N-[3-(dimethylamino)propyl]-3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanesulphonamide N-oxide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

OECD 422: Based on the histopathological findings in the liver of the males, together with the clinical chemistry observations, the NOAEL for parental toxicity was conservatively placed at 1 mg/kg body weight per day. Based on the absence of effects on fertility and developmental parameters, the NOAEL for fertility was placed at ≥ 20 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test (OECD 422)

A study was performed according to OECD guideline 422 and GLP principles. The objectives of this study (Triskelion, 2018) were to provide data on general toxicity and the possible effects of the test substance on reproductive performance and development of pups. The test substance was administered daily by oral gavage at dose levels of 1, 20 or 80 mg/kg body weight during a premating period of 10 weeks and during mating (1 week), gestation and lactation until 14 days after delivery. Male animals were sacrificed after at least 90 days of treatment. Because of mortality in the high-dose group, the high-dose level was reduced to 50 mg/kg body weight/day at day 44 of treatment. After 56 days after the start of treatment (premating period) the high-dose group was sacrificed because of deteriorating health.

The results of test substance analysis in the carrier (water) showed that, on average, the test substance was homogenously distributed in the carrier and that the concentrations of the test substances in the carrier were close to intended.

Three males and one female in the high-dose group were killed in moribund condition. These deaths were treatment-related and also occurred after the high-dose level had been reduced from 80 to 50 mg/kg bw/day. After 56 days of treatment the remaining male and female animals were sacrificed because of deteriorating health. The observations in these remaining high-dose animals were: Clinical signs, up to day 57 of treatment, in the high-dose group included dyspnoea, thin, muscle weakness, lethargic, hunched posture, piloerection, soiled fur, encrustation of nose, eyes, ears and legs, discharge of the nose and eyes, macrophthalmia, and a swollen leg. Weekly detailed clinical examinations confirmed the above daily clinical observations in the high-dose group. Mean body weights and food consumption were decreased in the and high-dose groups in both sexes. A decrease in cholesterol levels phospholipid levels in high-dose males was noted after 56 days of treatment. The relative liver and kidney weights were higher in high-dose males. Macroscopically, in the high-dose group, enlarged spleens and mesenteric lymph nodes were found and pale/yellow spots/nodules were found in the liver and longs.

The following observations were made in the control, low- and mid-dose groups: No treatment-related clinical signs were noted in the mid- and low-dose groups. The results of the neurobehavioral observations and motor activity assessment did not indicate any neurotoxic potential of the test substance in rats. No changes were observed in body weight. Body weight change was only slightly decreased at the start of treatment in all groups. Except from a slightly lower food consumption in mid-dose males at the initial stage of the study there were no other differences in food consumption. Haematology was conducted in 5 rats/sex/group at necropsy. There were no toxicologically relevant changes noted. Clinical chemistry, conducted in 5 rats/sex/group at necropsy, showed a treatment related decrease in cholesterol levels and in phospholipid levels in mid-dose males. Urea and potassium levels were increased in mid-dose males. No treatment-related differences were observed in relative and absolute organ weights in both sexes. Microscopic analysis of the control and the mid-dose groups, revealed treatment-related pathology in the liver, characterized by minimal to moderate centrilobular hepatocellular microvacuolation in the males of the mid-dose group. No centrilobular microvacuolation was observed in the control and the low-dose groups. In addition to the centrilobular microvacuolation, minimal to mild accumulation of alveolar macrophages was observed in the lungs of both males and females of the mid-dose groups. No accumulation of alveolar macrophages was found in the control and low-dose groups. There were no effects of the test substance on estrous cycle and on fertility and reproductive performance. Results of T4 hormone analysis in male parental animals and in male and female pups of postnatal day 13 did not show any significant effects between the groups. No effects were observed on pup observations, pup sex, pup survival and pups weight.

Based on the histopathological findings in the liver of the males, together with the clinical chemistry observations, the NOAEL for parental toxicity was conservatively placed at 1 mg/kg body weight per day. Based on the absence of effects on fertility and developmental parameters, the NOAEL for fertility and developmental toxicity was placed at ≥ 20 mg/kg body weight per day.

 

Dose-range finding study

The objective of this study (Triskelion, 2018) was to select dose levels for the subsequent combined repeated dose and reproduction toxicity screening study with the test substance in rats. Daily oral (gavage) administration of 0, 50, 250 or 1000 mg/kg bw the test substance to male and female Wistar rats for fourteen consecutive days resulted in:

- The spontaneous death of 2 male and 3 females in the 1000 mg/kg bw group on day 6 of the study. The remaining animals were sacrificed moribund based on clinical signs

and body weight loss.

- The spontaneous death of 1 female in the 250 mg/kg bw group on day 9 of the study. The remaining animals were sacrificed moribund based on clinical signs and body weight loss.

- In the 50 mg/kg bw group all animals survived the 14-day dosing period and showed no treatment-related clinical signs.

- Decreased body weight and body weight gain in the 250 and 1000 mg/kg bw groups. No effect on body weight in the 50 mg/kg bw group was observed.

- Decreased food consumption in the 250 and 1000 mg/kg bw groups. No effect on the food consumption in the 50 mg/kg bw group was observed.

- Clinical chemistry parameters showed treatment-related effects on the liver parameters (ALP, ALAT, ASAT, GGT) in the 250 and 1000 mg/kg bw groups.

- Dose related increase in mean kidney and liver weight in the 250 and 1000 mg/kg bw groups. No statistical significant changes in kidney and liver weight were observed in the 50 mg/kg bw group.

- Macroscopic examination of the animals at the scheduled and and unscheduled necropsies showed changes in the liver.

- Histopathological evaluation of the livers revealed a dose-dependent pathology in the liver, characterized by hepatocellular microvacuolation, mixed inflammation and necrosis in the 250 and 1000 mg/kg bw groups. No treatment-related pathology was observed in the control and 50 mg/kg bw groups.

Analysis of the test formulations showed that the test substance was homogeneously distributed and stable in the refrigerator for 8 days. The concentrations were close to intended. Based on these results dose levels of 250 and 1000 mg/kg bw exceed the maximum tolerated dose. Based on the macroscopic effects, the increase in liver weight and the effects on liver parameters in clinical chemistry, the liver is a sensitive target organ. Taking into account the longer duration of dosing in the subsequent OECD 422 study, which will be at least 10 weeks for males and 15 weeks for females, a dose level lower between 50 and 250 mg/kg bw is suggested as high dose in the subsequent study.

Effects on developmental toxicity

Description of key information

OECD 422: Based the observed effects in the high dose group, the NOAEL for maternal toxicity was placed at 20 mg/kg body weight per day. Based on the absence of effects on developmental parameters at the highest analysable dose, the NOAEL for developmental toxicity was placed at ≥ 20 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

20 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Combined repeated dose toxicity study with the reproduction/ developmental toxicity screening test (OECD 422)

A study was performed according to OECD guideline 422 and GLP principles. The objectives of this study (Triskelion, 2018) were to provide data on general toxicity and the possible effects of the test substance on reproductive performance and development of pups. The test substance was administered daily by oral gavage at dose levels of 1, 20 or 80 mg/kg body weight during a premating period of 10 weeks and during mating (1 week), gestation and lactation until 14 days after delivery. Because of mortality in the high-dose group, the high-dose level was reduced to 50 mg/kg body weight/day at day 44 of treatment. After 56 days after the start of treatment (premating period) the high-dose group was sacrificed because of deteriorating health.

The results of test substance analysis in the carrier showed that, on average, the test substance was homogenously distributed in the carrier and that the concentrations of the test substances in the carrier were close to intended. One female in the high-dose group was killed in moribund condition. These deaths were treatment-related and also occurred after the high-dose level had been reduced from 80 to 50 mg/kg bw/day. After 56 days of treatment the remaining female animals were sacrificed because of deteriorating health. The observations in these remaining high-dose animals are described below: Clinical signs noted, up to day 57 of treatment, in the high-dose group included dyspnoea, thin, muscle weakness, lethargic, hunched posture, piloerection, soiled fur, encrustation of nose, eyes, ears and legs, discharge of the nose and eyes, macrophthalmia, and a swollen leg. Weekly detailed clinical examinations confirmed the above daily clinical observations in the high-dose group. Mean body weights and food consumption were decreased in the and high-dose groups in both sexes. Macroscopically, in the high-dose group, enlarged spleens and mesenteric lymph nodes were found and pale/yellow spots/nodules were found in the liver and longs. The following observations were made in the control, low- and mid-dose groups: No treatment-related clinical signs were noted in the mid- and low-dose groups. The results of the neurobehavioral observations and motor activity assessment did not indicate any neurotoxic potential of the test substance in rats.

No changes were observed in body weight. Body weight change was only slightly decreased at the start of treatment in all groups. There were no other differences in food consumption.

Hematology was conducted in 5 rats/sex/group at necropsy. There were no toxicologically relevant changes noted. No treatment-related differences were observed in relative and absolute organ weights. Microscopic analysis of the control and the mid-dose groups, revealed minimal to mild accumulation of alveolar macrophages which was observed in the lungs of of the mid-dose groups. No accumulation of alveolar macrophages was found in the control and low-dose groups. There were no effects of the test substance on estrous cycle and on fertility and reproductive performance. Results of T4 hormone analysis in male and female pups of postnatal day 13 did not show any significant effects between the groups. No effects were observed on pup observations, pup sex, pup survival and pups weight.

Conclusions: Based the observed effects in the high dose group, the NOAEL for maternal toxicity was placed at 20 mg/kg body weight per day. Based on the absence of effects on developmental parameters, the NOAEL for fertility and developmental toxicity was placed at ≥ 20 mg/kg body weight per day.

 

Dose-range finding study

The objective of this study (Triskelion, 2018) was to select dose levels for the subsequent combined repeated dose and reproduction toxicity screening study with the test substance in rats. Daily oral (gavage) administration of 0, 50, 250 or 1000 mg/kg bw the test substance to male and female Wistar rats for fourteen consecutive days resulted in:

- The spontaneous death of 2 male and 3 females in the 1000 mg/kg bw group on day 6 of the study. The remaining animals were sacrificed moribund based on clinical signs

and body weight loss.

- The spontaneous death of 1 female in the 250 mg/kg bw group on day 9 of the study. The remaining animals were sacrificed moribund based on clinical signs and body weight loss.

- In the 50 mg/kg bw group all animals survived the 14-day dosing period and showed no treatment-related clinical signs.

- Decreased body weight and body weight gain in the 250 and 1000 mg/kg bw groups. No effect on body weight in the 50 mg/kg bw group was observed.

- Decreased food consumption in the 250 and 1000 mg/kg bw groups. No effect on the food consumption in the 50 mg/kg bw group was observed.

- Clinical chemistry parameters showed treatment-related effects on the liver parameters (ALP, ALAT, ASAT, GGT) in the 250 and 1000 mg/kg bw groups.

- Dose related increase in mean kidney and liver weight in the 250 and 1000 mg/kg bw groups. No statistical significant changes in kidney and liver weight were observed in the 50 mg/kg bw group.

- Macroscopic examination of the animals at the scheduled and and unscheduled necropsies showed changes in the liver.

- Histopathological evaluation of the livers revealed a dose-dependent pathology in the liver, characterized by hepatocellular microvacuolation, mixed inflammation and necrosis in the 250 and 1000 mg/kg bw groups. No treatment-related pathology was observed in the control and 50 mg/kg bw groups.

Analysis of the test formulations showed that the test substance was homogeneously distributed and stable in the refrigerator for 8 days. The concentrations were close to intended. Based on these results dose levels of 250 and 1000 mg/kg bw exceed the maximum tolerated dose. Based on the macroscopic effects, the increase in liver weight and the effects on liver parameters in clinical chemistry, the liver is a sensitive target organ. Taking into account the longer duration of dosing in the subsequent OECD 422 study, which will be at least 10 weeks for males and 15 weeks for females, a dose level lower between 50 and 250 mg/kg bw is suggested as high dose in the subsequent study.

Justification for classification or non-classification

Based on the available data classification for reproductive / developmental toxicity is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.