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Administrative data

Description of key information

According to two repeated dose studies by oral administration in rats, the findings at or more than 50 mg/kg/day were considered toxicologically significant. The test substance was not toxic at 20 mg/kg/day in both sexes in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (MHW Japan, 1998). Nevertheless, the NOAEL was considered to be 10 mg/kg/day in a 90-day study (Atochem, 1999). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Two studies were available for evaluation, both of them were oral administration studies. One study was conducted according to OECD TG 422 in compliance with GLP (MHW Japan, 1998), the other one was conducted according to OECD TG 408 in compliance with GLP (Atochem, 1999). Both studies were identified as key studies and are summarised below.

1) MHW Japan (1998): Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test

According to the OECD test guidelines for combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422), SD (Crj:CD) rats (12 animals/group/sex) were administered doses of 0 (vehicle; corn oil), 4, 20, and 100 mg/kg/day by gavage. The dosing period for males was 43 days, and females were dosed from 14 days before mating to day 3 of lactation.

At 100 mg/kg/day, two females died, and males showed a transient suppression of body weight gain and a decrease in food consumption. At necropsy, thickening of the wall of the forestomach and enlargement of the pancreatico-duodenal lymph nodes were observed in both sexes. At histopathology, ulceration, inflammatory cell infiltration and hyperplasia of the mucosa in the forestomach and hyperplasia of plasma cells in the pancreatico-duodenal lymph nodes were observed in both sexes. Additionally, atrophy of the thymus was observed in females. At haematology and blood chemistry, increased ratios in reticulocyte, platelet and segmented neutrophil counts and a decrease in albumin were observed in males.

At 20 mg/kg/day, ulceration, inflammatory cell infiltration and hyperplasia of the mucosa in the forestomach were observed in two males. However, these changes were not statistically significant, and were considered to be not toxicologically relevant. No effects were observed at 20 mg/kg/day in females.

At 4 mg/kg/day, no effects were observed.

The NOAEL for the repeated dose toxicity is considered to be 20 mg/kg/day for both sexes.

2) Atochem (1999): Repeated Dose 90-Day Oral Toxicity Study in Rodents

According to the OECD test guideline for repeated dose 90-day oral toxicity study in rodents (OECD TG 408), SD (Crl:CD) rats were administered doses of 0 (vehicle; peanut oil), 2, 10, and 50 mg/kg/day by gavage. The dosing period for males and females was 13 weeks. Twenty rats/sex were used in the control group, 10 rats/sex in the low and intermediate dose groups and 25 rats/sex in the high dose group.

At 50 mg/kg/day, non-sporadic or imminent death occurred in 13 males and 9 females. Twenty-one of these deaths (except one male) occurred during the exposure period. The cause of death was lung lesions, which were considered to be due to direct irritation from regurgitated stomach contents.

No clinical signs related to this compound were observed at 2 and 10 mg/kg/day. Ptyalism and/or loud breathing were observed in a few animals at 50 mg/kg/day. However, it was transient and the animals recovered. Therefore, it was considered to be unrelated to the test substance. There were no effects at 2 and 10 mg/kg/day.

There was an increase in neutrophil counts and a decrease in lymphocyte counts at haematology at 50 mg/kg/day. There were no changes in absolute and relative organ weights. There were no effects in food consumption, ophthalmology, blood biochemistry and urinalysis.

At 50 mg/kg/day, the following macroscopic changes, considered to be related to treatment, were seen in decedents and animals that survived the treatment period: greyish foci in the mucosa of the forestomach in 11/20 males and 13/19 females, enlargement of the pancreatic lymph nodes in 5/20 males and 6/19 females, and dilatation or reddish colour of the lungs in 7/20 males and 6/19 females. No macroscopic changes were seen in animals killed at the end of the recovery period. There were no effects of treatment on any of the tissues examined in males or females at 2 or 10 mg/kg/day.

At 50 mg/kg/day, the following histopathological changes, considered to be related to treatment, were seen in decedents and surviving animals after 13 weeks treatment: ulceration, hyperplasia/hyperkeratosis, infiltration or granulation tissue formation in the submucosa, oedema in mucosa and submucosa and necrosis of the mucosa/submucosa in the forestomach, alveolar haemorrhage or oedema and congestion in lungs. At 10 mg/kg/day, hyperplasia/hyperkeratosis and oedema and inflammatory cell infiltration (all due to direct local irritation of the test substance) of the forestomach submucosa were seen in 4 males. These findings were almost of minimal grade which were not regarded to be adverse effects.

The NOAEL for the repeated dose toxicity is considered to be 10 mg/kg/day for both sexes.

Justification for classification or non-classification

EU classification according to Annex VI of the Directive 67/548/EEC:

- No classification required.

GHS classification according toAnnex I 1272/2008 CLP (EU GHS):

- No classification required.