1,1,2,2,3,3,4,4,4-nonafluoro-N-(2-hydroxyethyl)-N-methylbutane-1-sulphonamide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

The subacute oral toxicity and potential for reproductive and developmental toxicity (screening level) of T-7599 (white powder, purity >99.9%, CASRN 34454-97-2, Lot 6) was evaluated in Sprague-Dawley rats following repeated oral doses. This study was performed in compliance with OECD GLP (1998), US FDA GLP 21 CFR 58, and Japanese MHW GLP (1997). The study method was based on OECD 422 (1996) and US EPA In Vivo Reproductive and Mutagenicity Tests (1982). T-7599 was prepared in 0.5% carboxymethylcellulose (CMC) for the first 4 days of the study and then was prepared in 1.0% CMC for the remainder of the study. Rats (15/sex/dose) received repeated doses of 0 (vehicle), 10, 50, or 250 mg/kg/day via oral gavage at a dose volume of 10 mL/kg. Male rats received their respective doses once daily beginning at 14 days before cohabitation and continuing after the cohabitation period for minimum total of 28 days. Female rats received their respective doses once daily beginning at 14 days before cohabitation and continuing until Day 5 of lactation (LD 5). Within each dosage group, one male rat was assigned per one female rat during the cohabitation period (maximum of 14 days). Mating was confirmed by examining female rats for spermatozoa in vaginal smears and/or absence of copulatory plug. After 36 days of dosage, all males were euthanized. On LD 5 and 6, all surviving pups and females were euthanized, respectively. Parameters evaluated: clinical observations (at least daily), body weight (daily during dosing), food consumption (at least weekly), estrous cycling, litter sizes, pup viability, clinical and necropsy observations of pups, maternal behavior, functional observational battery (5/sex/dose), and hematology and clinical biochemistry (5/sex/dose). Gross necropsy and histological evaluation of select organs were performed on males and females. All males and females survived. Significant increases in excess salivation, perioral substance and urine-stained abdominal fur was observed in the 250 mg/kg/day treated male rats. No abnormal clinical observations were noted in female rats. Body weight gains and absolute and relative food consumption were significantly reduced in the 50 and 250 mg/kg/day-treated males. Body weight gains of the females were significantly reduced during the precohabitation period in the 250 mg/kg/day dose group, but body weights and body weight gains were not significantly affected during gestation or lactation. Terminal body weights of the female rats were reduced in the 250 mg/kg/day dose group. No gross abnormalities were observed upon necropsy. Absolute liver weights were significantly increased in 250 mg/kg/day-treated males and females. Liver weights relative to terminal body weights were significantly increased in the 50 and 250 mg/kg/day treated males. The ratio of liver weight to brain weight was significantly increased in the 250 mg/kg/day-treated males and females. Microscopic examination revealed minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most males treated at 250 mg/kg/day and in 4/10 males treated at 50 mg/kg/day. Also in three 250 mg/kg/day-treated males, necrosis of individual enlarged hepatocytes was observed in the centrilobular areas. Minimal or mild hypertrophy of centrilobular hepatocytes was also observed in most females treated at 250 mg/kg/day. In both males and females, the hypertrophy was due to an increased amount of finely granular, dense eosinophilic cytoplasm. In both males and females, increased kidney weights were noted in the 250 mg/kg group and in males alone in the 50 mg/kg group. No microscopic changes were noted in the kidneys (male or female) upon histopathology. Microscopic examination of the thymus revealed an increased incidence and severity of atrophy of the thymic lobules in female rats treated at 250 mg/kg/day. No toxicologically relevant findings in the organ weight and histopathology of the thymus in male rats. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular mucosa of 2 males in the 250 mg/kg/day group. Minimal to mild edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 control group males, 2 males in the 50 mg/kg/day group, and 1 male in the 250 mg/kg/day group. Moderate edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 males in the 250 mg/kg/day group. Thus, the edema/inflammation was observed at a slightly higher incidence and severity in the 250 mg/kg/day dose group. No microscopic changes in the gastrointestinal tract of females were noted. There were no abnormal clinical or necropsy observations in the F1 generation pups. The number of liveborn pups was significantly reduced and the number of stillborn pups was significantly increased in the 250 mg/kg dosage group. The viability index and number of pups surviving per liter on postpartum day 5 were significantly reduced in the 250 mg/kg dosage group. Pup body weight was also reduced in the 250 mg/kg dosage group on postpartum days 1 and 5. Based on the results of the study, the repeat dose toxicity No Observed Adverse Effect Level (NOAEL) for the test article is 50 mg/kg/day. The male and female reproductive NOAEL is 250 mg/kg/day and the developmental NOAEL is 50 mg/kg/day.

Short description of key information:
A repeat-dose oral toxicity study with combined reproductive/developmental screening test was conducted on C4 Alcohol. The results of the study are:

A 28 day oral study resulted in a male and female reproductive NOAEL of 250 mg/kg/day, and a developmental NOAEL of 50 mg/kg/day when tested according to OECD 422.

Effects on developmental toxicity

Description of key information

A repeat-dose oral toxicity study with combined reproductive/developmental screening test was conducted on C4 Alcohol.  The results of the study are: 
A 28 day oral study resulted in a male and female reproductive NOAEL of 250 mg/kg/day, and a developmental NOAEL of 50 mg/kg/day when tested according to OECD 422.

Additional information

The subacute oral toxicity and potential for reproductive and developmental toxicity (screening level) of T-7599 (white powder, purity >99.9%, CASRN 34454-97-2, Lot 6) was evaluated in Sprague-Dawley rats following repeated oral doses. This study was performed in compliance with OECD GLP (1998), US FDA GLP 21 CFR 58, and Japanese MHW GLP (1997). The study method was based on OECD 422 (1996) and US EPA In Vivo Reproductive and Mutagenicity Tests (1982). T-7599 was prepared in 0.5% carboxymethylcellulose (CMC) for the first 4 days of the study and then was prepared in 1.0% CMC for the remainder of the study. Rats (15/sex/dose) received repeated doses of 0 (vehicle), 10, 50, or 250 mg/kg/day via oral gavage at a dose volume of 10 mL/kg. Male rats received their respective doses once daily beginning at 14 days before cohabitation and continuing after the cohabitation period for minimum total of 28 days. Female rats received their respective doses once daily beginning at 14 days before cohabitation and continuing until Day 5 of lactation (LD 5). Within each dosage group, one male rat was assigned per one female rat during the cohabitation period (maximum of 14 days). Mating was confirmed by examining female rats for spermatozoa in vaginal smears and/or absence of copulatory plug. After 36 days of dosage, all males were euthanized. On LD 5 and 6, all surviving pups and females were euthanized, respectively. Parameters evaluated: clinical observations (at least daily), body weight (daily during dosing), food consumption (at least weekly), estrous cycling, litter sizes, pup viability, clinical and necropsy observations of pups, maternal behavior, functional observational battery (5/sex/dose), and hematology and clinical biochemistry (5/sex/dose). Gross necropsy and histological evaluation of select organs were performed on males and females. All males and females survived. Significant increases in excess salivation, perioral substance and urine-stained abdominal fur was observed in the 250 mg/kg/day treated male rats. No abnormal clinical observations were noted in female rats. Body weight gains and absolute and relative food consumption were significantly reduced in the 50 and 250 mg/kg/day-treated males. Body weight gains of the females were significantly reduced during the precohabitation period in the 250 mg/kg/day dose group, but body weights and body weight gains were not significantly affected during gestation or lactation. Terminal body weights of the female rats were reduced in the 250 mg/kg/day dose group. No gross abnormalities were observed upon necropsy. Absolute liver weights were significantly increased in 250 mg/kg/day-treated males and females. Liver weights relative to terminal body weights were significantly increased in the 50 and 250 mg/kg/day treated males. The ratio of liver weight to brain weight was significantly increased in the 250 mg/kg/day-treated males and females. Microscopic examination revealed minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most males treated at 250 mg/kg/day and in 4/10 males treated at 50 mg/kg/day. Also in three 250 mg/kg/day-treated males, necrosis of individual enlarged hepatocytes was observed in the centrilobular areas. Minimal or mild hypertrophy of centrilobular hepatocytes was also observed in most females treated at 250 mg/kg/day. In both males and females, the hypertrophy was due to an increased amount of finely granular, dense eosinophilic cytoplasm. In both males and females, increased kidney weights were noted in the 250 mg/kg group and in males alone in the 50 mg/kg group. No microscopic changes were noted in the kidneys (male or female) upon histopathology. Microscopic examination of the thymus revealed an increased incidence and severity of atrophy of the thymic lobules in female rats treated at 250 mg/kg/day. No toxicologically relevant findings in the organ weight and histopathology of the thymus in male rats. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular mucosa of 2 males in the 250 mg/kg/day group. Minimal to mild edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 control group males, 2 males in the 50 mg/kg/day group, and 1 male in the 250 mg/kg/day group. Moderate edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 males in the 250 mg/kg/day group. Thus, the edema/inflammation was observed at a slightly higher incidence and severity in the 250 mg/kg/day dose group. No microscopic changes in the gastrointestinal tract of females were noted. There were no abnormal clinical or necropsy observations in the F1 generation pups. The number of liveborn pups was significantly reduced and the number of stillborn pups was significantly increased in the 250 mg/kg dosage group. The viability index and number of pups surviving per liter on postpartum day 5 were significantly reduced in the 250 mg/kg dosage group. Pup body weight was also reduced in the 250 mg/kg dosage group on postpartum days 1 and 5. Based on the results of the study, the repeat dose toxicity No Observed Adverse Effect Level (NOAEL) for the test article is 50 mg/kg/day. The male and female reproductive NOAEL is 250 mg/kg/day and the developmental NOAEL is 50 mg/kg/day.

Justification for classification or non-classification

The test article is classified as Repr. 2 according to CLP criteria.