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




							OFFICE OF CHEMICAL SAFETY 							                   AND POLLUTION PREVENTION



January 9, 2015


MEMORANDUM



SUBJECT:	PC Code: 711393, 711394; Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts; Human Health Risk Assessment and Ecological Effects Assessment to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations.


All PC Code: 711933, 711934  
DP Barcode: N/A  
Decision No.:  N/A
Regulatory Action:  Inert Tolerance Exemption; 40 CFR 180.920
Petition No: IN-10671
All CAS Reg. No: 68954-91-6 and 68815-56-5
Inert Tracking No: N/A



		
FROM:	Lisa Austin, Ph.D., Toxicologist  
		Chemistry, Inert and Toxicology Assessment Branch (CITAB)
		Registration Division (7505P)

THROUGH:	Kerry Leifer, Team Leader
		Chemistry, Inert and Toxicology Assessment Branch (CITAB)
		Registration Division (7505P)

TO:		PV Shah, Ph.D., Branch Chief
		Chemistry, Inert and Toxicology Assessment Branch (CITAB)
		Registration Division (7505P)

EXECUTIVE SUMMARY

   EPA received a petition (IN-10671) from Exponent, on behalf of BASF, requesting an exemption from the requirement of a tolerance for the use of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts specifically, for CAS Reg. Nos. 68954-91-6 and 68815-56-5 as inert ingredients used as surfactants in pesticide products used for seed treatment not to exceed 0.125% weight/weight on all food, feed and oil crops under 40 CFR part 180.920.  EPA published the notice of filing (NOF) for this petition in the Federal Register on September 5, 2014 (79 FR 53009).  No substantial comments were received in response to this notice.
   
   Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts, CAS Reg. No. 68954-91-6 consists of a C10-C12 linear alkyl alkoxy carbon chain and average polyethoxylation (POE) =5 and CAS Reg. No. 68815-56-5 consists of a C10-C16 linear carbon chain and average polyethoxylation (POE) = 4.5.  Data are not available for CAS Reg. No. 68954-91-6.  However, subchronic studies are available on CAS Reg. No. 68815-56-5.  Since CAS Reg. No. 68954-91-6 (linear alkyl chain length C10-C12) is a component of CAS Reg. No. 68815-56-5 (linear carbon chain length C10-C16) the available data were used to bridge data to CAS Reg. No. 68954-91-6.  These studies are sufficient to assess the subchronic toxicity of CAS Reg. No. 68954-91-6 as the only difference between the compounds is the range of carbon chain lengths and the testing of the broader carbon chain length of C10-C16 in CAS Reg. No. 68815-56-5 would include any effects that might be seen in tests of the narrower - linear carbon chain length of C10-C12 (in CAS Reg. No. 68954-91-6).  Reproduction and developmental toxicity studies were not available for review for either compound, however, based on analogy to well-known metabolic pathways for other linear alkyl ethers, the major pathway in the primary metabolism of both compounds is expected to be oxidative-reductive ether cleavage. Therefore, the metabolism of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers,) disodium salts  would result in the formation of the corresponding alkyl alcohol alkoxylate such as C12AE6 (CAS Reg. No. 9002-92-0), a substance previously reviewed by the Agency.  C12AE6 is similar to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts in carbon chain length and average ethoxylation.  Therefore, C12AE6 reproduction and developmental toxicity were used as surrogate data for potential reproductive and developmental effects of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.

   The acute oral and dermal toxicity of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts is low (toxicity category IV).  The LD50 is >5000 mg/kg in the rat (oral) and rabbit (dermal).  They are irritating to the eyes and non-irritating to the skin in rabbits.  They are not dermal sensitizers.  Acute inhalation toxicity studies were not available.

	Subchronic toxicity studies were available in the rat and dog for CAS Reg No. 68815-56-5 was administered via the diet in both studies.  In a 90 day oral toxicity study in rats, decreased body weight gain was observed at 4% (equivalent to 2000 mg/kg/day (LOAEL)) of CAS Reg No. CAS 68815-56-5.  The NOAEL was 1% (equivalent to 500 mg/kg/day).  In a 90 day toxicity study in dogs, toxicity was not observed at 500 mg/kg/day (NOAEL), the highest dose tested. 

	A developmental toxicity study via gavage was available in rabbits.  C12AE6 (CAS Reg. No. 9002-92-0), a postulated metabolite of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, caused ataxia and decreased body weight gain in maternal animals at 100 mg/kg/day.  The maternal NOAEL was 50 mg/kg/day.  No data were available on fetal effects; therefore, this study was considered unacceptable.

	In a two-generation reproduction study in rats, C12AE6 (CAS Reg. No. 9002-92-0), a postulated metabolite of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, caused decreased body weight gain in parental animals at 0.05% (equivalent to 250 mg/kg/day).  The NOAEL was 0.1% (equivalent to 50 mg/kg/day).  Offspring toxicity was manifested as decreased weight gain in pups, increased embryo lethality and soft tissue anomalies at 0.5% (equivalent to 250 mg/kg/day).  The NOAEL was 0.1% (equivalent to 50 mg/kg/day).  Although, fetal qualitative susceptibility is observed in this study concern, is low because it occurs only in the presence of maternal toxicity.

   Chronic/carcinogenicity studies with poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts were not available.  However, a DEREK structural alert analysis was conducted with poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C12)-alkyl ethers, disodium salt (CAS Reg No. 68954-91-6) and indicated no structural alerts for carcinogenicity or mutagenicity.  Therefore, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are not expected to be carcinogenic.

	Mutagenicity studies were not available for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  However, an Ames test is available on CAS Reg. No. 68439-50-9, a surrogate alkyl alcohol alkoxylate.  The test was negative.  

   Neurotoxicity and immunotoxicity studies were not available for review.  However, evidence of neurotoxicity and immunotoxicity was not observed in the submitted studies.
   
   Metabolism studies on poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts were not available for review.  However, based on analogy to known metabolic pathways for linear alkyl ethers, the major pathway in the primary metabolism is expected to be oxidative-reductive ether cleavage.  Therefore, the primary metabolism of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts occurs via oxidative-reductive ether hydrolysis resulting in the formation of linear alkyl alcohols and polyethylene glycol metabolites.  The alcohols would undergo oxidation by alcohol dehydrogenase and aldehyde dehydrogenase to generate a fatty acid metabolite that is degraded by β-oxidation to CO2 and H2O.  The polyethylene glycol metabolites would be degraded via oxidation by alcohol dehydrogenase and aldehyde dehydrogenase to generate a dienoic polyethylene ether acid that may be conjugated and excreted. Also, the alcohol function may be sulfated by sulfotransferases and excreted.   
   
   EPA has determined that reliable data show the safety of infants and children would be adequately protected if the 10x FQPA SF was retained to account for an incomplete database.
   
   There was no hazard attributable to a single exposure seen in the toxicity database for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  Therefore, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are not expected to pose an acute risk.  
   
   Chronic dietary risk assessments were conducted on poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts (CAS Reg. No. 38640-62-9) using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), Version 3.16.  The chronic analysis was based on a two-generation reproduction toxicity study in rats with a LOAEL of 250 mg/kg/day based on decreased body weight gain.  The NOAEL was 50 mg/kg/day.  The uncertainty factor of 100 (10x for intraspecies variability and 10x for inter species extrapolation) was used for the chronic endpoints.  The 10x FQPA SF was retained to account for an incomplete database.  One hundred percent crop treated was assumed, default processing factors and tolerance-level residues for all foods and use limitations of not more than 0.125% by weight in pesticide formulations.  Conservative estimated drinking water concentrations of (100 ppb) were incorporated directly into the dietary assessment.  The chronic dietary risk assessment shows that the chronic dietary risk estimates are not of concern (i.e., <100% cPAD).  For the U.S. population, the exposure for food and water utilized 5.1% of the cPAD.  The chronic dietary risk estimate for the highest exposed population subgroup, non-nursing infants, is 16.2 % of the cPAD.  RD has not identified any concerns for carcinogenicity relating to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts; therefore, a cancer dietary exposure assessment was not performed.
   
	Occupational handler and post-application risks are not of concern for all scenarios.  

	In a closed bottle biodegradability test on CAS Reg. No. 68815-56-5 biodegraded to 80.7% after 28 days.  Therefore, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are expected to biodegrade.  Also, CAS Reg. No. 68954-91-6 was over 90% biodegraded in seven days by a bacteria culture using the surface tension method.  They are also not expected to be acutely toxic to aquatic organisms based on a 96 hour acute toxicity study in rainbow trout. 

	Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. 
	
	Taking into consideration all available information on poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, CAS Reg. Nos. 68954-91-6 and 68815-56-5, EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, CAS Reg. Nos. 68954-91-6 and 68815-56-5.  Therefore, the establishment of an exemption from tolerance under 40 CFR 180.920 for residues of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts specifically, for CAS Reg. Nos. 68954-91-6 and 68815-56-5 when used as an inert ingredient in seed treatment pesticide formulations at a concentration not to exceed 0.125% by weight in the end-use formulation can be considered safe under section 408 of the FFDCA.    


1.	BACKGROUND

   On November 26, 2013 Exponent submitted a petition (IN-10671) on behalf of BASF, Inc. requesting an exemption from the requirement of a tolerance for the use of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts (PEG-AESDS) specifically, for CAS Reg. Nos. 68954-91-6 and 68815-56-5 as inert ingredients used as surfactants in pesticide products used for seed treatment not to exceed 0.125% weight/weight on all food, feed and oil crops under 40 CFR part 180.920.  EPA published the Notice of Filing for this petition in the Federal Register on September 5, 2014 (79 FR 53009).  No substantial comments were received in response to this notice.  
   
   This document provides an assessment of the risk to human health and the environment for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts (PEG-AESDS) specifically, for CAS Reg. Nos. 68954-91-6 and 68815-56-5 as inert ingredients used as surfactants in pesticide products used for seed treatment at a concentration not to exceed 0.125% by weight on all food, feed and oil crops.


2.	PHYSICAL AND CHEMICAL PROPERTIES


   The physicochemical data (Table 1) for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are based on the EPISuite physicochemical estimations for C12 (lauryl) alkyl ether chain length and POE = 5 which should be the major constituent of the mixture of CAS Reg. No. 68815-56-5, as postulated by the registrant.


Table 1.  Physical and Chemical Properties of Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts 
                                   Parameter
                                     Value
                                    Source
                                   Structure
                                       
                 As it appears in the Registrant's petition
                                 Chemical Name
Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts 
                                       
                                     CAS #
                           68954-91-6 and 68815-56-5
                              EPISuite Estimates
                                       
                               Molecular Weight
                                    616.72
                                       
                                 Common Names
                                   PEG-AESDS
                                       
                              Melting Point (°C)
                                    349.84
                                       
                             Boiling Point  (°C)
                                    831.50
                                       
                          Vapor Pressure (Pa at 25C)
                                   1.16E-18
                                       
                          Partition Coefficient (Kow)
                                     -4.91
                                       
                         Water Solubility @ 25C (mg/L)
                                      1E6
                                       
                             Henry's Law Constant
                          3.98 x 10-23 (atm m[3]/mol)
                                       


3.	Hazard Assessment

	Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts, CAS Reg. No. 68954-91-6 consists of a C10-C12 linear alkyl alkoxy carbon chain and average polyethoxylation (POE) =5 and CAS Reg. No. 68815-56-5 consists of a C10-C16 linear carbon chain and average polyethoxylation (POE) = 4.5.  Data are not available for CAS Reg. No. 68954-91-6.  However, subchronic studies are available on CAS Reg. No. 68815-56-5.  Since CAS Reg. No. 68954-91-6 (linear alkyl chain length C10-C12) is a component of CAS Reg. No. 68815-56-5 (linear carbon chain length C10-C16) the available data were used to bridge data to CAS Reg. No. 68954-91-6.  These studies are sufficient to assess the subchronic toxicity of CAS Reg. No. 68954-91-6 as the only difference between the compounds is the range of carbon chain lengths and the testing of the broader carbon chain length of C10-C16 in CAS Reg. No. 68815-56-5 would include any effects that might be seen in tests of the narrower - linear carbon chain length of C10-C12 (in CAS Reg. No. 68954-91-6).  Reproduction and developmental toxicity studies were not available for review for either compound, however, based on analogy to well-known metabolic pathways for other linear alkyl ethers, the major pathway in the primary metabolism of both compounds is expected to be oxidative-reductive ether cleavage. Therefore, the metabolism of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers,) disodium salts  would result in the formation of the corresponding alkyl alcohol alkoxylate such as C12AE6 (CAS Reg. No. 9002-92-0), a substance previously reviewed by the Agency.  C12AE6 is similar to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts in carbon chain length and average ethoxylation.  Therefore, C12AE6 reproduction and developmental toxicity were used as surrogate data for potential reproductive and developmental effects of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.

Acute Toxicity Studies

Table 2.  Acute Toxicity Profile of Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts
                                  Study Type
                                    Results
                               Toxicity Category
                               Acute Oral - rat
                           LD50 > 5,000 mg/kg bw
                                      IV
                             Acute Dermal - rabbit
                           LD50 > 5,000 mg/kg bw
                                      IV
                             Eye Irritation-rabbit
                                   Irritant
                                      IV
                           Dermal Irritation-rabbit
                                 Not Irritant
                                       
Dermal-species unknown
                               Not a sensitizer
                                       


90-day Oral Toxicity-Rat:
		
		In a 90 day oral toxicity study, random bred rats (20/sex/dose) were administered CAS Reg. No. 68815-56-5 via the diet at concentrations of 0% (vehicle control), 0.25, 1 or 4% (equivalent to 125, 500 or 2000 mg/kg/day).  The bodyweight and food consumption were recorded weekly.  Hematology analysis and urinalysis were conducted at 6 and 13 weeks.  Histopathological examination was performed on 10 rats/sex in the high dose and vehicle control groups.  Organ weights were taken for 10 rats/sex/dose level.  The effects in this study were limited to a significant decrease in body weight gain in males and females at 4% when compared with the vehicle control group.  The LOAEL was 4% (approximately equivalent 2000 mg/kg/day) based on decreased body weight gain.  The NOAEL was 1% (equivalent 500 mg/kg/day)(MRID 49219302).

90-day Oral Toxicity-Dog:

		In a 90 day oral toxicity study, purebred young beagle dogs (4/sex/dose) were administered CAS Reg. No. 68815-56-5 via the diet at concentrations of 0% (vehicle control), 0.12, 0.50 or 2% (equivalent to 0, 30, 125, 500 mg/kg/day).  The dogs were observed daily for clinical effects and body weight was recorded weekly.  Hematology parameters were evaluated pre-test and monthly thereafter.  Urinalysis and clinical chemistry were performed pre-test and at study termination.  Gross pathology was performed on all animals in all dose groups, and organ weights were recorded for all animals.  Histopathological evaluation was performed on all animals in all dose groups.  Slight but non-significant body weight loss was reported in the 2% dose group when compared to controls.  No changes in food consumption or feed efficiency were reported in any dose group.  No adverse treatment-related effects on hematology, organ weight, gross pathology, or histopathology were reported.  The NOAEL was 2% (equivalent to 500 mg/kg/day), the highest dose tested (MRID 49219301).  

Reproduction/Developmental Toxicity Studies

Rats
   
   In a two-generation study, developmental toxicity of C12AE6 (CAS Reg. No. 9002-92-0) in rats was evaluated.  Groups of 25 Charles River rats of both sexes were fed C12AE6 in the diet at dosage levels of 0, 0.05, 0.1 and 0.5%, equivalent to 0, 25, 50 and 250 mg/kg/day.  General behavior, appearance and survival were not affected by treatment. At the 0.5% dose level, adults and pups gained less weight than the control rats.  In the 0.5% dose group, there was a statistical increase in embryo lethality and soft tissue anomalies and at the 0.1% there was a statistical decrease in mean fetal liver weight.  Neither of these effects was considered to be treatment-related by the authors as they showed no dose response characteristics.  Although not specifically reported, it appeared that the NOAEL for maternal toxicity was 0.1% (equivalent to 50 mg/kg/day).  The LOAEL was 0.5% (equivalent to 250 mg/kg/day) based on decreased weight gain.  The NOAEL for developmental and teratogenic toxicity was set at the 0.1% (equivalent to 50 mg/kg/day) dose level.  The LOAEL was 0.5% (equivalent to 250 mg/kg/day) based on decreased weight gain in pups, increased embryo lethality and soft tissue anomalies.  No more detailed study information was provided (Talmage, 1994 as cite in MRID 49297601).

Rabbits
	
	In a study with C12AE6 (CAS Reg. No. 9002-92-0), twenty-five female rabbits were orally administered doses of 0, 50, 100 or 200 mg/kg/day of C12AE6 from day 2 to day 16 of gestation (NOT GIVEN)(Talmage, 1994).  Caesareans were performed on the 28th day of pregnancy. A definite increase in maternal toxicity, evidenced by ataxia and a slight decrease in body weight was observed at 100 and 200 mg/kg/day.  No effects were observed for parameters such as corpora lutea, implantations, number of live fetuses and spontaneous abortions.  Nine control rabbits and 31 treated rabbits died during the study.  Surviving rabbits at the 200 mg/kg/d dose level generally showed slight losses of body weight.  In seven treated and two control rabbits early deliveries were recorded.  The NOAEL for this study based on the maternal toxicity was therefore assumed to be greater than 50 mg/kg/day.  The LOAEL was 100 mg/kg bw/day based on ataxia and decreased body weight.  No more detailed study information was available (Little, 1977; Shell Chemicals Ltd., 2002; Talmage, 1994 as cited in MRID 49297601).  This study was considered unacceptable since fetal effects were not reported.

Chronic/Carcinogenicity 

	Chronic/carcinogenicity studies with poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts are not available.  However, a DEREK structural alert analysis was conducted with CAS Reg No. 68815-56-5 and indicated no structural alerts for carcinogenicity or mutagenicity.  Although, DEREK results indicated an equivocal structural alert for nephrotoxicity, kidney related toxicity was not observed in subchronic studies in rats and dogs treated with poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  Therefore, based on the lack of structural alerts for carcinogenicity and the absence of nephrotoxicity in submitted studies, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are not expected to be carcinogenic.


Mutagenicity 
   
	Mutagenicity studies were not available for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  However, an Ames test is available on CAS Reg. No. 68439-50-9, a surrogate alkyl alcohol alkoxylate.  The test was negative (as cited in the registrant's petition).  
    

Dermal Toxicity-Rat

	Neither dermal toxicity nor dermal absorption studies are available for review for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.

Neurotoxicity and Immunotoxicity

	Neither neurotoxicity nor immunotoxicity studies are available for review.  However, evidence of neurotoxicity or immunotoxicity was not observed in the submitted studies.
   
Metabolism-Rat

	Metabolism studies are not available for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  However, the registrant postulates that metabolism occurs as follows.  This summary is reproduced from the registrant's petition.  Based on analogy to known metabolic pathways for linear alkyl ethers, such as diethyl ethers, the major pathway in the primary metabolism can be postulated to be oxidative-reductive ether cleavage.

   ::Oxidative-reductive ether hydrolysis occurring through the action of CYP 450 2EI or ether oxidase in the liver results in the formation of sulfosuccinic disodium salt aldehyde and alkyl polyethoxylate ether metabolites.
   :: The sulfosuccinic disodium salt aldehyde metabolite should be readily oxidized by aldehyde dehydrogenase and generate sulfosuccinic acid and corresponding sodium salts which may be excreted directly and/or conjugated and excreted.
   
   ".... the PEG-AESDS the alkyl polyethoxylate ether metabolite is analogous to JITF CST 1 Alkyl Alcohol Alkoxylate (AAA) non-ionic surfactants and the Alcohol Alkoxylate surfactants reported by HERA (2007) and as such would undergo additional metabolism comparable to the AAA inert ingredients."
   
   ::Consistent with proposed AAA surfactant metabolism (HERA, 2007), the PEG-AESDS alkyl polyethoxylate ether metabolite may also undergo CYP 450 mediated- hydrolysis to generate Linear Alkyl Alcohols and Polyethylene Glycol (Average POE = 5) metabolites.  The C10-C12 (or C10-C16) Alcohol mixture would undergo sequential oxidation by alcohol dehydrogenase and aldehyde dehydrogenase to generate a fatty acid metabolite that is sequentially degraded by β-oxidation to CO2 and H2O.
   ::The Polyethylene Glycol (POE average n= 5) metabolites would be oxidatively degraded by well-documented pathways through sequential oxidation by alcohol dehydrogenase and aldehyde dehydrogenase (Webster et al., 2007) to generate a dienoic polyethylene ether acid that may be conjugated and excreted.  Alternatively, it is also reported that the alcohol function may be sulfated by sulfotransferases and excreted.
   
   
Table 3.  Toxicology Profile for Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts
                           Guideline No./ Study Type
                                     Doses
                                    Results
                                       
90 Day Oral Toxicity Study-rat
0, 0.25, 1 or 4% (equivalent to 125, 500 or 2000 mg/kg/day)
NOAEL = 1% (equivalent to 500 mg/kg/day).
LOAEL = 4% (2000 mg/kg/day) based on decreased body weight gain.
90 Day Oral Toxicity Study-Dog
0, 0.12, 0.50 or 2% (equivalent to 30, 125, 500 mg/kg/day)
NOAEL = 2% (equivalent to 500 mg/kg/day).
LOAEL was not established.
2-Generation Reproduction Study-Rats
0.05, 0.1 and 0.5%
(equivalent to equal to 25, 50 and 250 mg/kg/day)
Maternal NOAEL = 0.1% (equivalent to 50 mg/kg bw/day).
Maternal LOAEL = 0.5% (equivalent to 250 mg/kg/day) based on decreased weight gain.
Offspring NOAEL = 0.1% (equivalent to 50 mg/kg bw/day).
Offspring LOAEL =0.5% (equivalent to 250 mg/kg/day) based on decreased weight gain in pups, increased embryo lethality and soft tissue anomalies.
Developmental Toxicity Study-Rabbit
0, 50, 100 or 200 mg/kg bw/day
Maternal NOAEL = 50 mg/kg bw/day.
Maternal LOAEL = 100 mg/kg/day based on ataxia and decreased body weight.
Developmental NOAEL =Not reported.
Developmental LOAEL =Not reported.
Ames Test
Not Provided.
Negative


4. Toxicity Endpoint Selection

Table 4. -- Summary of Toxicological Doses and Endpoints for Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts for Use in Human Health Risk Assessment
Exposure/Scenario
Point of Departure and Uncertainty/Safety Factors
RfD, PAD, LOC for Risk Assessment
Study and Toxicological Effects
Acute dietary 
(General populations)
An acute effect was not found in the database therefore an acute dietary assessment is not necessary.
Chronic dietary 
(All populations)
NOAEL = 50 mg/kg/day  
UFA = 10x
UFH = 10x

FQPA SF = 10x
Chronic RfD = 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day
Two-Generation Reproduction Toxicity Study-Rat
LOAEL =250 mg/kg/day based on decreased weight gain.
Dermal short-, intermediate- and long-term (1 to 30 days, 1 to 6 months and  >6 months)
NOAEL = 50 mg/kg/day  
(Dermal absorption rate = 100%)
UFA = 10x
UFH = 10x

FQPA SF = 10x
LOC for MOE = 1000
Two-Generation Reproduction Toxicity Study-Rat
LOAEL =250 mg/kg/day based on decreased weight gain.
Inhalation short-, intermediate- and long-term (1 to 30 days, 1 to 6 months and  >6 months)
NOAEL = 50 mg/kg/day
(Inhalation absorption rate = 100%)

UFA = 10x
UFH = 10x

FQPA SF = 10x
LOC for MOE = 1000
Two-Generation Reproduction Toxicity Study-Rat
LOAEL =250 mg/kg/day based on decreased weight gain.
Cancer   (Oral, dermal, inhalation)
Based on a DEREK structural alert analysis and the lack of mutagenicity, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts are considered not likely to be carcinogenic.
UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFs = Extrapolation of subchronic to chronic exposure. FQPA SF = Food Quality Protection Act Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.

	The two-generation reproduction study in the rat was selected for all exposure scenarios and durations for this risk assessment.  The NOAEL in this study was 50 mg/kg/day.  The LOAEL was 250 mg/kg/day based on decreased weight gain.  This study represents the lowest NOAEL in the database in the most sensitive species.  The dermal and inhalation absorption rates were assumed 100%.  The standard inter- and intra-species uncertainty factors of 10x were applied.  
     
5.  Special Considerations for Infants and Children
     
   Section 408 of the FFDCA provides that EPA shall apply an additional margin of safety for infants and children in the case of threshold effects to account for prenatal and post natal toxicity and the completeness of the database on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children.  EPA concludes that the FQPA safety factor of 10x be retained for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts for the following reasons:
   
i.	The database is considered adequate for FQPA assessment.  The following acceptable studies are available:

      90-Day studies in the rat and dog (2)
      Two generation study in rat (1, on structurally similar chemical)
      

ii.	The reproduction toxicity study with poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts was not available for review.  However, a two-generation reproduction toxicity study in rats was available on a postulated metabolite that is similar in carbon chain length and average polyethoxylation.  In this study, parental toxicity (decreased weight gain) and offspring toxicity (decreased weight gain in pups, increased embryo lethality and soft tissue anomalies) were observed at 250 mg/kg/day.  Although, qualitative fetal susceptibility is observed, concern is low because fetal toxicity occurs only in the presence of maternal toxicity, there is a well-established NOAEL and the cRfD (0.050 mg/kg/day) is based on this study.  Therefore, these effects will be protected.  

iii.	Neurotoxicity studies were not available for review.  However, signs of potential neurotoxicity were not observed in any of the submitted studies.  EPA concluded that neurotoxicity and developmental neurotoxicity studies are not required at this time.  

iv.	Immunotoxicity studies were not available for review.  However, signs of potential immunotoxicity were not observed in any of the submitted studies.  EPA concluded that the immunotoxicity study is not required at this time.

v.	The dietary food exposure assessment utilizes proposed tolerance level or higher residues and 100% CT information for all commodities.  In addition, a conservative drinking water concentration value of 100 parts per billion (ppb) was used to assess the contribution to drinking water.  By using these screening-level assessments, chronic exposures/risks will not be underestimated.

Taking into consideration the available information, EPA concludes the additional 10X FQPA safety factor be retained to account for an incomplete database.


6. Exposure Assessment
   
1.  In evaluating dietary exposure to the poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, EPA considered exposure under the petitioned for exemptions from the requirement of a tolerance. EPA assessed dietary exposures from poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts in food as follows:
   
   i. Acute exposure.  No adverse effects attributable to a single exposure of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts were seen in the toxicity databases.  Therefore, an acute dietary risk assessment for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts is not necessary.
         
   ii. Chronic exposure.  In conducting the chronic dietary exposure assessment using the Dietary Exposure Evaluation Model DEEM - FCID[TM], Version 3.16, EPA used food consumption information from the U.S. Department of Agriculture's (USDA's) 2003-2008 National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA).  As to residue levels in food, no residue data were submitted for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  In the absence of specific residue data, EPA has developed an approach which uses surrogate information to derive upper bound exposure estimates for the subject inert ingredient.  Upper bound exposure estimates are based on the highest tolerance for a given commodity from a list of high use insecticides, herbicides, and fungicides.  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 dietary exposure assessment, the Agency assumed that the residue level of the inert ingredient would be no higher than the highest tolerance for a given commodity.  Implicit in this assumption is that there would be similar rates of degradation (if any) between the active and inert ingredient and that the concentration of inert ingredient in the scenarios leading to these highest levels of tolerances would be no higher than the concentration of the active ingredient.
   
         The Agency believes the assumptions used to estimate dietary exposures lead to an extremely conservative assessment of dietary risk due to a series of compounded conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingredient will overstate exposure.  The concentrations of active ingredient in agricultural products are generally at least 50 percent of the product and often can be much higher.  Further, pesticide products rarely have a single inert ingredient; rather there is generally a combination of different inert ingredients used which additionally reduces the concentration of any single inert ingredient in the pesticide product in relation to that of the active ingredient.  In the case of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, EPA used the aforementioned assumptions to conduct the dietary exposure assessment. 

          Second, the conservatism of this methodology is compounded by EPA's decision to assume that, for each commodity, the active ingredient which will serve as a guide to the potential level of inert ingredient residues is the active ingredient with the highest tolerance level. This assumption overstates residue values because it would be highly unlikely, given the high number of inert ingredients, that a single inert ingredient or class of ingredients would be present at the level of the active ingredient in the highest tolerance for every commodity.  Finally, a third compounding conservatism is EPA's assumption that all foods contain the inert ingredient at the highest tolerance level.  In other words, EPA assumed 100 percent of all foods are treated with the inert ingredient at the rate and manner necessary to produce the highest residue legally possible for an active ingredient.  In summary, EPA chose a very conservative method for estimating what level of inert residue could be on food, then used this methodology to choose the highest possible residue that could be found on food and assumed that all food contained this residue.  No consideration was given to potential degradation between harvest and consumption even though monitoring data shows that tolerance level residues are typically one to two orders of magnitude higher than actual residues in food when distributed in commerce.
          
          Accordingly, although sufficient information to quantify actual residue levels in food is not available, the compounding of these 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.
   
   iii. Cancer.  Based on a lack of structural alerts in a DEREK structural alert analysis and the lack of mutagenicity, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are not expected to be carcinogenic.  Therefore, a cancer dietary exposure assessment was not performed. 
   
2. Dietary exposure from drinking water.  For the purpose of the screening level dietary risk assessment to support this request for an exemption from the requirement of a tolerance for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, a conservative drinking water concentration value of 100 parts per billion (ppb) based on screening level modeling was used to assess the contribution to drinking water for chronic dietary risk assessments for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  These values were directly entered into the dietary exposure model.

3. From non-dietary exposure.  The term ``residential exposure'' is used in this document to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets).  However, residential exposure is not expected for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts as the use is for agricultural (seed treatment) purposes only.


7. Aggregate Risk and Determination of Safety
   
   EPA determines whether acute and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the acute population adjusted dose (aPAD) and chronic population adjusted dose (cPAD).  The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safety factors (SFs).  EPA calculates the aPAD and cPAD by dividing the POD by all applicable UFs.  For linear cancer risks, EPA calculates the probability of additional cancer cases given the estimated aggregate exposure.  Short-, intermediate-, and chronic-term 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.
   
   1.  Acute risk.  There was no hazard attributable to a single exposure seen in the toxicity database for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  Therefore, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts is not expected to pose an acute risk. 
   
   2.  Chronic risk. A chronic aggregate risk assessment takes into account exposure estimates from chronic dietary consumption of food and drinking water using the exposure assumptions discussed in this unit for chronic exposure.  Since there are no residential uses, chronic aggregate exposure takes into account food and water dietary exposures only.  The chronic dietary exposure from food and water to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts (CAS Reg. Nos. 68954-91-6 and 68815-56-5) are 5.1% of the cPAD for the U.S. population and 16.2% of the cPAD for non-nursing infants, the most highly exposed population subgroup.
   
   3.  Short- and Intermediate-term risks.  Short- and intermediate-term aggregate exposure takes into account short- and intermediate-term residential exposures plus chronic exposure to food and water (considered to be a background exposure level).  Since, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts has no uses that would result in short- or intermediate-term residential exposures, the Agency has determined that it is appropriate to aggregate chronic exposure through food and water only.
   
   4.   Aggregate cancer risk for U.S. population.  The EPA has not identified any concerns for carcinogenicity relating to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.   


8. Occupational Exposure/Risk Pathway

      A.	Occupational Handler Risk

	The occupational exposure/risk from commercial seed treatment was determined using the HED (Health Effects Division) "Occupational Exposure and Risk From Commercial Seed Treatment - Margin of Exposure (MOE) Calculation".  For this current assessment, default values were used for the amount of seed/day that are typically treated at commercial seed treatment facilities on soybean (Appendix).  The soybean crop was selected because it has the highest amount of seeds treated per day.  The occupational exposure assessment was based upon a toxicological No Observed Adverse Effect Level (NOAEL) of 50 mg/kg/day from a two-generation reproduction toxicity study in rats.  Therefore, the Agency assumes 100 % absorption via the dermal and inhalation routes of exposure.  

	The Agency believes that typically commercial seed treatment pesticide handlers would be exposed to short-term (1 - 30 days) exposures.  However, in the event that intermediate-term exposures (1 - 6 months) might occur this exposure scenario was included in the assessment.  

	A Margin of Exposure (MOE)  than 1000 is adequate to protect pesticide handlers and for post-application exposures to agricultural workers.  Provided that occupational pesticide handlers use label prescribed PPE (i.e., long pants, long sleeved shirt, shoes + socks and chemical resistant gloves such as nitrile, butyl, neoprene, barrier laminate, polyvinyl chloride or Viton), MOEs > 1000 and are therefore not of concern.  The MOEs presented are for short- (1-30 days) and intermediate-term (1 - 6 months) exposures.  

   RD traditionally considers a level of concern (LOC) for risk assessments to be an MOE of 100 based on the standard 10X inter and 10X intra species extrapolation safety factors.  An additional 10x FQPA safety factor was applied to account for an incomplete data.  Therefore, the LOC was for MOEs below 1000.
   
      B.	Occupational Post application Risk
	RD uses the term post-application to describe exposures that 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, including activities related to crop production, 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.
	Post-application exposure is not expected based on poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts' use as a seed treatment.  Therefore, post-application exposure was not assessed.  

9. Cumulative Exposure:

   Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the EPA consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity."  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts and any other substances and, this material does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts 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 the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.


10. Environmental Fate 

   In a Closed Bottle Ready Biodegradability Test (OECD 301D) an estimated 80.7% degradation of CAS Reg. No. 68815-56-5 occurred within 28-Days (Lee, 1993).  Also, using the surface tension method, it was found that CAS RN 68954-91-6 was over 90% biodegraded in seven days by a bacteria culture acclimated to the surfactant beforehand (MRID 49219305).


11. Ecotoxicity 
   
   A 96 hour acute toxicity study was conducted on rainbow trout with concentrations of CAS Reg. No. 68954-91-6 at 0, 62.5, 125, 250, 500 and 1000 ppm.  The LC50 = 218, demonstrating that CAS Reg. No. 68954-91-6 is not acutely toxic to rainbow trout (MRID 49219307).  A 96 hour acute toxicity study was also conducted with Bluegill Sunfish (MRID 49219304).  The fish were treated with 0, 24, 32, 42, 56 and 75 mg/l of CAS Reg. No. 68954-91-6.  The LC50=67 mg/l.  Therefore, based on these studies, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts surfactants are not expected to be acutely toxic to aquatic organisms.  
   
   
12. Environmental Justice

   Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).
   
   As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.


13.	Human Studies

   This assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide.  These studies, listed below, have received the appropriate ethical review for use in risk assessment.
   
   The PHED Task Force, 1998.  The Pesticide Handler Exposure Database (PHED), Version 1.1.  Task Force members: Health Canada, U.S. Environmental Protection Agency, the California Department of Pesticide Regulation, and the American Crop Protection Association; released August 1998.


14. Risk Characterization

   EPA received a petition (IN-10671) from Exponent, on behalf of BASF, requesting an exemption from the requirement of a tolerance for the use of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts specifically, for CAS Reg. Nos. 68954-91-6 and 68815-56-5 as inert ingredients used as surfactants in pesticide products used for seed treatment not to exceed 0.125% weight/weight on all food, feed and oil crops under 40 CFR part 180.920.  EPA published the notice of filing (NOF) for this petition in the Federal Register on September 5, 2014 (79 FR 53009).  No substantial comments were received in response to this notice.
   
   Poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, alkyl ethers, disodium salts, CAS Reg. No. 68954-91-6 consists of a C10-C12 linear alkyl alkoxy carbon chain and average polyethoxylation (POE) =5 and CAS Reg. No. 68815-56-5 consists of a C10-C16 linear carbon chain and average polyethoxylation (POE) = 4.5.  Data are not available for CAS Reg. No. 68954-91-6.  However, subchronic studies are available on CAS Reg. No. 68815-56-5.  Since CAS Reg. No. 68954-91-6 (linear alkyl chain length C10-C12) is a component of CAS Reg. No. 68815-56-5 (linear carbon chain length C10-C16) the available data were used to bridge data to CAS Reg. No. 68954-91-6.  These studies are sufficient to assess the subchronic toxicity of CAS Reg. No. 68954-91-6 as the only difference between the compounds is the range of carbon chain lengths and the testing of the broader carbon chain length of C10-C16 in CAS Reg. No. 68815-56-5 would include any effects that might be seen in tests of the narrower - linear carbon chain length of C10-C12 (in CAS Reg. No. 68954-91-6).  Reproduction and developmental toxicity studies were not available for review for either compound, however, based on analogy to well-known metabolic pathways for other linear alkyl ethers, the major pathway in the primary metabolism of both compounds is expected to be oxidative-reductive ether cleavage. Therefore, the metabolism of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers,) disodium salts  would result in the formation of the corresponding alkyl alcohol alkoxylate such as C12AE6 (CAS Reg. No. 9002-92-0), a substance previously reviewed by the Agency.  C12AE6 is similar to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts in carbon chain length and average ethoxylation.  Therefore, C12AE6 reproduction and developmental toxicity were used as surrogate data for potential reproductive and developmental effects of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.

   The acute oral and dermal toxicity of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts is low (toxicity category IV).  The LD50 is >5000 mg/kg in the rat (oral) and rabbit (dermal).  They are irritating to the eyes and non-irritating to the skin in rabbits.  They are not dermal sensitizers.  Acute inhalation toxicity studies were not available.

	Subchronic toxicity studies were available in the rat and dog for CAS Reg No. 68815-56-5 was administered via the diet in both studies.  In a 90 day oral toxicity study in rats, decreased body weight gain was observed at 4% (equivalent to 2000 mg/kg/day (LOAEL)) of CAS Reg No. CAS 68815-56-5.  The NOAEL was 1% (equivalent to 500 mg/kg/day).  In a 90 day toxicity study in dogs, toxicity was not observed at 500 mg/kg/day (NOAEL), the highest dose tested. 

	A developmental toxicity study via gavage was available in rabbits.  C12AE6 (CAS Reg. No. 9002-92-0), a postulated metabolite of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, caused ataxia and decreased body weight gain in maternal animals at 100 mg/kg/day.  The maternal NOAEL was 50 mg/kg/day.  No data were available on fetal effects; therefore, this study was considered unacceptable.

	In a two-generation reproduction study in rats, C12AE6 (CAS Reg. No. 9002-92-0), a postulated metabolite of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, caused decreased body weight gain in parental animals at 0.05% (equivalent to 250 mg/kg/day).  The NOAEL was 0.1% (equivalent to 50 mg/kg/day).  Offspring toxicity was manifested as decreased weight gain in pups, increased embryo lethality and soft tissue anomalies at 0.5% (equivalent to 250 mg/kg/day).  The NOAEL was 0.1% (equivalent to 50 mg/kg/day).  Although, fetal qualitative susceptibility is observed in this study concern, is low because it occurs only in the presence of maternal toxicity.

   Chronic/carcinogenicity studies with poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts were not available.  However, a DEREK structural alert analysis was conducted with poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C12)-alkyl ethers, disodium salt (CAS Reg No. 68954-91-6) and indicated no structural alerts for carcinogenicity or mutagenicity.  Therefore, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are not expected to be carcinogenic.

	Mutagenicity studies were not available for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  However, an Ames test is available on CAS Reg. No. 68439-50-9, a surrogate alkyl alcohol alkoxylate.  The test was negative.  

   Neurotoxicity and immunotoxicity studies were not available for review.  However, evidence of neurotoxicity and immunotoxicity was not observed in the submitted studies.
   
   Metabolism studies on poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts were not available for review.  However, based on analogy to known metabolic pathways for linear alkyl ethers, the major pathway in the primary metabolism is expected to be oxidative-reductive ether cleavage.  Therefore, the primary metabolism of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts occurs via oxidative-reductive ether hydrolysis resulting in the formation of linear alkyl alcohols and polyethylene glycol metabolites.  The alcohols would undergo oxidation by alcohol dehydrogenase and aldehyde dehydrogenase to generate a fatty acid metabolite that is degraded by β-oxidation to CO2 and H2O.  The polyethylene glycol metabolites would be degraded via oxidation by alcohol dehydrogenase and aldehyde dehydrogenase to generate a dienoic polyethylene ether acid that may be conjugated and excreted. Also, the alcohol function may be sulfated by sulfotransferases and excreted.   
   
   EPA has determined that reliable data show the safety of infants and children would be adequately protected if the 10x FQPA SF was retained to account for an incomplete database.
   
   There was no hazard attributable to a single exposure seen in the toxicity database for poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts.  Therefore, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are not expected to pose an acute risk.  
   
   Chronic dietary risk assessments were conducted on poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts (CAS Reg. No. 38640-62-9) using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), Version 3.16.  The chronic analysis was based on a two-generation reproduction toxicity study in rats with a LOAEL of 250 mg/kg/day based on decreased body weight gain.  The NOAEL was 50 mg/kg/day.  The uncertainty factor of 100 (10x for intraspecies variability and 10x for inter species extrapolation) was used for the chronic endpoints.  The 10x FQPA SF was retained to account for an incomplete database.  One hundred percent crop treated was assumed, default processing factors and tolerance-level residues for all foods and use limitations of not more than 0.125% by weight in pesticide formulations.  Conservative estimated drinking water concentrations of (100 ppb) were incorporated directly into the dietary assessment.  The chronic dietary risk assessment shows that the chronic dietary risk estimates are not of concern (i.e., <100% cPAD).  For the U.S. population, the exposure for food and water utilized 5.1% of the cPAD.  The chronic dietary risk estimate for the highest exposed population subgroup, non-nursing infants, is 16.2 % of the cPAD.  RD has not identified any concerns for carcinogenicity relating to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts; therefore, a cancer dietary exposure assessment was not performed.
   
	Occupational handler and post-application risks are not of concern for all scenarios.  

	In a closed bottle biodegradability test on CAS Reg. No. 68815-56-5 biodegraded to 80.7% after 28 days.  Therefore, poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts are expected to biodegrade.  Also, CAS Reg. No. 68954-91-6 was over 90% biodegraded in seven days by a bacteria culture using the surface tension method.  They are also not expected to be acutely toxic to aquatic organisms based on a 96 hour acute toxicity study in rainbow trout. 

	Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. 
	
	Taking into consideration all available information on poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, CAS Reg. Nos. 68954-91-6 and 68815-56-5, EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts, CAS Reg. Nos. 68954-91-6 and 68815-56-5.  Therefore, the establishment of an exemption from tolerance under 40 CFR 180.920 for residues of poly(oxy-1,2-ethanediyl), α-(3-carboxy-1-oxosulfopropyl)-ω-hydroxy, (C10-C16 )-alkyl ethers, disodium salts specifically, for CAS Reg. Nos. 68954-91-6 and 68815-56-5 when used as an inert ingredient in seed treatment pesticide formulations at a concentration not to exceed 0.125% by weight in the end-use formulation can be considered safe under section 408 of the FFDCA.   



REFERENCES


BASF. (2014) References to Support the Petition for Exemption from the Requirement of a Tolerance for Residues of Poly Glycol Alkyl Ether Sulfosuccinate Disodium Salts (PEG-AESDS) Surfactants as Inert Ingredients for Seed Treatment under 40 CFR 180.920.  BASF-TP-001-14-01. MRID 49297601.

Bowman, J.H. (1987). Acute toxicity of Ct-315-87 to bluegill sunfish (lepomis macrochirus).Unpublished report, Analytical Bio-Chemistry Laboratories, Inc, Columbia, Missouri, Report Number 36259. MRID 49219304.

Cooke, D. (1990). Aquatic toxicity tests versus onchorhyncus mykiss. Unpublished report, United States Testing Company, Inc., Hoeboken, New Jersey, Study Number 063102-10. MRID 49219307.

Lee, C. (1993). Ready Biodegradability-Closed Bottle Test. Unpublished report, Exxon Biomedical Sciences Inc., East Millston, New Jersey, Study ID 143994. MRID 49219305.

Tegeris, A.S. (1975) Ninety-day Dog Feeding Study on A-102.  Unpublished report, Pharmacopathics Research Laboratories, Inc., Laurel, Maryland, Study ID 75-101. MRID 49219301.

Underwood, P.C., Tegeris, A.S. (1975) Ninety-day Rat Feeding Study on A-102.  Unpublished report, Pharmacopathics Research Laboratories, Inc., Laurel, Maryland, Study ID 90R-A102. MRID 49219302.








APPENDIX


EPA                                                     Ver. 3.16, 03-08-d
US EPA                                       Ver. 3.16, 03-08-d
DEEM-FCID Chronic analysis for PEG-AESDS  NHANES 2003-2008 2-day
Residue file name: C:\Documents and Settings\laustin\My Documents\DEEM Version 3.16\INERTS_57ACTIVE_100PPBH2OREV PEG registrant.R08
                                                  Adjustment factor #2 used.
Analysis Date 09-11-2014/12:08:01     Residue file dated: 09-11-2014/12:07:14
Reference dose (RfD, Chronic) = .05 mg/kg bw/day
COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)
===============================================================================
                    Total exposure by population subgroup
-------------------------------------------------------------------------------

                                                    Total Exposure
                                         -----------------------------------
          Population                         mg/kg             Percent of   
           Subgroup                       body wt/day             Rfd       
--------------------------------------   -------------       ----------------
Total US Population                         0.002562                 5.1%
Hispanic                                    0.002511                 5.0%
Non-Hisp-White                              0.002613                 5.2%
Non-Hisp-Black                              0.002163                 4.3%
Non-Hisp-Other                              0.002966                 5.9%
Nursing Infants                             0.002510                 5.0%
Non-Nursing Infants                         0.008096                16.2%
Female 13+ PREG                             0.002380                 4.8%
Children 1-6                                0.004042                 8.1%
Children 7-12                               0.002310                 4.6%
Male 13-19                                  0.001770                 3.5%
Female 13-19/NP                             0.001949                 3.9%
Male 20+                                    0.002298                 4.6%
Female 20+/NP                               0.002577                 5.2%
Seniors 55+                                 0.002401                 4.8%
All Infants                                 0.006372                12.7%
Female 13-50                                0.002445                 4.9%
Children 1-2                                0.004779                 9.6%
Children 3-5                                0.003753                 7.5%
Children 6-12                               0.002457                 4.9%
Youth 13-19                                 0.001860                 3.7%
Adults 20-49                                0.002446                 4.9%
Adults 50-99                                0.002440                 4.9%
Female 13-49                                0.002442                 4.9%

-----------------------------------------------------------------------------

OCCUPATIONAL EXPOSURE AND RISK FROM COMMERCIAL SEED TREATMENT
MARGIN OF EXPOSURE (MOE) CALCULATION- Soybean

                               HANDLER EXPOSURES










                                                                               
                              Unit Exposure (UE)
                                  mg/lbs.ai 
                                Daily Exposure
                                   mg/kg/day
                Total Combined Short- and Intermediate-term MOE

                                                                               
                                    Dermal
                                  Inhalation
                                    Dermal
                                  Inhalation
                            Dermal & Inhalation

                                                           Loader / Applicator:
                                                                         0.0230
                                                                        0.00034
                                                                       0.000716
                                                                       0.000011
                                                                          68798
                                                                         Sewer:
                                                                         0.0062
                                                                        0.00023
                                                                       0.000193
                                                                       0.000007
                                                                         249725
                                                                        Bagger:
                                                                         0.0091
                                                                        0.00016
                                                                       0.000283
                                                                       0.000005
                                                                         173405
                                                           Multiple Activities:
                                                                         0.0420
                                                                        0.00160
                                                                       0.001308
                                                                       0.000050
                                                                          36829

