Document wrOxaGxpBvjxx1DabKVaG95Bo

ORIGINA DOCS NOT CONTAIN CBI 3325^ DuPont Haskell Global Centers for Health and Environmental Sciences 1090 Elkton Road, P.O. Box 50 Newark, DE 19714-0050 January 18, 2011 Via Federal Express Document Processing Center (Mail Code 7407M) Room 6428 Attention: 8(e) Coordinator Office of Pollution Prevention and Toxics U.S. Environmental Protection Agency 1201 Constitution Ave., NW Washington, DC 20004 Dear 8(e) Coordinator: 8E HQ 06 164 7 8 9 1 10 0 0 0 0 7 1 V 0^0 ____- UD T 3* re _- o -o o r~* i O -<T < r.1" cn CD 8EHO-Q6-16436/8EHO-06-16478 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propionic acid, ammonium salt CAS # 62037-80-3 This letter is a supplement to our letter of July 15, 2010 and summarizes the final results of a reproduction/developmental toxicity screening study in mice with the above referenced test substance. This test substance is subject to a Consent Order, P-08-509. The test substance was administered once daily via oral gavage to groups o f F0 mice (CD-I; 25 per sex per dose group) at doses of 0 (deionized water), 0.1, 0.5, or 5 mg/kg/day at a dose volume of 10 ml/kg/day. Male mice (F0) were dosed for a minimum of 70 days prior to mating and continued until the day of scheduled euthanasia. Female mice (F0) were dosed for a minimum o f 14 days prior to mating and continued throughout mating, gestation, and lactation until the day o f scheduled euthanasia following weaning o f offspring. For females that did not have positive signs of mating or delivery, dosing continued until the day o f euthanasia. Fi males and females were dosed beginning in postnatal day (PND) 21 until the day o f euthanasia. Clinical signs, body weights, and food consumption were recorded throughout the study. At scheduled euthanasia, all animals underwent a gross external and internal examination; selected organs/tissues were weighed and/or retained for histopathologic examination. Reproductive performance was assessed by gonadal function, mating behavior, conception, parturition and lactation of the F0 generation and the development o f offspring from conception through day 40 o f postnatal life. Developmental landmark data (vaginal patency and balanopreputial separation) were collected for F! offspring. Plasma samples for toxicokinetic analyses were collected from culled pups and pooled by litter on PND 4. Plasma samples for toxicokinetic analyses were also prepared from a terminal bleed for F0 females, weanlings that were not selected for developmental landmarks (PND 21), and weanlings designated for developmental landmarks (PND 40). F0 and F, survival were unaffected by test substance administration at all dosage levels. Test substance-related, but non-adverse increases in body weights/gains and food consumption were observed in F0 males and females at 5 and 0.5 mg/kg/day. Test substance-related lower mean body weights and body weight gains were noted for F! males and females in the 5 mg/kg/day group throughout the pre-weaning period. Mean body weights in the 5 mg/kg/day females were similar to the control group by PND 35 and the differences in body weights observed in the males were progressively less from PND 21-40. There were no test substance-related body weight or body weight gain differences from the control group in F! males and females in the 0.1 and 0.5 mg/kg/day groups. Delays in the attainment o f balanopreputial separation and vaginal patency were noted in the F[ males and females in the 5 mg/kg/day group when compared to the control group. However, these delays were attributed to the effects on mean body weight noted in this group during the pre-weaning period and not considered to be a direct effect of O&NTAfNSfoO GBI test substance administration. No test substance-related effects were observed on F0 reproductive performance (mating, fertility, or copulation indices, and mean days between pairing and coitus), mean gestation length, the process o f parturition, mean numbers o f implantation sites, or unaccounted-for sites. Mean numbers o f Fi pups bom, live litter size, percentage o f males at birth, postnatal survival, and the general physical condition of the F! pups were unaffected by test substance administration at all dosage levels. A slight increase in the incidence of gross white areas in liver in the 5 mg/kg/day F0 females correlated with microscopic focal necrosis. There were no test substance-related gross findings in the F0 males and females in the 0.1 and 0.5 mg/kg/day groups or in the F0 males in the 5 mg/kg/day group. F] necropsy findings did not indicate any correlation to test substance administration. Microscopic examination o f the reproductive organs of both males and females revealed no test substance-related effects at any dose level tested. Microscopically, minimal to moderate hepatocellular hypertrophy was present in both sexes of F0 adults at dose levels o f 0.5 and 5 mg/kg/day. A corresponding increase in liver weight parameters was observed at both dose levels. Hepatocellular hypertrophy was characterized by cytoplasmic eosinophilic stippling that is consistent with peroxisome proliferation. In the 5 mg/kg/day F0males and females, other liver lesions included increases in single cell necrosis, mitotic figures, lipofuscin pigment, and focal necrosis (females only). A low incidence of single cell necrosis was also present in the 0.5 mg/kg/day male group. Microscopic examination of the kidneys of all F0 adults revealed a minimal increase in non-adverse tubular cell hypertrophy in males given 0.5 and 5 mg/kg/day. This finding correlated with an increase in mean absolute kidney weight in both sexes given 5 mg/kg/day. The mean maternal plasma concentrations of test substance measured two hours after dosing on day 21 o f lactation were 903, 4966, and 36420 ng/ml in the 0.1, 0.5, and 5 mg/kg/day dose groups, respectively. In postnatal day 4 F! pups, mean plasma levels were lower (approximately 2- to 4-fold) than the lactation day 21 maternal values. In postnatal day 21 F, pups, mean plasma levels o f test substance in all dose groups were markedly less (approximately 40- to 60-fold lower) than the respective lactation day 21 maternal values. In the F) offspring samples on postnatal day 40 that had been directly dosed since weaning on postnatal day 21, mean plasma levels of test substance were similar to those o f the respective maternal dose groups sampled at postnatal day 21. This information is submitted in accordance with current guidance issued by EPA indicating EPA's interpretation o f Section 8(e) o f the Toxic Substances Control Act or, where it is not clear that reporting criteria have been met, it is submitted as a precautionary measure and because it is information in which EPA may have an interest. 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