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EC number: 204-574-5 | CAS number: 122-78-1
Oral (OECD 422), rat: NOAEL systemic = 100 mg/kg bw/day in males and females
The test substance was tested in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening study according to OECD Guideline 422 and in compliance with GLP (2017). Twelve Sprague Dawley rats per sex and dose were treated via gavage with the test substance at doses of 25, 100 and 400 mg/kg bw/day, respectively. The control group received the vehicle corn oil. Additionally, non-mated recovery groups of 6 rats per sex were allocated to the control and high dose group. Males of the main group were dosed once daily for a total of 49 days (for 2 weeks prior to mating, during 2 weeks of mating and 21 days of post-mating), and females of the main group were dosed once daily for 2 weeks prior to mating, throughout gestation and for 13 days after delivery. Also, males and females of the recovery groups were dosed for 49 days. The high dose recovery group was assigned to a two week treatment free period. The dose levels were selected based on the results of repeated dose 2-week dose range-finding study in which salivation and increased absolute and/or relative liver weights in males and females and increased relative uterus weights in females were observed at 500 mg/kg bw/day.
General systemic observations including mortality, general clinical signs, body weights, body weight gain, food consumption, functional behavior examination, motor activity examination, macroscopic findings, hematology, coagulation, clinical chemistry, organ weights and microscopic findings were measured and conducted. Thyroid hormone (T4) level in blood was also analysed for adult males at sacrifice.
One female was found moribund at 400 mg/kg bw/day. Two males and one female were found dead at 400 mg/kg bw/day. These females showed irregular respiration before their moribund state or death.
Salivation was observed in males and females at 400 mg/kg bw/day during the dosing period, but it was not considered to have toxicological significance since it was caused by physicochemical characteristics.
Thickening of the forestomach was noted in some males at 100 mg/kg bw/day, and in moribund, dead and some surviving animals at 400 mg/kg bw/day. The macroscopic lesions were found microscopically as diffuse hyperkeratosis and squamous cell hyperplasia in these animals. The finding macroscopically noted as “focus” of the forestomach in one dead female at 400 mg/kg bw/day was described microscopically as submucosal hemorrhage/edema and multifocal necrosis/focal erosion.
Centrilobular hepatocellular hypertrophy of the liver was noted in some dead males, and surviving males and females at 400 mg/kg bw/day. These findings were not observed in animals of the recovery groups. Centrilobular hepatocellular hypertrophy was regarded as an adaptive response to the test substance, therefore it was considered to be of no toxicological significance.
Erythrophagocytosis and diffuse lymphoid hyperplasia were observed in the mesenteric lymph nodes in some males and females at 400 mg/kg bw/day. However, these findings were reversible in the recovery group. Thymic atrophy (small thymus) was observed in two dams whose pups were all dead.
High values of BUN (blood urea nitrogen) and Crea (creatinine) were noted in one moribund female and one surviving female at 400 mg/kg bw/day. Also, occult blood and erythrocytes in the urine were noted in two males. However, there was no suspicious morphological change in the kidneys of those animals. Therefore, the changes were considered to be of no toxicological significance.
No test substance-related adverse effects were noted in the results of body weights, food consumption, sensory function, motor activity and hematology in adult animals of both sexes, as well as in the thyroid hormone analysis in adult males in the test substance-dosed groups.
In conclusion, the NOAEL of the test substance for local toxicity was considered to be 25 mg/kg bw/day for males and 100 mg/kg/day for females, based on thickening of the forestomach with diffuse hyperkeratosis and squamous cell hyperplasia in males at 100 mg/kg bw/day and in females at 400 mg/kg bw/day. Additionally, erythrophagocytosis and diffuse lymphoid hyperplasia of mesenteric lymph nodes and thymus atrophy was observed in some males and females at 400 mg/kg bw/day. Thus, the NOAEL and LOAEL for systemic repeated dose toxicity were found to be 100 and 400 mg/kg bw/day respectively in both sexes. Since the adverse effects can mainly be attributed to local effects caused by the corrosive properties (Skin corr. 1B) of the test substance, no STOT-RE was assigned.
The available data on repeated oral dose toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and are therefore conclusive but not sufficient for classification. The observed adverse effects of thickening of the forestomach with diffuse hyperkeratosis and squamous cell hyperplasia and submucosal hemorrhage/edema and multifocal necrosis/focal erosion can mainly be attributed to local effects caused by the corrosive properties (Skin Corr. 1B) of the test substance. Additionally, erythrophagocytosis and diffuse lymphoid hyperplasia of mesenteric lymph nodes in both sexes as well as thymus atrophy in females were observed at 400 mg/kg bw/day. These effects are presumably secondary effects, therefore no STOT-RE was assigned.
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