Document ID: EPA-HQ-OPP-2016-0183-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-06-01T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 
PETITIONS PUBLISHED IN THE FEDERAL REGISTER   
 
EPA Registration Division contact: Janet Whitehurst 703-305-6129 or P.V. Shah, 703-308-1846 
 
BASF Corporation 
 
PP IN-10829 
 
 	EPA has received a pesticide petition (IN-10545) from BASF Corporation, c/o Lewis & Harrison, LLC, 122 C Street NW, Suite 740, Washington DC 20001, requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish an exemption from the requirement of a tolerance for Pentaerythritol Tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate) (CAS Reg. No. 668319-8) under §180.910 and §180.930  when used as an antioxidant/stabilizer in pesticide formulations with a limit of 5% when used on food crops pre- and post-harvest and 3% when used on animals. 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 Pentaerythritol Tetrakis (3-(3,5-di-tert-butyl-
4-hydroxyphenyl)propionate) (hereinafter "PT"). 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. 
 
 Acute toxicity 
 
PT is of low toxicity via the oral, dermal, and inhalation routes. PT is not irritating and not corrosive to eyes and skin. PT is not a dermal sensitizer. 
 
 Acute oral toxicity 
 
The acute oral toxicity of PT is greater than 10,250 mg/kg-bw.  
 
 Acute dermal toxicity. 
 
The acute dermal toxicity of PT is greater than 3,160 mg/kg bw. 
 
 	 
 Acute inhalation toxicity. 
 
The acute inhalation toxicity of PT is greater than 1.95 mg/L. 
 
 Acute eye irritation. 
 
PT is not irritating or corrosive to eyes. 
 
 Acute skin irritation. 
 
PT is not irritating or corrosive to skin. 
 
 Skin sensitization 
 
PT is not a dermal sensitizer. 
 
 Genotoxicity 
 
No evidence of genotoxicity or chromosomal effects was observed in mutagenicity studies conducted with PT.  
 
 Reverse Mutation Assay 
 
In a bacterial reverse mutation assay, PT was tested in several Salmonella typhimurium strains 
(TA98, TA100, TA1535 and TA1537) at concentrations of 10, 25, 50, 100 and 250 μg/0.1 mL (with) and 5, 10, 25, 50 and 100 μg/0.1 mL (without) metabolic activation. Positive controls were also included; however, their responses were not reported. Precipitation of the test material was evident at the 100 μg/0.1 mL. No increase was observed in reverse mutations with or without metabolic activation. PT was not mutagenic in this assay. 
 
 Chromosomal Aberration Assay  
 
In a chromosomal aberration assay, Chinese hamsters (4/sex/dose) were administered 0, 500, 1,000 or 2,000 mg/kg-bw PT in 2.0% sodium carboxymethyl cellulose for 2 consecutive days. Animals were sacrificed and bone marrow was harvested after the colcemide injection 2 hours after the second dose. Positive and negative controls were used in the assay. PT did not induce chromosomal aberrations in this assay. 
 
 Mammalian Micronucleus Test 
 
In a nuclear anomaly test, male and female Chinese hamsters received 500, 1,000 or 2,000 mg/kg-bw PT in 0.5% carboxymethyl cellulose for 2 consecutive days. Animals were sacrificed 24 hours following the second treatment and bone marrow scored for chromosomal anomalies. Positive and negative controls were also used. The percentage of cells displaying anomalies of nuclei did not differ from the negative control. PT did not induce chromosomal aberrations in this assay. 
 
 Dominant Lethal Assay 
 
In a dominant lethal assay, albino male mice (20/dose) were administered PT via oral gavage at single doses of 0, 1,000 or 3,000 mg/kg-bw/day. Males were mated with a pair of untreated females each week for up to 6 weeks. Females were examined daily for evidence of pregnancy (vaginal plug). Pregnant females were necropsied on day 14 and the number of live embryos and embryonic deaths were recorded. Mating ratio, number of implantations and embryonic deaths did not differ between control and treated animals. No evidence of dominant lethal effects was noted. PT was negative in this dominant lethal effect assay. 
 
 Reproductive and developmental toxicity. 
          
No significant reproductive or developmental effects were noted in any of the tests conducted. 
 
 Reproductive toxicity. 
 
In a two-generation reproductive study Crl:COBS CD (SD) BR rats (F0 generation) were administered PT in the diet for 13 weeks (males) and 10 weeks (females) prior to mating at concentrations of 1000, 3000 and 10,000 ppm (approximately 50, 150 and 500 mg/kg-bw/day). One male and one female were paired for mating for a period of 20 days and vaginal smears were taken daily throughout the mating period. Dams were allowed to rear their young to day 21 postpartum; 24 male and 24 female pups were retained as the F1 generation. Following selection of the F1 generation, a male and a female from each litter were selected for organ weight analysis and preservation of tissues. The remaining animals were euthanized and examined macroscopically. No mortality occurred among animals of either the F0 or F1 generation nor were there any consistent effects that could be attributed to treatment, including clinical signs of toxicity, food consumption, body weight gain and efficacy of food utilization, reproductive capacity as assessed by mating performance, pregnancy rate and duration of gestation, findings at necropsy. 
 
Systemic/Reproductive Toxicity: 
LOAEL: > 500 mg/kg-bw/day 
NOAEL: ~ 500 mg/kg-bw/day (based on no effects at HDT) 
 
            b. Developmental toxicity. 
 
PT is not maternally toxic and shows equivocal signs of developmental toxicity in one species only. 
                   i. Rats 
 
Pregnant Sprague-Dawley rats were administered PT via oral gavage at doses of 150, 500 or 
1000 mg/kg-bw/day during days 6 through 15 of gestation. Rats were sacrificed on gestation day 21, females necropsied and fetuses were removed by caesarean section. At the low- and intermediate-dose levels, an increase in food consumption was noted in dams during treatment period (no effect on body weight gain). Increased rate of delayed ossification was seen at low and intermediate doses, but at the high dose, the delayed ossification rate was comparable to the control group. Because there was no dose-response, this finding was not considered treatment related. There were no other effects reported. 
 
Maternal/Developmental Toxicity 
LOAEL: > 1000 mg/kg-bw/day 
NOAEL: 1,000 mg/kg-bw/day (based on no effects at HDT) 
                   ii. Mice 
 
Pregnant female mice were administered PT via oral gavage at doses of 150, 500 or 1000 mg/kgbw/day during days 6 through 15 of gestation. Mice were sacrificed on gestation day 18; females were necropsied and fetuses were removed by caesarean section. No maternal toxicity was apparent in any of the treated animals when compared to control. The rates of implantation and resorptions, as well as the average weights of the fetuses were comparable for all groups. Low- and high-dose group fetuses had minor skeletal deviations from controls. Fetuses from the 150 mg/kg-bw/day group had higher incidences of ossification of the phalangeal nuclei of the hind limb and the calcanei were also markedly different from controls. In a dose-response trend, there were increasing fetuses with incompletely ossified sternebrae, leading to a marked increase at the high-dose when compared to controls. No other findings were reported. 
 
Maternal Toxicity: 
LOAEL: > 1,000 mg/kg-bw/day (based on no effects at HDT) 
NOAEL: 1,000 mg/kg-bw/day 
 
Developmental Toxicity: 
LOAEL: 150 mg/kg-bw/day (based on incompletely ossified sternebrae) NOAEL: Not established 
 
 Subchronic toxicity 
 
 Subchronic oral toxicity. 
 
In a 13-week oral dog study, no adverse effects were reported up to 250 mg/kg-bw/day (highest dose tested). 
 
 Chronic toxicity. 
 
 Chronic feeding.  
 
In a chronic feeding study in the rat, the literal no-effect level was 3,000 ppm corresponding to 135-166 mg/kg/day. However, no toxicological significance can be attached to the sporadic marginal reduction in bodyweight gain in rats fed 10,000 ppm since no corroborative evidence was seen. Therefore, the no-effect level can justifiably be set at 10,000 ppm equivalent to 446547 mg/kg/day.  
 
 	 
 Carcinogenicity. 
 
In a 24-month mouse dietary carcinogenicity study, body-weight gain of female groups 3 and 4 (300 and 1,000 mg/kg feed) was significantly lower but within a range of about 10% from the control group values. No clinical symptoms and no signs of local and/or systemic toxicity were observed. Apart from a slight, significant increase of the mean adrenal weights and ratios in male mice of group 2, 3 and 4 (100, 300 and 1000 mg/kg feed) and in females of group 3 (300 mg/kg feed) the analysis of organ weights and organ weight ratios revealed no consistent treatment related effects. Neither gross nor microscopic changes in the organs and tissues related to the treatment were noted. Numerous benign and malignant tumors were observed in both control and treated mice. Frequency and type of the neoplasms occurring in these animals were not influenced by the treatment. Also other gross and histopathological lesions and changes seen in both control and test animals and described as congenital, degenerative or inflammatory in origin are attributed to the naturally occurring diseases which are common in aged mice of this breeding colony. It can be inferred from the observations made during the above study that PT when administered to mice daily in the diet over a period of 24 months at dietary levels of 100, 300 and 1000 mg/kg feed corresponding to a mean daily intake of 12, 41 and 126 mg/kg bw. in male and 11, 3 5 and 107 mg/kg bw. in female animals respectively did not produce inflammatory, degenerative, proliferative or neoplastic lesions. 
 
 Animal metabolism.  
 
There are no animal metabolism data available on PT. However, animal metabolism data should not be required for PT since PT is not a mutagen, reproductive toxin or endocrine disruptor. PT has been safely used over many years in organic substrates such as plastics, synthetic fibers, elastomers, adhesives, waxes, oils and fats. There is nothing to indicate that PT 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 PT 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 PT as an inert ingredient in pesticide formulations applied to crops pre- and postharvest. PT has low toxicity and exposure to residues above toxicity levels of concern are not anticipated.  
 
A quantitative dietary risk assessment for the PT is not necessary since there are no toxicity endpoints of concern that are associated with dietary ingestion of the PT. Nonetheless, a quantitative risk assessment has been conducted using the LOAEL for developmental effects in the mouse developmental toxicity study.  Specifically, a Reference Dose (RfD) of 0.5 mg/kg/day was calculated based on a LOAEL of 150 mg/kg/day in the using a 10x uncertainty factor for inter- and intra-species extrapolation. An additional 3x FQPA safety factor was added to account for the equivocal evidence of developmental toxicity in mice. The chronic Population Adjusted Dose (cPAD) is also 0.5 mg/kg/day.  
 
The chronic dietary exposure due to PT use as an inert ingredient in pesticide formulations applied to growing crops pre- and post-harvest was assessed.  
 
Dietary exposures from the use of PT in agricultural pesticides and occurrence in drinking water are based on the same approach that was used for the Alkyl Alcohol Alkoxylates. Using this approach is reasonable since both PT and AAAs have the same non-pesticidal product uses. Accordingly, the product concentration of PT and AAAs should be similar. 
 
In the dietary exposure assessment for food crops, upper bound dietary exposure estimates are derived from a dietary exposure model developed by the Agency. The model is based on dietary exposure data from 57 high-use agricultural pesticides and an adjustment factor of 0.5 (assumes up to 50% inert in the formulation). The maximum use of PT proposed in formulations for food products is 5%. As such, an additional adjustment factor has been applied to the dietary exposure values (0.05 PT/0.5 AAA model = 0.1 additional adjustment). 
 
The dietary exposure values for PT are shown in the table below. An acute dietary assessment was not conducted since an acute toxicity endpoint applicable to dietary exposure was not identified. The %cPAD (population adjusted dose) was calculated by dividing the chronic dietary exposure by the chronic RfD of 0.5 mg/kg/day.   
 
           Summary of Dietary (Food and Drinking Water) Exposure and Risk for PT 

                               Population Subgroup 
Acute Dietary 
                                   Exposure 
 (mg/kg/day) 
%aPAD 
                     Chronic Dietary Exposure (mg/kg/day) 
%cPAD 
                           General U.S. Population 
                          No acute endpoint selected 
                                  0.0191509 
                                     3.83 
                                 All Infants 

                                  0.0397082 
                                     7.94 
                                 Children 1-2 

                                  0.0624005 
                                    12.48 
                                 Children 3-5 

                                  0.0461958 
                                     9.24 
                                Children 6-12 

                                  0.0255310 
                                     5.11 
                                 Youth 13-19 

                                  0.0144122 
                                     2.88 
                                 Adults 20-49 

                                  0.0144401 
                                     2.89 
                                  Adults 50+ 

                                  0.0152076 
                                     3.04 
                                Females 13-49 

                                  0.0145389 
                                     2.91 
 
Generally, a dietary risk estimate that is less than 100% of the acute or chronic PAD does not exceed the Agency's risk concerns. The %cPAD calculated for the general population (3.83%), adults (2.89-3.04%), and females 13-49 (2.91%) is 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 PT.  
 
FFDCA Section 408 requires an additional ten-fold 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 PT has been performed and BASF believes the FQPA safety factor can be reduced from the default 10x to 3x for the following reasons: 
  
 The availability of a substantial and scientifically sound mammalian toxicology database that includes acute, repeat dose, mutagenicity, reproductive, developmental, and chronic toxicity (including carcinogenicity) data for PT; 
 Testing indicating that there was equivocal to no evidence of developmental toxicity or malformations in the developing offspring (incompletely ossified sternebrae noted in the mouse teratology study only);  
 There is no evidence to suggest that PT would have an adverse effect on the reproductive organs;  
 PT does not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system. PT has been evaluated in acute, repeated dose, mutagenicity, reproductive, developmental, and chronic toxicity (including carcinogenicity) studies capable of detecting effects on endocrine mediated events and has not demonstrated any endocrine-related effects. 
 
The %cPAD calculated for infants and children (2.88-12.48%) is 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 PT. 
 
A dietary exposure and risk assessment has not been conducted for the animal use of PT.  It is assumed that the use of PT in pesticide formulations applied pre- and post-harvest to food crops provides "worst-case" dietary exposures and risks.  Since all dietary risk estimates for agricultural use are below 100%, no dietary risk issues are anticipated for the on-animal use of PT. 
 
	i. 	Food.  
 
Food crop exposures are well below 100% of the cPAD, and are therefore below EPA's established level of concern for all U.S. subpopulations.  
    ii. 	Drinking water.  
       
Drinking water exposure is not likely from the use of PT as an inert ingredient in pesticide products. Exposures to residues above toxicity levels of concern are not anticipated.  
 
 	 
 Cumulative Effects 
 
PT does not share a common mechanism of toxicity with any other pesticide active and/or inert ingredient. 
 
 Safety Determination 
 
The proposed use of PT will not increase the current exposure due to other non-pesticide exposures.  
 
 U.S. population.  
 
The %cPAD calculated for the general population (3.83%), adults (2.89-3.04%), and females 1349 (2.91%) is 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 PT.  
 
 Infants and children. 
 
FFDCA Section 408 requires an additional ten-fold 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 PT has been performed and BASF believes the FQPA safety factor can be reduced from the default 10x to 3x for the following reasons: 
  
 The availability of a substantial and scientifically sound mammalian toxicology database that includes acute, repeat dose, mutagenicity, reproductive, developmental, and chronic toxicity (including carcinogenicity) data for PT; 
 Testing indicating that there was equivocal to no evidence of developmental toxicity or malformations in the developing offspring (incompletely ossified sternebrae noted in the mouse teratology study only);  
 There is no evidence to suggest that PT would have an adverse effect on the reproductive organs;  
 PT does not belong to a class of chemicals known or suspected of having adverse effects on the estrogen receptor or endocrine system. PT has been evaluated in acute, repeated dose, mutagenicity, reproductive, developmental, and chronic toxicity (including carcinogenicity) studies capable of detecting effects on endocrine mediated events and has not demonstrated any endocrine-related effects. 
 
The %cPAD calculated for infants and children (2.88-12.48%) is 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 PT. 
 
 	 
 International Tolerances 
 
There are no CODEX MRLs established for PT.