrestrial plants, and soil microorganisms show low potential to cause harm to the environment. Therefore, at this time the Agency considered the risk for ecotoxicity and the risk to environmental systems acceptable. 
Based upon the factors summarized above, the Agency approves the use of 2-phenoxyethanol under 40 CFR § 180.910 as an inert ingredient in pesticide formulations at a maximum concentration of 0.2% by weight. 






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Cosmetic Ingredient Review (CIR) (1990) Final Report on the Safety Assessment of Phenoxyethanol. Journal of The American College of Toxicology. Vol 9, Number 2 pg 259-277. 
ECHA (2017). REACH Database for, 2-phenoxyethanol https://echa.europa.eu/registration-dossier/-/registered-dossier/15160/1. Last accessed March 30, 2018.
US EPA (2000) by Fortmann, R C., N. Roache, A. Ng, and J.C S. Chang. Measurements of Volatile Organic Compounds and Particles During Application of Latex Paint with an Airless Sprayer. Presented at Engineering Solutions to IAQ Problems, Raleigh, NC, 7/17-19/2000. Retrieved on May 26, 2019 from https://nepis.epa.gov/Exe/ZyNET.exe/P100P6KU.TXT?ZyActionD=ZyDocument&Client=EPA&Index=2000+Thru+2005&Docs=&Query=&Time=&EndTime=&SearchMethod=1&TocRestrict=n&Toc=&TocEntry=&Qfield=&QfieldYear=&QfieldMonth=&QfieldDay=&IntQFieldOp=0&ExtQFieldOp=0&XmlQuery=&File=D%3A%5Czyfiles%5Cindex%20Data%5C00thru05%5CTxt%5C00000035%5CP100P6KU.txt&User=ANONYMOUS&Password=anonymous&SortMethod=h%7C-&MaximumDocuments=1&FuzzyDegree=0&ImageQuality=r75g8/r75g8/x150y150g16/i425&Display=hpfr&DefSeekPage=x&SearchBack=ZyActionL&Back=ZyActionS&BackDesc=Results%20page&MaximumPages=1&ZyEntry=1&SeekPage=x&ZyPURL#
US EPA's Office of Pesticide Programs (OPP), Antimicrobials Division (AD). Memorandum dated March 23, 2018, Science Review of the AEATF II Brush/Roller Painting Human Exposure Monitoring Study (AEATF II Project ID AEA09; MRID 50521701). 

US EPA's Office of Pesticide Programs (OPP), Health Effect Division (HED) 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, https://www.epa.gov/sites/production/files/2015-08/documents/usepa-opp-hed_residential_sops_oct2012.pdf

                                  Appendix A


U.S. EPA                                                        Ver. 3.16, 03-08-d
DEEM-FCID Chronic analysis for INERTS- 2-PHENOXYETHANOL    NHANES 2003-2008 2-day
Residue file name: C:\Users\dsunderl\OneDrive - Environmental Protection Agency (EPA)\IN-11069\models\IN-11069 INERTS_57ACTIVE_100PPBH2OREV.R08
                                                     Adjustment factor #2 used.
Analysis Date 08-01-2019/10:29:32     Residue file dated: 08-01-2019/10:27:47
Reference dose (RfD, Chronic) = 3.69 mg/kg bw/day
COMMENT 1: Inert 57 active ingredients + drinking water (100ppb) at 0.02% in formulation on all crops
===============================================================================
                    Total exposure by population subgroup
-------------------------------------------------------------------------------

                                                    Total Exposure
                                         -----------------------------------
          Population                         mg/kg             Percent of   
           Subgroup                       body wt/day             Rfd       
--------------------------------------   -------------       ----------------
Total US Population                         0.000076                 0.0%
Hispanic                                    0.000083                 0.0%
Non-Hisp-White                              0.000074                 0.0%
Non-Hisp-Black                              0.000070                 0.0%
Non-Hisp-Other                              0.000089                 0.0%
Nursing Infants                             0.000099                 0.0%
Non-Nursing Infants                         0.000184                 0.0%
Female 13+ PREG                             0.000066                 0.0%
Children 1-6                                0.000219                 0.0%
Children 7-12                               0.000091                 0.0%
Male 13-19                                  0.000054                 0.0%
Female 13-19/NP                             0.000054                 0.0%
Male 20+                                    0.000056                 0.0%
Female 20+/NP                               0.000061                 0.0%
Seniors 55+                                 0.000061                 0.0%
All Infants                                 0.000158                 0.0%
Female 13-50                                0.000059                 0.0%
Children 1-2                                0.000282                 0.0%
Children 3-5                                0.000194                 0.0%
Children 6-12                               0.000100                 0.0%
Youth 13-19                                 0.000054                 0.0%
Adults 20-49                                0.000058                 0.0%
Adults 50-99                                0.000061                 0.0%
Female 13-49                                0.000059                 0.0%

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