Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: oral: LOAEL (female) =< 12 mg/kg bw/day, LOAEL (male) =< 1.5 mg/kg bw/day (similar to OECD 408, GLP, rel.2, K)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
1.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The key study is GLP-compliant and of high quality (Klimisch score = 2).
System:
endocrine system
Organ:
pituitary gland
thyroid gland

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

This study evaluated the potential toxicity of the test substance, AMITROLE, administered daily by oral route (gavage) for ten weeks in rats when compared to that of an anti-thyroidal reference substance, 6-propyl-2-thiouracil (PTU). The study was performed according to a protocol similar to the OECD guideline No. 408 and under GLP compliance.

Three principal groups, each of five male and five female Sprague-Dawley rats received the test substance, AMITROLE, daily, by oral route (gavage), at 1.5, 12 and 100 mg/kg bw/day (groups 2, 3 and 4). Two principal additional groups, each of five males and five females, were given the vehicle alone (group 1: purified water) or PTU (group 5) at 30 mg/kg bw/day under the same conditions, and acted as control and reference groups respectively. From day57(first day of week 8) of the study, animals of group 2, which initially received 1.5 mg/kg bw/day of AMITROLE, were given the test substance at 330 mg/kg bw/day and the dose-level was also increased in the reference group (group 5, PTU) to 60 mg/kg bw/day for a new treatment period of15days.

Satellite animals (nine males and nine females) were given the test substance at 100 mg/kg bw/day of under the same conditions for the determination of plasma levels of the test substance at designated time observations (15, 30 min and 1, 2, 4, 8 and 24 hours) after the first dosing. After the last sampling, all satellite animals were killed and discarded without necropsy.

The animals were checked daily for mortality and clinical signs. The food consumption and body weight of the animals were measured once a week. Haematology and blood biochemistry investigations were performed on all surviving animals on days 21 and 42. Additional blood samples were taken for thyroid function evaluation on days 7, 21 and 42, on all surviving animals.

At the end of the treatment period, the animals were killed and a macroscopicpost-mortemexamination was perfonned. Thyroids with parathyroids and the pituitary gland were weighed (all surviving animals) and submitted to a microscopic examination (animals of control and high dose-level groups).

The absorption and elimination of the substance were evaluated by HPLC in serum from satellite animals which received a single administration of AMITROLE at the dose-level of 100mg/kg bw.

Absorption of the test substance was observed at all time points in both sexes and comparable Cmaxwere noted 2 hours after the administration of the test substance (394 and 341 µg/mL inmalesand females respectively).Extent ofabsorption,asmeasured byAUC0 -24h wassome whatgreater in the males than in the females (725 and 668 µg/h respectively).Elimination, estimated by apparent tmaxwas not influenced by gender (2 hours for both sexes).

The test substance (up to 12 mg/kg bw/day) and the reference substance (up to 30 mg/kg bw/day) were clinically well-tolerated.The effects observed in animals given the test substance at 100mg/kg bw/day or those which received PTU at 30 and then 60 mg/kg w/day were related to the anti-thyroidal properties of the test or reference substances. When compared to the reference substance, the treatment with the test substance resulted in a less marked inhibition of thyroid function.

Under the test conditions, the Lowest Observed Adverse Effect Level (LOAEL) was lower than or equal to 12 mg/kg bw/day in females and lower than or equal to 1.5 mg/kg bw/day in males according to observed effects on thyroid and pituitary glands, including changes in thyroidal hormone levels, especially the TSH levels observed on day 42.

Furtheremore, observations performed during the evaluation of the toxicity to reproduction, i.e. two generation reproductive toxicity in rats and developmental toxicity in rats (not observed in rabbit studies), were consistent with the thyroid effects observed during the repeated dose toxicity.

Justification for classification or non-classification

Harmonized classification:

The substance has an harmonized classification in STOT-RE Category 2 (H373: May cause damage to organs through prolonged or repeated exposure) for repeated dose toxicity according to the Regulation (EC) No 1272/2008.

Self-classification:

No additionnal self-classification is proposed.

Specific target organ toxicity: repeated exposure (Oral):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – repeated exposure via oral route are met since adverse effects were observed on endocrine system (thyroid and pituitary glands) after exposure to any doses (lowest dose= 1.5 mg/kg bw/day). Thyroid effects were also observed in developmental toxicity studies in rats but not in rabbits.

Effects on thyroid activity (increase) was the reason for the harmonized classification in STOT-RE Category 2 (H373:May cause damage to organs through prolonged or repeated exposure). Therefore, no addition self-classification is proposed.

Specific target organ toxicity: repeated exposure (Inhalation):

No data available.

Specific target organ toxicity: repeated exposure (Dermal):

No data available.