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EC number: 945-733-5 | CAS number: -
The analytical procedure was successfully validated with respect to specificity of the analysis, method accuracy and precision.
The homogeneity was confirmed for the test material in purified water formulations at nominal concentrations of 10 mg/mL and 200 mg/mL during distribution between the bottles, during magnetic stirring for up to 4 hours, ambient temperature storage (15 to 25 °C) for 1 day and refrigerated storage (2 to 8 °C) for up to 15 days.
The mean concentrations of the test material in test formulations analysed for the study were within +10/-15 % of nominal concentrations, confirming accurate formulation, with the exception of Week 1 Groups 2 to 4. The difference from mean remained within 4 %, confirming precise analysis, with the exception of Week 1 Groups 2 to 4. The procedural recoveries remained within the validated range, confirming the continued accuracy of the analytical procedure.
Mean Serum T4 Concentration (pg/mL)
Adult terminal males
Male offspring on Day 13 of age
Female offspring on Day 13 of age
Summary of Findings in the Stomach for Animals Killed After 6 Weeks of Treatment.
Depression(s), Glandular Mucosa
Number of tissues examined
The incidence and distribution of all other findings were considered incidental and unrelated to test material.
Summary of Treatment Related Findings in the Stomach of Animals Killed After 6 Weeks of Treatment.
Hypertrophy, Mucous Cells
The developmental toxicity of the test material was assessed according to OECD test guideline OECD 422 and in compliance with GLP.
The purpose of this study was an assessment of general systemic toxic potential in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, with administration of the test material by oral gavage administration for at least five weeks. Three groups of ten male and ten female rats received the test material at doses of 100, 300 or 1 000 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 13 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 13 of lactation. The F1 generation received no direct administration of the test material; any exposure was in utero or via the milk. A similarly constituted Control group received the vehicle, purified water, at the same volume dose as treated groups. During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity observations, grip strength, motor activity, body weight, food consumption, water consumption, haematology (peripheral blood), blood chemistry, urinalysis (males only), oestrous cycles, pre-coital interval, mating performance, fertility, gestation length, thyroid hormone analysis, organ weight and macroscopic pathology and histopathology investigations were undertaken. The clinical condition, litter size and survival, sex ratio, body weight, ano-genital distance and macropathology for all offspring were also assessed. Nipple counts were performed on male offspring on Day 13 of age. Blood samples were collected from selected offspring on Day 4 (not analysed) and Day 13 of age for thyroid hormone analysis.
Parental (F0) responses
There was no premature death related to treatment with the test material. Clinical condition, behaviour in the arena, sensory reactivity, grip strength and motor activity were unaffected by treatment. There were no signs seen in association with dosing.
The slight variations of mean body weights and body weight gains in females during the dosing period were considered likely to be related to litter size and not treatment with the test material. The food consumption of all animals was considered unaffected by treatment. Oestrous cycles, pre-coital interval, fertility, mating performance, gestation length and index were unaffected by treatment. There was no effect of treatment on the number of implantations or litter size. Haematological investigations of the plasma and biochemical examinations of the blood did not reveal any findings that could be attributed to treatment. There was no effect of treatment on the circulating levels of thyroxine (T4) in adult males or in the Day 13 offspring.
The evaluation of organ weights of males after 5 weeks of treatment and of females on Day 13 of lactation revealed no significant differences when compared with the Controls.
At macroscopic examination, depressions of the glandular mucosa were seen in the majority of males receiving 1 000 mg/kg/day. No microscopic correlate was seen for the gross finding of depressions in the stomach of males given 1 000 mg/kg/day. At histopathological examination, mucous cell hypertrophy of the glandular region of the stomach was seen in males given 100, 300 or 1 000 mg/kg/day. This was considered to be an irritant effect of the test material, although considered non-adverse. F1 Litter Responses
The clinical condition of the offspring, offspring survival and sex ratio were unaffected by parental treatment. Litter size and offspring body weight on Day 1 of age were unaffected by treatment; offspring weight gain was slightly high at 100, 300 and 1 000 mg/kg/day. This is considered to be related to the slightly lower litter sizes in these groups and not an effect of treatment with the test material. Ano-genital distance of both male and female offspring on Day 1 of age and male nipple counts on Day 13 of age showed no effects of parental treatment. Macroscopic examination of offspring that died prior to the scheduled termination or were killed on Day 13 of age did not reveal any findings that were considered related to parental treatment at any dose level.
In conclusion, oral administration of the test material to parental Han Wistar rats at dose levels of 100, 300 or 1 000 mg/kg/day for five weeks to males and for two weeks before pairing, throughout gestation and up to Day 13 of lactation in females was well-tolerated in the adult animals with no treatment related adverse effects observed.
Reproductive performance, fertility and offspring survival were unaffected by parental treatment. There was no effect of treatment on the number of implantations, litter size or the growth of the offspring. In the context of this study, the test material, the test material, showed no evidence of being an endocrine disruptor.
Under the conditions of the study the no-observed-adverse-effect-level (NOAEL) for systemic toxicity and for developmental toxicity was considered to be 1 000 mg/kg/day, the highest tolerable dose tested.
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