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Description of key information

Key information:

Repeated dose toxicity study (OECD 422, Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test): A systemic NOAEL was established at 15.0 mg/kg bw and a LOEC 45 mg/kg bw/day; Read across from analogue source substance;

Supporting information:

Short-term repeated dose toxicity: oral: rat NOAEL was determined to be 30 ppm. The NOAEL was based on the increases in mean absolute and relative liver weight observed in the 300 and 3000 ppm dose groups and the decreases in mean body weights and body weight gains observed in the 3000 ppm dose group.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
15 mg/kg bw/day
Study duration:
subchronic
Species:
rat
System:
urinary
Organ:
kidney

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Combined repeated dose toxicity and reproduction/developmental toxicity screening test

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. A dosing volume of 5 mL/kg body weight was applied in all groups. Male animals were sacrifices after 90 days of exposure.

In life parameters included clinical observations, body weight and food consumption. 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.

No effects on hormone levels (T4) were observed in adult males. Microscopic evaluation revealed treatment related histopathological changes in the kidneys, characterized by mild to moderate (multi)focal tubular dilatation in 5/12 high-dose males and 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. Based on the histopathological changes in the kidney in the males the NOAEL for systemic toxicity was considered to be 15 mg/kg body weight per day.

14-day dose range finding 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 classified as STOT-RE 2 (H373: May cause damage to organs through prolonged or repeated exposure) in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.