


EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: [P. V. Shah, (703) 308-1846]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

PP IN-10720. (EPA - HQ - OPP - 2014-0633). The firm Lewis and Harrison, 122 C Street NW., Suite 505, Washington, DC 20001 one behalf of the BASF Corporation 100 Park Ave., Florham Park, NJ 07932 requests to establish an exemption from the requirement of a tolerance for residues of methane sulfonic acid  (CAS No. 75-75-2) when used as a pesticide inert ingredient in pesticide formulations under §180.930 and §180.940(a)  when used as a acid cleaner in pesticide formulations with a limit of 3% when used on animals; and 15% (5,000 ppm in use-dilution solution) when used in antimicrobial formulations for food-contact surface sanitizing in public eating places, dairy-processing equipment, and food-processing equipment and utensils. The petitioner believes no analytical method is needed because  residue data, including an analytical method, is not pertinent or required for this petition since an exemption from tolerance is requested. 
  Contact: Registration Division/OPP.  
EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

   Residue Chemistry 
   
Residue data, including an analytical method, is not pertinent or required for this petition since an exemption from tolerance is requested. 
   
   Toxicological Profile 
   
An extensive safety data base has been complied on Methanesulfonic Acid (MSA). The safety data base includes acute, subchronic, developmental toxicity, and mutagenicity studies. Data have been submitted as part of the High Production Volume program in EPA's Office of Pollution Prevention and Toxics. Those data are summarized below. 
   
        1. Acute toxicity 
   
MSA is of low toxicity via the oral, dermal, and inhalation routes. At high concentrations, MSA can be severely irritating and corrosive to eyes and skin. MSA is not a dermal sensitizer. 
   
              a. Acute oral toxicity 
   
The acute oral toxicity of MSA ranges from 649 mg/kg (>750 mg/kg ♂; 461 mg/kg ♀) for anhydrous acid to 1,157.5 mg/kg (860.1 mg/kg ♂; 2,407.6 mg/kg ♀) for a 70% solution. >5,000 mg/kg.  
   	 
                     i. Acute oral toxicity in Sprague Dawley rats: Anhydrous MSA 
   
Groups of five rats/sex were exposed by oral gavage to 300, 500 and 750 mg/kg bw anhydrous (99.6% pure) MSA (Elf Atochem, 1988). Clinical signs included salivation, decreased activity, wobbly gait, breathing abnormalities, apparent hypothermia, decreased/no defecation, feces small in size, urine stain, hunched posture, unkempt appearance, rough haircoat, piloerection, extremities pale in color, de hydration, emaciation, distended abdomen, decreased food consumption and dark material around the facial area. Body weight loss was noted for one male at 300 mg/kg bw, two females and one male at 500 mg/kg bw, and one male at 750 mg/kg bw during the study day 0-7. Body weight loss was noted for one male each at 300 mg/kg bw and 750 mg/kg bw during the study day 7-14. Body weight gain was noted for all other surviving animals during the test period. Gross pathology findings observed in the animals that died included distension/abnormal content/reddened mucosa in the digestive tract, dark red/mottled lungs, blackish-purple spleens, dark red lymph nodes, stained glandular mucosa in the stomach and body fat depletion/discoloration/adhesions in the abdominal cavity. Necropsy findings on study day 14 for the animals that survived included abnormal content in the digestive tract and thickened mucosa in the stomach. The acute oral LD50 of anhydrous MSA in the male rat was greater than 750 mg/kg bw and 461 mg/kg bw in the female rat, and 649 mg/kg bw in the sexes combined. 
                    
				 ii. Acute oral toxicity in Sprague Dawley rats: 70% MSA 
   
Groups of five rats/sex were exposed by oral gavage to 500, 1000, and 1500 mg/kg bw 70% MSA in water (Elf Atochem, 1997a). Clinical signs included salivation, breathing abnormalities, wobbly gait, decreased activity, decreased defecation, rough haircoat, urine/fecal stain and dark material around the facial area. Body weight loss was noted for two animals at 1000 mg/kg bw during the study day 0-7 and for one animals each at 300 mg/kg bw 1000 mg/kg bw during the study day 7-14. Body weight gain was noted for all other surviving animals during the test period. Gross internal findings were observed only in the animals that died and included abnormal content and reddened/thickened mucosa and discoloration in the digestive tract, dark red foci on the liver and blackish-purple spleens. The acute oral LD50 of 70% MSA in the male rat was 860 mg/kg bw, 2408 mg/kg bw in the female rat, and 1158 mg/kg bw in the sexes combined. 

			 iii. Acute oral toxicity in Wistar rats: 98% MSA 
   
Five male rats were exposed by oral gavage to anhydrous MSA (98% pure) at 0.25, 0.5 ml/kg bw. Three rats were exposed at 1.0 ml/kg bw (Union Carbide, 1975). At all dose levels, rats were sluggish and presented an unsteady gait. In addition, at 1.0 ml/kg bw, deep breathing was immediately observed. At 0.25 ml/kg bw, 2/5 rats died. At 0.5 ml/kg bw 5/5 rats died; and at 1.0 ml/kg bw 2/3 rats died. Necropsy findings included livers mottled and burned, stomach burned, pylorus hemorrhaged and gas filled, intestines hemorrhaged, injected and gas filled, kidneys mottled and slightly congested. The LD50 was 0.28 ml/kg bw.  
   	 
 Acute dermal toxicity. 
   
The acute dermal toxicity of MSA ranges from greater than 200 to less than 2,000 mg/kg bw. 	
 
			i.  Acute dermal toxicity in New Zealand White rabbits: 70% MSA  

In an OECD 402 test, one male New Zealand White rabbit was dosed dermally at 1000 mg/kg bw of 70% MSA in water (Atofina, 2002). Since no irritation was noted, an additional nine animals (4 males and 5 females) were dosed. The test article was kept in contact with the skin for 24 hours. Animals were observed for mortality, toxicity and pharmacological effects, body weights recorded and animals were examined for gross pathology. Dermal responses were recorded 24 hours post-dosing and on days 7 and 14. All animals survived the treatment. Instances of few feces were the only abnormal signs noted during the observation period. Dermal responses were slight to well-defined on day 1, absent to severe on day 7 and absent to slight on day 14. Body weight changes and necropsy results were normal. The LD50 was greater than 1000 mg/kg bw. 

			 ii. Acute dermal toxicity in albino rabbits: Anhydrous MSD 
   
Six albino rabbits were exposed to 200 and 2000 mg/kg bw anhydrous MSA (purity not specified) under occlusive cover for 24 hours (Pennwalt, 1978). Skin contact with 2000 mg/kg bw caused intense and prolonged pain. The skin was dark grey in appearance and scattered  portions were separating from the subcutaneous tissues. Two rabbits died and 1 rabbit was euthanized. There were no mortalities at 200 mg/kg bw. Erythema was present over the entire trunk of each animal together with numerous small lesions. There were no clinical signs and animals gained weight during the 7-day observation period. The LD50 was greater than 200 and less than 2000 mg/kg bw. 
   
 Acute inhalation toxicity. 
   
No mortalities have been noted in several tests conducted with rats and mice. Insufficient volatility of methane sulfonic acid limits the actual exposure and therefore toxicity risks. 
   
 Acute inhalation toxicity in mice: 99% MSA 
   
In testing using 99% MSA, 20 mice were exposed to whole body atmospheric. No effects of any kind were discernible in any of the 20 mice either during or after exposure for 1 hour to saturated vapor (at 20°C). All showed normal gains in body weight during the subsequent 7 -day observation period.  
   
 Acute eye irritation. 
   
At high concentrations, MSA can be severely irritating and corrosive to eyes. 
   
 Acute eye irritation in albino rabbits: 99% MSA 
   
In acute eye irritation testing using rabbits, 0.1 mL of 99% MSA was instilled in the eyes of two animals in a single administration. One of the two animals had a rinse of the treated eye with flowing water (initiated 20 to 30 seconds after instillation and continued for one minute).  Animals were observed at 10 minutes; 1, 2, 3, 4, 24, 48, and 72 hours; and 4, 5, 6, and 7 days post-treatment.  
   
Each instillation caused excruciating pain. In the unwashed eye, the reaction involved all ocular tissues and occurred immediately; the conjunctivae became completely necrotic (white) without evident swelling; the iris was dilated with ragged edges and failed to 
react to light; and the cornea opacified completely within 24 hours. In the washed eye, the reaction did not differ significantly from that of unwashed eye. 
   
Under the conditions of this test, MSA is extremely corrosive to eye. 
   
              e. Acute skin irritation. 
   
At high concentrations, MSA can be severely irritating and corrosive to skin. 
   
                     i. Acute skin irritation in albino rabbits: 99% MSA 
   
In acute skin irritation testing with albino rabbits, six animals were dosed with either 200 or 2,000 mg/kg of 99% MSA utilizing a pre-fitted impervious sleeve for 24 hours. At the conclusion of the exposure period, the test substance was removed with a saturated solution of sodium bicarbonate and the animals were observed for a period of seven days.  
   
For animals treated with 2,000 mg/kg, skin contact caused intense and prolonged pain. At the end of exposure, the skin of each animal was dark gray in appearance and scattered portions were separating from the subcutaneous tissues. Two rabbits died the following night (28 hours after initial contact) and one rabbit was euthanized three days after treatment for humane reasons. 
   
At 200 mg/kg, no mortality was seen in any test animals. Erythema (score 2) was present over the entire trunk of each animal together with numerous small lesions which resembled acid burns. Animals nevertheless remained asymptomatic and gained body weight during the observation period. 
   
Under the conditions of this test, dermal exposure to 99% MSA at 2,000 mg/kg is highly toxic (severe skin injuries causing death), whereas 200 mg/kg exposure induces minor skin lesions (erythema and acid burns) but no systemic toxicity. 

				 ii. Acute skin irritation in mice: 99% MSA 
   
In acute skin irritation testing with mice, the tails of four anesthetized mice were immersed in 99% MSA to a depth of 4 cm. One hour later the tissue reaction was terminated by plunging the appendages into a saturated solution of sodium bicarbonate for a period of 30 seconds. The tail of each mouse was white when exposure was terminated and the appendage fell off in a day or two. 
Under the conditions of this test, 99% MSA is corrosive to mouse skin. 
   
              f. Skin sensitization 
   
MSA is not a dermal sensitizer. 
   
                     i. Skin sensitization in Hartley guinea pig: 70% MSA  
   
In sensitization testing using the Buehler method in Hartley guinea pigs, 20 animals per dose were exposed to the test substance for both the induction and challenge test. A control group of five males and five females was similarly dosed with water. The induction consisted of a 50% occlusive epicutaneous dose, while the challenge was a 25 % occlusive epicutaneous dose. There were three 6-hour applications in 14 days followed by the challenge exposure over 24 hours. 
   
The induction schedule consisted of the following: 
   
 On day 1, dermal application with 0.3 mL of test substance (treated group) or with the vehicle (control group) on the left shoulder. 
 On day 7, the same region received another topical application 
 On day 14, this same site was treated by a last topical application All these applications lasted approximately 6 hours. 
   
For the challenge dose, on day 28, all the animals received 0.3 ml of the test substance at the concentration of 25% in their right flank. The challenge exposure duration was 24 hours. There was no rechallenge and no positive control. 
   
Animals were examined 24 hours after each induction and the challenge application. 
   
A preliminary study was conducted in order to determine the concentrations to be tested in the main study. The irritation potential of 70% MSA at levels of undiluted, 50%, 25%, 10%, 5%, 2.5%, 1% and 0.5% was evaluated in two groups of four animals each. Four levels of test material were evaluated per animals. Dilutions were obtained with distilled water (w/v). Each application consisted of 0.3 mL of different solutions applied into a 25 mm Hill Top Chamber, which was placed on animals clipped back for 6 hours. The day after, animals were depilated and two hours later, examined for irritation. Another score was performed 40 hours after exposure. 
   
RESULTS OF PILOT STUDY: Undiluted 70% MSA produced grades of 2, 1 and +-, with edema, blanching and scabbing on two sites. Testing at 50%, 25%, 10%, 5%, 2.5% and 1% produced grades of +-, while 0.5% produced grades of +- and 0. Consequently, the 50% concentration was chosen for use at induction for the test group, since it caused no greater than mild to moderate primary irritation. Moreover, the 25% concentration was selected for challenge, because it caused no more than slight irritation. 
   
RESULTS OF DEFINITIVE TEST: None of the test animals responded with a skin grade that would have been suggestive of sensitization. 
Under the conditions of this test, MSA is not a sensitizer. 
   
 Genotoxicity 
   
No evidence of genotoxicity or chromosomal effects was observed in mutagenicity studies conducted with MSA.  
   
 Reverse Mutation: 98.8% MSA (anhydrous) and 70% MSA 
   
Bacterial reverse mutation assays (OECD 471) were conducted with anhydrous MSA (98.8% pure) (SNEAP, 1990) and 70% in water (Pennwalt, 1989a). No genotoxicity was observed on Salmonella typhimurium tester strains TA1535, TA1537, TA1538, TA98 and TA100 up to the cytotoxicity threshold of 5000 μg/plate in the presence and absence of metabolic activation. 
   
 Chromosomal Aberration: 70% MSA  
   
Groups of five mice/sex were given a single dose of MSA (70% in water) by oral gavage at 20, 100 or 500 mg/kg bw (Pennwalt, 1989b). Concurrent vehicle and positive control group of mice were similarly dosed with distilled water or chlorambucil, respectively. The test method was comparable to OECD 474. There was no evidence of induced chromosomal or other damage leading to micronucleus formation in polychromatic erythrocytes of treated mice 24, 48 or 72 hours after oral administration. 
   
 Reproductive and developmental toxicity. 
            
No reproductive or developmental effects were noted in any of the tests conducted. 
   
 Reproductive toxicity. 
   
In an OECD 421 study, groups of 12 rats/sex were exposed to MSA (70.5% in water) by oral gavage at doses of 250, 500 and 1000 mg/kg bw/day (Arkema and Chevron Phillips, 2005). Males were exposed 4 weeks before mating, during the mating period (2 weeks) and until sacrifice. Females were exposed 4 weeks before mating, during the mating period (2 weeks), pregnancy (3 weeks), lactation until day 4 postpartum (pp) inclusive, and until sacrifice (day 5 pp). One male animal died at 1000 mg/kg bw/day on day 33 and one female given 250 mg/kg bw/day was found dead on day 10 post-coitum. There were no test article related clinical signs of toxicity. There were no effects on body weights or food consumption. There were no effects on mating index, pre-coital interval, fertility index, duration of gestation, delivery data or postnatal and neonatal losses. There were no effects on the mean number of liveborn pups per litter. Minor differences, considered to be of no toxicological significance, were observed in the weights of testes and epididymides between treated and control males. Macroscopic post-mortem examination revealed no treatment-related effects. No microscopic treatment-related changes were observed for testicular staging or for the ovaries, including semi-quantitative evaluation of the morphological characteristics of ovarian physiology. The no observed effect level (NOEL) for parental toxicity and for toxic effect on reproductive performance and on progeny is 1000 mg/kg bw/day. 

 Developmental toxicity. 
   
                     i. OECD 414 Oral rangefinding study in female rats: 70.15% MSA  
   
A range finding study was conducted according to OECD 414 (Elf Atochem, 1996d). Groups of 8 female rats were exposed by oral gavage to doses of MSA (70.15% in water) of 0 (control), 25, 50, 100, 200 and 300 mg/kg bw/d on gestation days 5-15. Treatment-related clinical signs observed consisted of rales, labored respiration and gasping in the 100, 200 and 300 mg/kg bw/d groups. Findings of red material around the nose and/or mouth in the 100, 200 and 300 mg/kg/d groups often correlated with occurrences of the aforementioned respiratory abnormalities. These findings appeared to be a function of the dosage concentration; rather the dosage level, as they were observed with similar frequency in the 100, 200 and 300 mg/kg/d groups, each of which received the test article at a concentration of 50 mg/ml. There were no deaths. Slight mean body weight losses and reduction in food consumption occurred in the 100, 200 and 300 mg/kg bw/day groups during gestation days 6-9 when evaluated on a group mean basis. However, several animals in these groups experienced large, transient body weight losses and corresponding large decreases in food consumption on one or more occasions during the first days of the dosing period. Mean body weights, gravid uterine weights, net body weights and net body weight gains were unaffected by treatment at all dose levels. No treatment related internal necropsy findings were observed at any dose level. And no effects were observed at any dose level on intrauterine growth and survival. No external developmental variations of malformations were observed in any of the foetuses in the treated groups. 

                    	 ii. OECD 414 Oral definitive study in female rats: 70.15% MSA  
   
In an OECD 414 study, groups of 25 female rats were exposed to MSA (70.15% in water) by oral gavage at doses of 0 (control), 25, 100 and 400 mg/kg bw from gestation day 6 through 15 (Elf Atochem, 1996c). There were no test article related clinical signs and no deaths. There were no effects on body weight or food consumption. At necropsy, intrauterine growth and survival were unaffected by test article administration at all dose levels. There were no test article related fetal malformations or developmental variations. A dose level of 400 mg/kg bw/day was considered to be the no observable adverse effect level (NOAEL) for maternal toxicity and developmental toxicity. 

			 iii. OECD 421 Oral study in rats: 70.5% MSA  
   
In an OECD 421 study, groups of 12 rats/sex were exposed to MSA (70.5% in water) by oral gavage at doses of 250, 500 and 1000 mg/kg bw/day (Arkema and Chevron Phillips, 2005). Males were exposed 4 weeks before mating, during the mating period (2 weeks) and until sacrifice. Females were exposed 4 weeks before mating, during the mating period (2 weeks), pregnancy (3 weeks), lactation until day 4 postpartum (pp) inclusive, and until sacrifice (day 5 pp). There were no effects on postnatal and neonatal losses; the mean number of liveborn pups per litter; pup mortality or clinical signs; pup body weight; or pup sex ratio. The NOEL for developmental effects was 1000 mg/kg bw/day. 
   
   	 
 Subchronic toxicity 
   
 Subchronic oral toxicity. 
   
 7-day dietary exposure in rats: 98% MSA (anhydrous) 
   
Five rats/sex were exposed to concentrations of MSA (98% anhydrous) in the diet of 0.043%, 0.159%, 0.382% and 1.635% (males) and 0.045%, 0.183%, 0.479% and 1.80% (females) for seven days (Union Carbide Corporation, 1975). These concentrations were equivalent to 0, 51, 185, 420, 1805 mg/kg bw/d (males) and 0, 55, 201, 551, 2122 mg/kg bw/d (females). There were no deaths, no effects on body weights or organ weights. The NOAEL was 1805 mg/kg/day for males and 2122 mg/kg/day for females. 
   
 Subchronic dermal toxicity. 
   
There are no available subchronic dermal toxicity studies for MSA. 
   
 Subchronic inhalation toxicity. 
   
 5-day nose-only inhalation in rats: 69.9% MSA 
   
Five rats/sex were exposed by nose-only inhalation to MSA (69.9% aqueous solution) at concentrations of 0 (control) 0.026, 0.082, 0.23 and 0.74 mg/L for 6 hours/day for 5 days (Elf Atochem, 1996a). There were 2 and 3 deaths in the 0.23 and 0.74 mg/L groups, respectively. Rales were the only clinical sign observed in the 0.23 and 0.74 mg/L groups. Mean body weights and food consumption were generally reduced in males and females in the 0.74 mg/L group throughout the study. There were no effects on organ weights and no gross findings at necropsy. Microscopic findings in the nasal cavities included mucosal necrosis, suppurative inflammation and/or nasal exudate in males and females in the 0.23 and 0.74 mg/L groups. The NOEL for systemic toxicity was found to be 0.082 mg/L. 

			 ii. 28-day nose-only inhalation in rats: 69.9% MSA 
   
Fifteen rats/sex were exposed by nose-only inhalation to MSA (69.9% aqueous solution) at concentrations of 0 (control) 0.026, 0.073 and 0.242 mg/L for 6 hours/day for 5 days/week for four weeks (Elf Atochem, 1996b). There was a two-week recovery period following the 4-week exposure period. During the exposure phase of the study, 4, 1, 1 and 5 animals in the control, low-, mid- and high-exposure groups, respectively, were found dead. These deaths were not considered test article related. Clinical signs were reported only during the exposure period and consisted of rales and an increased incidence of yellow matting on various body surfaces in the high-exposure group animals. Matting was also observed in the mid -exposure group males. A transient reduction in mean body weight gain during the first week of exposure and slightly decreased food consumption throughout the exposure period were noted for the high-exposure group males. There were no effects on hematology, urinalysis, or organ weights. There was a statistically significant increase in blood urea nitrogen and aspartate aminotransferase in the high-exposure group males and females, respectively, at the study week 4 evaluations, but returned to levels comparable to the control group after the two-week recovery period. There were no test article related gross findings in the animals that were found dead during the study and no gross findings in animals at the end of the study. Test article-related microscopic findings were observed in the nasal turbinates of the high-exposure group rats that were found dead and in all treated groups at the study week 4 and 6 evaluations. The severity of some of the findings observed after the two-week recovery period suggested at least partial recovery from the irritative effects of the test article. Based on the compound-induced lesions observed in the nasal turbinates, the no observed effect level (NOEL) for local irritation was considered to be less than 0.026 mg/L. The NOEL for systemic toxicity was considered to be 0.026 mg/L. 
   
 Chronic toxicity.  
   
There are no chronic/oncogencity studies available on MSA. However, chronic studies should not be required for MSA since MSA is not a mutagen, reproductive toxin or endocrine disruptor. There is nothing to indicate that MSA will have any adverse chronic effects on humans or the environment.  
   
 Animal metabolism.  
   
There are no animal metabolism data available on MSA. However, animal metabolism data should not be required for MSA since MSA is not a mutagen, reproductive toxin or endocrine disruptor. There is nothing to indicate that MSA will have any adverse chronic effects on humans or the environment.  
   
 Metabolite toxicology.  
   
There are no metabolites of toxicological concern. 
   
 Endocrine disruption.  
   
There is no information or evidence to indicate that MSA is an endocrine disruptor. 
   
  C. Aggregate Exposure 
   
     1. Dietary exposure.  
   
Dietary (food and drinking water) and residential (dermal and inhalation) exposures are possible from the use of MSA as an inert ingredient in antimicrobial formulations. MSA has been demonstrated to be readily biodegradable, which reduces the likelihood of residues on food. For the same reason, no significant contributions to drinking water are expected from the use of MSA as inert ingredients in pesticide products. MSA has low toxicity and exposure to residues above toxicity levels of concern are not anticipated.  
   
A quantitative dietary risk assessment for the MSA is not necessary since there are no toxicity endpoints of concern that are associated with dietary ingestion of the MSA. Nonetheless, a quantitative risk assessment has been conducted using the systemtic NOEL from the reproduction study.  Specifically, a Reference Dose (RfD) of 10 mg/kg/day was calculated based on a NOEL of 1,000 mg/kg/day in the OECD 421 study in rats using a 10x uncertainty factor for inter- and intra-species extrapolation. The chronic Population Adjusted Dose (cPAD) is also 10 mg/kg/day. No additional uncertainty factor was added to the cPAD calculation as the reproductive and developmental toxicity studies do not indicate any additional susceptibility for infants and children. 
   
The chronic dietary exposure due to MSA use as an inert ingredient in disinfectants (sanitizer) used on food-contact surfaces was assessed. This assessment calculated the Daily Dietary Dose (DDD) and the Estimated Daily Intake (EDI). The assessment considered: application rates, residual solution or quantity of solution remaining on the treated surface without rinsing with potable water, surface area of the treated surface which comes into contact with food, pesticide migration fraction, and body weight. These assumptions are based on FDA guidelines (FDA, 2003).  
   
The EDI calculations presented in this assessment assume that food can contact either 2,000 cm[2] or 4,000 cm[2] (50% and 100% of the FDA worst-case scenario) of treated surfaces, and that 10% of the material would migrate to food. The 10% migration rate is based on Agency Residential Standard Operation Procedures. These daily estimates were conservatively used to assess chronic dietary risks (i.e., percent chronic population adjusted dose or %cPAD). 
   
Assuming a level of 5,000 ppm of MSA in the use dilution solution, the following EDI is calculated: 
   
  EDI: 100% FDA Worst Case 
  
  EDI = 1 mg/solution  x  5,000 ug  x  4,000 cm[2]  x 10%  =  2,000 ug/person/day
                      cm2              1,000 mg     person/day                                   OR
  								   2.0 mg/person/day
   
  
  EDI: 50% FDA Worst Case 
       
  EDI = 1 mg/solution  x  5,000 ug  x  2,000 cm[2]  x 10%  =  1,000 ug/person/day
                      cm2              1,000 mg     person/day                                   OR
  								   1.0 mg/person/day 

   
The above calculation is for use of the substance in products that are used in public-eating facilities, which is worst-case. Use in food-processing plants would yield dramatically lower exposures. 
   
Assuming body weights for men (70 kg), women (60 kg), and infants and children (15 kg), the following percent DDD values are calculated: 
   
  DDD: 100% FDA Worst Case 
   
 Male:   	 	2.0 mg/person/day / 70 kg/person = 0.029 mg/kg/day 
 Female: 	 	2.0 mg/person/day / 60 kg/person = 0.033 mg/kg/day 
 Infants/Children: 	2.0 mg/person/day / 15 kg/person = 0.13 mg/kg/day 
  DDD: 50% FDA Worst Case 
   
 Male:   	 	1.0 mg/person/day / 70 kg/person = 0.014 mg/kg/day 
 Female: 	 	1.0 mg/person/day / 60 kg/person = 0.017 mg/kg/day 
 Infants/Children: 	1.0 mg/person/day / 15 kg/person = 0.067 mg/kg/day 
   
Based on the calculated DDDs and the cPAD value of 10 mg/kg/day, the following percent cPAD estimates are derived: 
   
  % cPAD: 100% FDA Worst Case 
   
 Male:   	 	0.029 mg/kg/day / 10 mg/kg/day = 0.29% cPAD 
 Female: 	 	0.033 mg/kg/day / 10 mg/kg/day = 0.33% cPAD 
 Infants/Children: 	0.13 mg/kg/day / 10 mg/kg/day = 1.3% cPAD 
   
  % cPAD: 50% FDA Worst Case 
   
 Male:   	 	0.014 mg/kg/day / 10 mg/kg/day = 0.14% cPad 
 Female: 	 	0.017 mg/kg/day / 10 mg/kg/day = 0.17% cPad 
 Infants/Children: 	0.067 mg/kg/day / 10 mg/kg/day = 0.67% cPad 
   
MSA may contain the impurity, methyl methane sulfonate (MMS), which is of toxicological concern.  BASF has measured levels of 480 and 530 ppb in separate batches of 70% MSA, resulting in a mean value of 505 ppb.  Corrected for purity, this value is estimated at 721.4 ppb.  Because MMS is a known mutagen and a potential carcinogen we need to estimate the upper bound cancer risk from this dietary exposure.  FDA regulations state that a substance with a TD50 of 6.25 mg/kg bw/day will result in a one in a million risk level with a dietary exposure of 1.5 ug/person/day[1].  Based on this benchmark, we can use the lowest statistically significant TD50 for MMS of 31.6 mg/kg bw/day[2] to estimate the upper bound cancer risk from MMS exposure resulting from the use of MSA as an acid excipient in a sanitizing solution at a level of 1,000 ppm for the most vulnerable population, infants and children:

[1.] 21 CFR 170.39. We have used an FDA benchmark to simplify calculations.  EPA risk estimates would not be significantly different.
[2.] Gold, L.S., T.H. Slone, N.B. Manley, G.B. Garfinkel, L. Rohrbach and B.N. Ames (1997).  Carcinogenic Potency Database, Handbook of Carcinogenic Potency and Genotoxicity Databases (L.S. Gold & E. Zeiger, eds.) 1-605.
0.13 mg/kg bw/day x 721.4 ppb MMS in MSA = 9.38 x 10[-8] mg/kg bw/day MMS exposure 
   
9.38 X 10[-8] mg/kg bw/day  x 15 kg bw/person  x           1.0 x 10[-6]  x            6.25 mg/kg bw/day  = 1.9 x 10[-10]
                                                                                  0.0015 mg/person/day     31.6 mg/kg bw/day

The above estimated risk for a child is far smaller than what would ordinarily be considered negligible. 
   
   	 
	i. 	Food.  
   
Food contact exposures are well below 100% of the cPAD, and are therefore below EPA's established level of concern for all U.S. subpopulations. The combined exposure for males, females, and infants and children is < 1% of the cPAD, even for the 100% worst case scenario. 

 	ii. 	Drinking water.  
         
Drinking water exposure is highly unlikely from the use of MSA as an inert ingredient in antimicrobial pesticide products. Moreover, MSA are readily biodegradable according to OECD criteria, which reduce the likelihood of residues on food. Exposures to residues above toxicity levels of concern are not anticipated.  
   
 Cumulative Effects 
   
MSA does not share a common mechanism of toxicity with any other pesticide active and/or inert ingredient. 
   
 Safety Determination 
   
The proposed use of MSA will not increase the current exposure due to other non-pesticide exposures. The food-contact sanitizer use for all population subgroups combined is <1% of the cPAD.  
   
 U.S. population.  
   
  The % cPAD calculated for males (0.14-0.29%) and females (0.17-0.33%) is well below the level of concern. Based on these conservative exposure estimates, there is a reasonable certainty that no harm will result to the U.S. population from the aggregate exposure to MSA.  
   
 Infants and children. 
   
  FFDCA Section 408 requires an additional tenfold margin of safety for the protection of infants and children in case of threshold effects to account for prenatal and postnatal toxicity, and an inadequate toxicity database. Where an adequate and reliable database is available and there is a lack of evidence for increased susceptibility, the FQPA safety factor may be reduced or removed.  
         
  An evaluation of susceptibility and uncertainty issues associated with MSA has been performed, and EPA has previously reduced the FQPA safety factor from the default 10x to 1x for the following reasons:  
 The availability of a substantial and scientifically sound mammalian toxicology database that includes acute, repeat dose, reproduction, developmental, and endocrine data for MSA; 
 OECD testing indicating that there was no evidence of developmental toxicity or malformations in the developing offspring;  
 There is no evidence to suggest that MSA would have an adverse effect on the reproductive organs;  
 MSA does not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system. MSA has been evaluated in acute, repeated dose, developmental, and chronic toxicity studies capable of detecting effects on endocrine mediated events and have not demonstrated any endocrine-related effects. 
   
  The % cPAD calculated for infants and children (0.67-1.3%) is well below the level of concern. Based on these conservative exposure estimates, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure to MSA. 
   
   
 International Tolerances 
   
There are no CODEX MRLs established for MSA. 
   
   


