3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctanesulphonic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) determined a NOAEL ≥ 45 mg/kg bw for fertility and a NOAEL of 15 mg/kg bw/day for systemic parental toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

45 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

OECD 422 Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening

The study was performed according to OECD TG 422 and GLP principles (Triskelion 2018). The test substance was administered once daily by oral gavage, as a suspension in tap water. Controls were treated with vehicle (tap water) only. The study comprised 4 groups of 12 male and 12 female Wistar Han IGS rats (Crl:WI(Han)) each, viz. one control group that received the vehicle and three groups that received the test substance. The dose levels have been selected in consultation with the sponsor and are based on the results of a 2-weeks dose-range finding study with the test item in rats. The test substance was administered at dose levels of 5, 15 or 45 mg/kg body weight/day 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 90 days of exposure. A dosing volume of 5 mL/kg body weight was applied in all groups.

In life parameters included clinical observations, body weight, food consumption, mating, gestation and delivery parameters and individual pup parameters up to lactation day 13. At necropsy animals were macroscopically examined and several organs were examined microscopically. The oral administration of test substance was well tolerated. There were no mortalities or changes in clinical signs, neurobehavioural observations, growth, food intake, red blood cell variables, clotting potential and results on macroscopy. A treatment-relationship could not be ruled out for the lower mean total protein levels and mean albumin levels in the low dose and high dose males. However, in absence of a dose-response relationship and in view of the limited effect, this was not considered adverse. In addition the higher mean urea levels in high dose males were considered related to treatment. Microscopic evaluation revealed treatment related histopathological changes in the kidneys, characterized by mild to moderate (multi)focal tubular dilatation in 1/12 high-dose females. Because of this finding, the kidneys of the low- and mid-dose animals were also processed and examined microscopically. In these groups tubular dilatation was not observed. There was no effect of the test substance on male and female fertility or reproductive performance. There were no effects on the litter data in the number of pups, pup survival, growth, sex ratio and developmental parameters.

Based on the histopathological changes in the kidney the NOAEL for maternal toxicity was considered to be 15 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 stablished at ≥ 45 mg/kg body weight per day.

14 day Dose range finder

An oral (gavage) 14-day dose range finding study with test substance was performed in Wistar Han IGS rats (Crl:WI(Han)) (Triskelion 2018). The objective of this study was to provide data for selection of the dose levels to be used in the combined repeated dose and reproduction toxicity screening study.

In the two week dose range finding study, 4 groups of 5 males and 5 females each were dosed with 0, 10, 50 and 100 mg/kg body weight per day by oral gavage. A dosing volume of 10 mL/kg body weight was used in all groups. Drinking water was used as vehicle. The vehicle was used for dosing the control group and was used for diluting the test item to the appropriate concentrations.

Daily oral (gavage) administration of test substance to male and female Wistar rats for fourteen consequtive days resulted in:

• No mortalities and treatment-related clinical signs;

• Dose related decrease in body weight gain in the males of the 50 and 100 mg/kg bw groups and the females of the 100 mg/kg bw group;

• Decrease in food consumption in the males of the 50 and 100 mg/kg bw groups and the females of the 100 mg/kg bw group;

• Dose related effects on clinical chemistry parameters (creatinine levels and urea levels) in males in the 50 and 100 mg/kg group and females in the 100 mg/kg group;

• Dose related effects on organ weight (increased kidney weight) in males in the 50 and 100 mg/kg group and females in the 100 mg/kg group;

• No treatment related macroscopic changes.

Analysis of the test formulations showed that the test substance was a homogeneous suspension and stable in the refrigerator for 8 days.

Based on the above results treatment-related effects were observed at 50 and 100 mg/kg body weight test substance after 14 consecutive days of oral (gavage) administration. In view of the longer duration of dosing in the subsequent combined toxicity and reproduction screening study, which will be at least 10 weeks for males and 15 weeks for females, a dose level of approximately 50 mg/kg is suggested as high dose. This dose level is anticipated to induce effects on clinical chemistry parameters, organ weights and possibly body weight and is therefore considered an appropriate dose level for the high dose group in an OECD 422 study.

Effects on developmental toxicity

Description of key information

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) determined a NOAEL ≥ 45 mg/kg bw for developmental toxicity and a NOAEL of 15 mg/kg bw.day for maternal systemic toxicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

45 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

OECD 422 Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening

The study was performed according to OECD TG 422 and GLP principles (Triskelion 2018). The test substance was administered once daily by oral gavage, as a suspension in tap water. Controls were treated with vehicle (tap water) only. The study comprised 4 groups of 12 male and 12 female Wistar Han IGS rats (Crl:WI(Han)) each, viz. one control group that received the vehicle and three groups that received the test substance. The dose levels have been selected in consultation with the sponsor and are based on the results of a 2-weeks dose-range finding study with the test item in rats. The test substance was administered at dose levels of 5, 15 or 45 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 sacrifices after 90 days of exposure. A dosing volume of 5 mL/kg body weight was applied in all groups.

In life parameters included clinical observations, body weight, food consumption, mating, gestation and delivery parameters and individual pup parameters up to lactation day 13. At necropsy animals were macroscopically examined and several organs were examined microscopically.

The oral administration of test substance was well tolerated. There were no mortalities or changes in clinical signs, neurobehavioural observations, growth, food intake, red blood cell variables, clotting potential and results on macroscopy.

Microscopic evaluation revealed treatment related histopathological changes in the kidneys, characterized by mild to moderate (multi)focal tubular dilatation in 1/12 high-dose females. Because of this finding, the kidneys of the low- and mid-dose animals were also processed and examined microscopically. There was no effect of the test substance on female fertility or reproductive performance. There were no effects on the litter data in the number of pups, pup survival, growth, sex ratio and developmental parameters.

Based on the histopathological changes in the kidney in the females the NOAEL for maternal toxicity was considered to be 15 mg/kg body weight per day. Based on the absence of effects on fertility and developmental parameters, the NOAL for fertility and developmental toxicity was established at ≥ 45 mg/kg body weight per day.

14 day dose range finder study

An oral (gavage) 14-day dose range finding study with test substance was performed in Wistar Han IGS rats (Crl:WI(Han)) (Triskelion 2018). The objective of this study was to provide data for selection of the dose levels to be used in the combined repeated dose and reproduction toxicity screening study.

In the two week dose range finding study, 4 groups of 5 males and 5 females each were dosed with 0, 10, 50 and 100 mg/kg body weight per day by oral gavage. A dosing volume of 10 mL/kg body weight was used in all groups. Drinking water was used as vehicle. The vehicle was used for dosing the control group and was used for diluting the test item to the appropriate concentrations.

Daily oral (gavage) administration of test substance to male and female Wistar rats for fourteen consequtive days resulted in:

• No mortalities and treatment-related clinical signs;

• Dose related decrease in body weight gain in the males of the 50 and 100 mg/kg bw groups and the females of the 100 mg/kg bw group;

• Decrease in food consumption in the males of the 50 and 100 mg/kg bw groups and the females of the 100 mg/kg bw group;

• Dose related effects on clinical chemistry parameters (creatinine levels and urea levels) in males in the 50 and 100 mg/kg group and females in the 100 mg/kg group;

• Dose related effects on organ weight (increased kidney weight) in males in the 50 and 100 mg/kg group and females in the 100 mg/kg group;

• No treatment related macroscopic changes.

Analysis of the test formulations showed that the test substance was a homogeneous suspension and stable in the refrigerator for 8 days.

Based on the above results treatment-related effects were observed at 50 and 100 mg/kg body weight test substance after 14 consecutive days of oral (gavage) administration. In view of the longer duration of dosing in the subsequent combined toxicity and reproduction screening study, which will be at least 10 weeks for males and 15 weeks for females, a dose level of approximately 50 mg/kg is suggested as high dose. This dose level is anticipated to induce effects on clinical chemistry parameters, organ weights and possibly body weight and is therefore considered an appropriate dose level for the high dose group in an OECD 422 study.

Justification for classification or non-classification

Based on the available data, the test substance is not classified in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.