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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No adverse effects on fertilty were observed at the limit dose in male and female (pregnant) rats in the screening study (OECD 422). No adverse effects on parental fertility were mentioned in a literature publication on a 2 -year feeding study including a 6 -months pre-mating element.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Fertility was investigated in a study performed according to OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) and GLP (BASF SE 2012). The test substance was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0, 100, 300 and 1000 mg/kg bw/d. Drinking water served as vehicle. The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation and two weeks thereafter in females. After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating was discontinued as soon as sperm was detected in the vaginal smear. A detailed clinical observation was performed in all animals before initial test substance administration and, as a rule, thereafter at weekly intervals. Food consumption of the F0 parents was determined once weekly during premating. In dams food consumption was determined for gestation days 0 - 7, 7 - 14, 14 - 20 and lactation days 1 - 4. Body weights of F0 parents were determined once a week, in males throughout the study and in females during premating and mating. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, after the day of parturition (postnatal day [PND] 0) and on PND 4. The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4. Their viability was recorded. At necropsy on PND 4, all pups were sacrificed and examined macroscopically for external and visceral findings. Clinicochemical and hematological examinations as well as urinalyses were performed in 5 animals per sex and group towards the end of the administration period. Further, a functional observational battery was performed and motor activity was measured in 5 animals per sex and test group towards the end of the administration period. All F0 parental animals were sacrificed and assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

The NOEL for fertility was found to be 1000 mg/kg bw/d and the NOEL for females for general, systemic toxicity was 300 mg/kg bw/d based on reduced food consumption and decreased body weight change during the gestation at 1000 mg/kg bw/d. The NOEL for general, systemic toxicity in males was 1000 mg/kg bw.

Results on a 2 -year feedomg study in rats including mating and in-utero exposure were published in 1965 (Oettel H et al). Parental animals were fed a diet containing the substance at 1% dietary concentration, which corresponds to approximately to 100 mg/kg bw. After 6 months of treatment, mating was performed, and then both parental rats and offspring were fed the test material containing diet. The only interruption of treatment was done during the 2 -3 weeks after parturition; during this time animals received the normal diet. No details on reproductive parameters are provided; the study was intended as a carcinogenicity study. It is assumed that any striking observations on fertilty or development would have been mentioned.

Effects on developmental toxicity

Description of key information
No teratogenicity or developmental effects were observed in a GLP-compliant gavage study in rats (OECD 414).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
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

Teratogenicity was studied in Wistar rats in a GLP and OECD 414 compliant study (BASF 2017). Doses of 100, 300 and 1000 mg/kg bw were applied per gavage using drinking water as vehicle. No adverse effects on dams and on fetuses were observed at any dose group, showing that the substance is not teratogenic in rats. The blue test substances caused blue coloration of the feces at the high dose group. This is consistent with the blue coloration of the content of the intestine (presence of the blue test item) observed at necropsy.

Information on developmental toxicity in Wistar rats is also available at the screening level as can be derived from an OECD 422 study performed with 100, 300 and 1000 mg/kg bw (BASF 2012).

In general, all parameters were within the historical control range. There were no adverse on postnatal or perinatal viability. Pup weight and development were normal for all dose groups and no adverse effects were observed at pup necropsy. The rare event of of complete litter loss was recorded for one high dose group dam (animal no. 138).

For the parameter postimplantation loss, the average loss of 7.6% (mean of 7 litters) is within historical control data of 0.7 - 14.6% if the complete litter loss in animal no. 138 is excluded from the calculation. Since complete litter loss in Wistar rats is a rare event, no separate historical control data is routinely maintained. Manual review of the unpublished data of the test facility showed one control animal with a total implantation loss (4 implantation sites) and two control animals with a postimplantation loss of 93% (14 implantation sites). Considering that implantation losses were not observed in the full teratogenicity study (OECD 414) with a higher number of rats and that no adverse effects on fetuses and pups were observed, the above described complete litter loss is considered an incidental finding and not relevant for the hazard assessment.

 

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available screening study for fertility and developmental toxicity and the teratogenicity study in rats are considered reliable and suitable for classification purposes under 67/548/EEC. No adverse effects on fertility, development or teratogenicity were observed the limit dose of 1000 mg/kg bw. As a result the substance is not considered to be classified for fertility or developmental toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive2009/2/EG. 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available screening study for fertility and developmental toxicity and the teratogenicity study in rats are

reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for fertility or developmental toxicity under Regulation (EC) No. 1272/2008,as amended for the seventh time in Regulation (EC) No 2015/1221.

During the four days of postnatal life covered in the screening study, no effects via lactation were observed.