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. 

A. Residue Chemistry

Residue data, including an analytical method, is not pertinent or required for this petition since 

an exemption from tolerance is requested. 

B. Toxicological Profile

An extensive safety data base has been complied on Pentaerythritol Tetrakis (3-(3,5-di-tert-butyl4-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. 

1. 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.

a. Acute oral toxicity

The acute oral toxicity of PT is greater than 10,250 mg/kg-bw. 
2

b. Acute dermal toxicity.

The acute dermal toxicity of PT is greater than 3,160 mg/kg bw.

c. Acute inhalation toxicity.

The acute inhalation toxicity of PT is greater than 1.95 mg/L. 

d. Acute eye irritation.

PT is not irritating or corrosive to eyes. 

e. Acute skin irritation.

PT is not irritating or corrosive to skin. 

f. Skin sensitization

PT is not a dermal sensitizer. 

2. Genotoxicity

No evidence of genotoxicity or chromosomal effects was observed in mutagenicity studies 

conducted with PT. 

a. 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. 

b. 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. 

c. Mammalian Micronucleus Test
3

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. 

d. 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. 

3. Reproductive and developmental toxicity.

No significant reproductive or developmental effects were noted in any of the tests conducted.

a. 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 HDT1) 

 

1 HDT = Highest dose tested. 
4

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 

4. Subchronic toxicity

a. Subchronic oral toxicity.
5

In a 13-week oral dog study, no adverse effects were reported up to 250 mg/kg-bw/day (highest 

dose tested). 

5. Chronic toxicity.

a. 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. 

b. 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. 

6. 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. 

7. Metabolite toxicology. 
6

There are no metabolites of toxicological concern. 

8. 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. 
7

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. 
8

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. 

D. Cumulative Effects

PT does not share a common mechanism of toxicity with any other pesticide active and/or inert 

ingredient. 

E. Safety Determination

The proposed use of PT will not increase the current exposure due to other non-pesticide 

exposures. 

1. 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. 

2. 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 
9

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. 

F. International Tolerances

There are no CODEX MRLs established for PT.