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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Only screening study available.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information
Short description of key information:
No effects on fertility parameters were seen in a screening study (OECD 421, GLP) in rats.

Effects on developmental toxicity

Description of key information
A screening study in rats showed unexpected mortality in parental animals at 1000 and 500 mg/kg bw. Effects on the offspring (reduced number of pups born and body weight) were seen at 200 mg/kg bw. bw. The study followed OECD testing guideline 421 and was performed under GLP.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
A screening study in rats is available.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Three groups of 10 sexually mature males and 10 sexually mature females were dosed once daily orally, by gavage with the test item for two weeks before pairing, throughout the pairing period and until the day prior to necropsy for the males and Day 3 of lactation for females. Animals were dosed at 50, 200, or 1000 mg/kg bw/day. A similar group of males and females received the vehicle only, and served as controls. Since the dose of 1000 mg/kg bw/day caused mortality in 7 rats within one week, this group was terminated. A preliminary trial to see if animals would tolerate 500 mg/kg bw was discontinued after the first animal died at this dose group. Two further groups (12.5 mg/kg bw/day and an additional control group) were then added. A constant dose volume of 10 mL/kg bw was used and doses were adjusted according to the most recent body weight. Clinical observations, body weight, and food consumption were recorded at regular intervals throughout the study. After the two week pre-pairing dosing period, each female was paired with a male from the same group for up to four days (until mated). Vaginal smears were taken daily until sperm were found in the smear, whereupon the male was removed. Females were allowed to litter, and observations of total number of pups, pup sexes, pup body weights, clinical observations, and mortalities were made. Dams were killed on Day 4 of lactation with their litter, or on Day 25 of gestation if they had not littered. Males were killed after the females were necropsied. A macroscopic necropsy was performed for all animals and selected tissues from animals given 200 or 1000 mg/kg bw/day and initial control animals from Group 1 were examined microscopically

As result for the F0 Generation at 200 mg/kg bw/day black faeces, dark discoloured extremities and grey sperm plugs were observed. Body weight gains were slightly decreased in males. In females body weight gain was slightly impaired during the pre-pairing period, and moderately decreased during gestation, particularly during the last week. Body weights of females were decreased after birth and on Day 4 of lactation. Food consumption was slightly to moderately decreased in females during gestation and lactation. Haematological examinations revealed slightly decreased haemoglobin values in males and slightly decreased haematocrit values in both sexes. Additionally, decreased leucocyte counts, primarily of lymphocytes, were observed in females. Slightly decreased calcium concentrations were observed following clinical chemistry examinations in both sexes. At necropsy, the entire bodies of all animals were discoloured dark. There were no compound-related effects on mating performance, fertility, and gestation length. Rats dosed with 50 mg/kg bw/day also showed dark discoloured extremities, black faeces and grey copulation plugs. At necropsy, the entire bodies of all animals were discoloured dark. No other compound-related effects were observed. No compound-related effects were observed after administration at 12.5 mg/kg bw/day.

F1 Generation: At 200 mg/kg bw/day there was a significant increase in pup deaths up to lactation Day 4 and a decrease in both the mean number of pups born alive and the mean live birth index when compared with controls. All pups from dams given 200 mg/kg bw/day were abnormally dark in colour. Male as well as female pups had decreased group mean body weights on Day 1 and Day 4 of lactation accompanied by a decrease in group mean body weight gains. All pups from dams given 50 mg/kg bw/day were abnormally dark in colour when compared to control animals. No other compound-related effects were observed. No compound-related effects occurred at 12.5 mg/kg bw/day.

Justification for classification or non-classification

The screening study shows indication of developmental toxicity at doses also affected the parents by body weight loss. A final classification and labelling based on this screening study may not be feasible.

A more detailed discussion and submission of a CLH dossier is not performed because production of EC no. 403 -720 -7 has been ceased and the registration is set to inactive.

Additional information