# i EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: PV 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. TEMPLATE: Lyondell Chemical Company [ 1E7946 ] EPA has received a pesticide petition ( 1E7946 ) from Lyondell Chemical Company , 1221 McKinney Street, Houston, Texas 77010 requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to expand the exemption from tolerance for uses of 2 - methyl - 1,3 - propanediol (CASRN 2163 - 42 - 0) to include uses in food contact surface sanitizing solutions, 40 CFR § 180.940(a), in addition to existing uses on raw agricultural commodities and animals. EPA has determined that the petition contains data or information regarding the elements set fo rth in section 408 (d)(2) of FF DCA; 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 befo re EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. [NA - Remove] 2. Analytical method. [NA - Remove] 3. Magnitude of residues. [NA - Remove] B. Toxicological Profile 1. Acute toxicity. Acute Oral Toxicity in Rats/LD50 in Rats: Five healthy male and five healthy female Albino rats were dosed orally with 2 - Methyl - 1,3 - propanediol at 5.0 g/kg of body weight. All animals survived the 5.0 g/kg oral dose in generally good health. Body weight increases were normal. Necropsy results wer e normal in 8/10 animals. The LD50 was2 determined to be greater than 5.0 g/kg of body weight. Acute Dermal Toxicity in Rabbits/LD50 in Rabbits: Five healthy male and five healthy nulliparous and non - pregnant female New Zealand Albino rabbits were dosed d ermally with 2 - Methyl - 1,3 - propanediol at 2.0 g/kg of body weight. The test article was kept in contact with the intact skin for 24 hours. Nine of ten animals survived the 2.0 g/kg dermal application. One female died on day 12 with no abnormal predeath phy sical signs. The death did not appear to be related to the effect of the test article, as the animal appeared normal for 11 days. Body weight changes were normal in 7/9 survivors. Two animals lost weight during the study. Dermal reactions, were absent t o slight on day 1, and absent on days 7 and 14. Necropsy results of survivors were normal in 4/9 animals. The LD50 was calculated to be greater than 2.0 g/kg of body weight. Primary Dermal Irritation in Rabbits: Six healthy New Zealand Albino rabbits we re dosed dermally with 2 - Methyl - 1,3 - propanediol. 0.5 mL of the test article was applied to two intact and two abraded sites/rabbit for a total dose of 2.0 ml/rabbit. The test article was kept in contact with the skin for 4 hours. There was no erythema or edema noted during the observation period. Eye Irritation in Rabbits: Nine healthy New Zealand albino rabbits, free from evidence of ocular irritation or corneal damage, as determined by pretest fluorescein dye procedures, were dosed with 2 - Methyl - 1,3 - pro panediol. 0.1 mL of the test article was placed into the conjunctival sac of one eye of each rabbit. Six eyes remained unwashed. Three eyes were washed 20 - 30 seconds after dosing for one minute with lukewarm water. UNWASHED: All six eyes appeared normal during the study. WASHED: There was no corneal opacity or iritis. Slight conjunctival irritation, noted in 1/3 eyes, cleared by day 2. Two eyes appeared normal during the study. Acute (4 - hour) Inhalation Toxicity Study in Rats: One group of five male an d five female rats were exposed by nose - only to a test atmosphere containing the limit concentration of 5.1 ± 0.2 g 2 - Methyl - 1,3 - propanediol per m3 for a 4 - hour period. The Mass Median Aerodynamic Diameter (MMAD) of the particles in the aerosol was 2.4 @m with a mean geometric standard deviation of 1.4. Except for a slightly decreased breathing rate in the fourth hour of exposure in one female animal, no exposure - related abnormalities were seen during or shortly after exposure or during the 14 - day observati on period and no mortality occurred. For rats of this strain and age, mean body weight gain was considered to be within the normal range. Findings at necropsy were limited to the lungs. Thickened hyalin spots or small areas were seen on all lobes of the lungs in all female and in three male animals. In a fourth male animal small white areas were seen on all lobes of the lungs. It was concluded that the 4 - hour LC50 value of 2 - Methyl - 1,3 - propanediol is higher than 5.1 g/m3 for both sexes. Assessment of Contact Hypersensitivity in the Albino Guinea Pig (Maximization Test: Guinea pigs received intradermal and epidermal exposures of 2 - Methyl - 1,3 - propanediol. In the main study, the experimental animals were intradermally injected with a 10% concentration an d epidermally exposed to undiluted test substance, while the control3 animals were similarly treated, but with the vehicle only and with a dry patch. Two weeks after the epidermal application all animals were challenged with test substance concentrations of 100%, 50% and 25%, and the vehicle (distilled water). The epidermal exposure of 2 - Methyl - 1,3 - propanediol in the induction phase resulted in no skin irritation. The epidermal exposure of 2 - Methyl - 1,3 - propanediol in the challenge phase resulted in three pos itive sensitization reactions in response to the 50% test substance concentration. Under the conditions used in this study, 2 - Methyl - 1,3 - propanediol resulted in a sensitization rate of 15 per cent, and is considered to have mild sensitizing properties. 2. Genotoxicty. Evaluation of the Mutagenic Activity In An In Vitro Mammalian Cell Gene Mutation Test with V79 (Chinese Hamster Cells (with independent repeat): 2 - Methyl - 1,3 - propanediol was tested in an in vitro mammalian cell gene mutation test with V79 Chinese hamster cells in the presence and absence of a metabolic activation system (S9 - mix). 2 - Methyl 1,3 - propanediol was tested up to and including a concentration of 5000 ug/ml in the absence and presence of S9 - mix. It did not induce a significant, do se - related increase in the mutant frequency at the HPRT - locus in two independently repeated experiments with or without metabolic activation. The positive control chemicals ethylmethanesulphonate (6 mM) and dimethylnitrosamine (8mM) produced 14 to 23 - fol d and 8 to 10 - fold increases respectively in the mutant frequency, demonstrating the sensitivity of the assay and the activity of the S9 - mix. It was concluded that 2 - Methyl - 1,3 - propanediol is not mutagenic in the V79/HPRT gene mutation test system, as des cribed in this report. Evaluation of the Ability to Induce Chromosome Aberrations in Cultured Peripheral Human Lymphocytes (with independent repeat): 2 - Methyl - 1,3 - propanediol was examined for the induction of chromosome aberrations in cultured peripheral human lymphocytes in the presence and absence of a metabolic activation system (Aroclor - 1254 induced rat liver S9 - mix) at test levels up to 5000 ug/ml. The first experiment used a 24 h and 48 h fixation period, and the second experiment a 24 h fixation p eriod. None of the tested concentrations induced a statistically and biologically significant increase in the number of cells with chromosome aberrations, with or without S9 - mix. Positive control chemicals, mitomycin C and cyclophosphamide, both produced a statistically significant increase in the incidence of cells with chromosome aberrations, validating the optimal test conditions and metabolic activation system (S9 - mix). It is concluded that 2 - Methyl 1,3 - propanediol is not clastogenic in human lymphocyt es under the experimental conditions described. Evaluation of the Mutagenic Activity of in the Ames Salmonella/Microsome Test (with independent repeat): 2 - Methyl - 1,3 - propanediol was tested in the Ames Salmonella/microsome plate test up to and including a concentration of 5000 @g/plate in the absence and presence of S9 - mix. The test substance did not induce a dose - related increase in the number of reverent (His+) colonies in each of the four tester strains (TA1535; TA1537; TA98 and TA100). The results were confirmed in an independently repeated experiment. The test substance was not considered mutagenic in this test system.4 3. Reproductive and developmental toxicity. Embryotoxicity and Teratogenicity Study Administered by Oral Gavage in Wistar Rats: Timed pregnant female Wistar rats were administered 2 - Methyl - 1,3 - propanediol at dosage levels of 300, 600 or 1000 mg/kg body weight by oral gavage daily on gestation days 0 to 20. Control group females received daily oral administration of water (Milli U) . On day 21 of gestation, all females were euthanized. Oral dosing of pregnant female Wistar rats with 2 - Methyl - 1,3 - propanediol, at dose levels of 300, 600 or 1000 mg/kg body weight/day during days 0 to 20 of gestation inclusive, revealed no maternal toxic ity. Treatment at 600 and 1000 mg/kg body weight/day was associated with a slight increase in embryonic resorptions and a corresponding slight decrease in live litter size, compared with the concurrent controls. However, as all values remained within the l aboratory background control ranges, the findings were considered to be of doubtful toxicological significance. There was no indication of an adverse effect of 2 - Methyl - 1,3 - propanediol on morphological development or skeletal ossification in utero. In The No Observed Effect Level (NOEL) was 300 mg/kg body weight/day. In order to clarify the findings of the NOTOX study, subsequent expert review of the study and conduct of a second rat developmental toxicity study were performed. In the independent review, a reproductive and developmental expert, L. Irvine (TAS - Environ) compared the rate of embryonic resorptions with additional recent test and historical data for the same rat strain and supplier. The review revealed the following:

- By comparison with the additional data, it was obvious that the incidence of embryonic deaths in the control group in the 2 - Methyl - 1,3 - propanediol study was unusually low, while the values for the treated groups were typical for the strain.

- Statistically significant inter - grou p differences in resorptions would not be expected with a more representative control group.

- With no other indications of embryotoxicity and no dose - related difference in mean live litter sizes, findings of toxicological significance are highly unlikely. The second rat embryotoxicity and teratogenicity study also confirmed the results of the first study. An Oral (Gavage) Prenatal Developmental Toxicity Study in Rabbits: 2 - Methyl - 1,3 - propanediol in the test vehicle, deionized water, was administered to t hree groups of 25 bred New Zealand white rabbits once daily from gestation days 0 through 28. Dosage levels were 250, 500 or 1000 mg/kg/day administered at a dose volume of 0.25, 0.50, or 1.0 ml/kg, respectively. A concurrent control group composed of 25 bred females received the vehicle, deionized water, on a comparable regimen at 1.0 ml/kg. The route of administration was oral by gastric intubation. On gestation day 29, a laparohysterectomy was performed on all animals. One and two females in the 500 and 1000 mg/kg/day groups, respectively, died during the study, probably due to intubation trauma or aspiration; no relationship to test article administration was evident. There were no test article - related maternal clinical observations or effects on me an body weights, body weight gains, net body weights, net body weight gains, gravid uterine weights or food consumption at any dose level. There were no test article - related internal5 findings noted at the scheduled necropsy. Intrauterine growth and survi val were unaffected in the 250, 500 and 1000 mg/kg/day groups. No test article - related fetal malformations or developmental variations were noted in any fetuses in this study. Based on the results of this study, a dose level of 1000 mg/kg/day was consider ed to be the no observed - adverse - effect level (NOAEL) for maternal and developmental toxicity when 2 - Methyl - 1,3 - propanediol was administered orally to rabbits. An Oral (Gavage) Two - Generation Reproductive Toxicity Study in Rats: The study was conducted to evaluate the potential adverse effects of 2 - Methyl - 1,3 - propanediol administration on the reproductive capabilities of the F0 and F1 generations and on F1 and F2 neonatal survival, growth, and development. The test article was administered by gavage once daily for at least 70 consecutive days prior to mating to three groups of F0 and F1 parental Crl:CD®(SD)IGS BR rats (30/sex/group). A control group of identical design received deionized water on a comparable regimen. Test article administration continue d throughout mating, gestation and lactation, until euthanasia for F0 and F1 parental animals. All F0 and F1 females were allowed to deliver and rear their pups until weaning on lactation day 21. On that day, 35 pups/sex/group from the pairing of the F0 animals (including five extra animals/sex/group) were selected for use in the F1 generation. These animals were dosed from postnatal day (PND) 22 - 27, inclusively. On PND 28, 30 offspring/sex/group were selected to constitute the F1 generation. All surv iving F0 and F1 parental animals received a complete detailed gross necropsy following the completion of weaning of the F0 and F1 pups; selected organs were weighed. Designated tissues from 10 F0 and F1 parental animals/sex/group in the control and in the 1000 mg/kg/day groups were examined microscopically. No test article - related mortalities or clinical findings were observed in the F0 or F1 generation. All F1 animals that were paired survived to the scheduled necropsy. Reproductive parameters were not adversely affected by test article administration at dose levels of 100, 300 and 1000 mg/kg/day during the F0 or F1 generations. No adverse test article - related effects on weekly gestation or lactation body weight, body weight gain, food consumption or f ood efficiency were observed in the F0 or F1 generations. No test article - related macroscopic or microscopic internal findings were observed in the F0 or F1 generation males or females. Absolute and relative (to final body weight) organ weights were unaf fected by test article administration for males and females in the F0 or F1 generations. Mean F0 or F1 pup body weights, sex ratios, live litter sizes, numbers of dead pups on lactation day 0 and viability indices were unaffected by test article administr ation. No test article - related effects on physical development or behavioral responses were observed for the F1 pups. No test article - related internal findings were noted in the F0 or F1 pups at necropsy. Findings for selected weanling pups did not sugg est any effects of test article administration. In conclusion, no parental, neonatal or reproductive toxicity was observed as a6 result of test article administration at dose levels of 100, 300 and 1000 mg/kg/day. Based on the results of this study, the no - observed - adverse - effect level (NOAEL) for parental, neonatal and reproductive toxicity was considered to be 1000 mg/kg/day. 4. Subc hronic toxicity. Subacute 14 - Day Oral Toxicity by Daily Gavage in the Rat: In this subacute 14 - day toxicity study, 2 - Methyl - 1,3 - propanediol was administered daily by gavage to SPF - bred Wistar rats at 300, 600 or 1000 mg/kg/day, in order to provide a bas is for selection of dose levels for a 90 - day study. There were no treatment - related changes for any of the treatment groups for the parameters evaluated. From the results a definitive No Observed Effect Level (NOEL) of 1000 mg/kg/day was established. Assessment of 90 - Day Oral Toxicity in the Rat: In this sub - chronic 90 day oral toxicity study, 2 - Methyl - 1,3 - propanediol was administered daily by gavage to SPF - bred Wistar rats. The study consisted of four groups, each comprising 10 males and 10 females, and dosed at 0, 300, 600 or 1000 mg/kg/day. There were no treatment - related changes for any of the treated groups for the parameters evaluated at the end of treatment (week 13). From the results presented in this report, a definitive No Observed Effect Le vel (NOEL) of 1000 mg/kg/day was established. 5. Chronic toxicity. [NA - Remove] 6. Animal metabolism. [NA - Remove] 7. Metabolite toxicology . [NA - Remove] 8. Endocrine disruption . [NA - Remove] C. Aggregate Exposure 1. Dietary exposure. The inert in gredient, 2 - methyl - 1,3 - propanediol, will be added to water - soluble food contact surface sanitizer solutions as a solvent and/or surfactant at levels of no more than 4%. i. Food. The amount of 2 - methyl - 1,3 - propanediol expected to be present on food - cont act surfaces and transferred to food as residues is calculated using a model developed by the Food and Drug Administration (FDA) for assessing exposures to antimicrobial pesticide formulations. (Division of Food Chemistry and Technology, Center for Food S afety and Applied Nutrition, Food and Drug Administration, “Sanitizing Solutions: Chemistry Guidelines for Food Additive Petitions” (1988).) For calculation of severe worst - case exposures specific to 2 - Methyl - 1,3 - propanediol, the7 assessment assumes that 100% of the residue left on hard treated surfaces is captured through contact with food, and that 2 - Methyl - 1,3 - propanediol is always used at its upper limit of 4% in the formulation, even in very dilute formulations. Assuming an adult average weight of 71 .8 kg and a 6 year - old child average weight of 22.5 kg (6 years old), the highest dietary intakes of 2 - Methyl - 1,3 - propanediol are calculated to be 0.45 mg/kg/day and 0.13 mg/kg/day respectively for a formulation assumed to contain only 0.2% by weight anti microbial active ingredient. (Average adult weight for assessment purposes was taken from EPA’s Exposure Factors Handbook, page 175, and EPA’s Child - Specific Exposure Factors Handbook.) ii. Drinking water. [NA - Remove] 2. Non - dietary exposure . [NA - Remove] D. Cumulative Effects 2 - Methyl - 1,3 - propanediol has negligible acute and subchronic toxicity and would not contribute to cumulative toxicity effects if mixed with other related materials. E. Safety Determination 1. U.S. population. Even when extreme worst case exposure calculations are used in evaluating the safety of 2 - Methyl - 1,3 - propanediol, large Margins of Exposure are found for both adults and children exposed through diet. There is more than a reasonable certainty that no harm will result from aggregate exposures to 2 - Methyl - 1,3 - propanediol. 2. Infants and children . The worst - case Margins of Exposure calculated for children range from 7,572 to values more than 200 times higher. Based on these findings, it may be concluded that th ere is a reasonable certainty that no harm will result from aggregate exposure to 2 - Methyl - 1,3 - propanediol residues by infants and children. F. International Tolerances [There are no international tolerances ( i.e. , MRLs) for 2 - methyl - 1,3 - propanediol.

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