Urea, reaction products with diethylene glycol, formaldehyde and glyoxal

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

Fixapret PC, vor Magnesiumchlorid-Zugabewas administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg bw/d (test group 0), 100 mg/kg bw/d (test group 1), 300 mg/kg bw/d (test group 2) and 1000 mg/kg bw/d (test group 3) in a study according to OECD 422 guideline and GLP (BASF, 2013).

The objective of the study was to detect possible effects of the test substance on the integrity and performance of male and female reproductive systems including gonadal function, mating behavior, conception, gestation and parturition. Furthermore, it was intended to obtain information about the general toxicological profile including target organs and the no observed adverse effect level (NOAEL) after repeated oral administration. 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.

The parents' and the pups' state of health was checked each day, and parental animals were examined for their mating and reproductive performances.

After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear. F0 animals were examined for their reproductive performance including determinations of the number of implantations and the calculation of the postimplantation loss in all F0 females.

A detailed clinical observation (DCO) 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 under isoflurane anesthesia with CO₂and 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.

Towards the end of the administration period a functional observational battery was performed and motor activity was measured in 5 animals per sex and test group.

All F0 parental animals were sacrificed by decapitation, under isoflurane anesthesia, and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

The following test substance-related adverse findings were noted:

Test group 3: 1000 mg/kg bw/d

F0 PARENTAL ANIMALS

Clinical Examinations

·          No test substance-related, adverse findings were noted.

Reproductive Performance

·          No test substance-related, adverse findings were noted.

Clinical Pathology

·          No test substance-related, adverse findings were noted.

Pathology

·          No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/ Gross Findings

·          No test substance-related, adverse findings were noted.

Test group 2: 300 mg/kg bw/d

F0 PARENTAL ANIMALS

Clinical Examinations

·          No test substance-related, adverse findings were noted.

Reproductive Performance

·          No test substance-related, adverse findings were noted.

Clinical Pathology

·          Notest substance-related, adverse findings were noted.

Pathology

·          No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/ Gross Findings

·          No test substance-related, adverse findings were noted.

Test group 1: 100 mg/kg bw/d

F0 PARENTAL ANIMALS

Clinical Examinations

·          No test substance-related, adverse findings were noted

Reproductive Performance

·          No test substance-related, adverse findings were noted.

Clinical Pathology

- No test substance-related, adverse findings were noted.

Pathology

·          No test substance-related, adverse findings were noted.

F1 PUPS

Clinical Examinations/ Gross Findings

- No test substance-related, adverse findings were noted.

CONCLUSION

The NOAEL for general, systemic toxicity was 1000 mg/kg bw/day.

The NOAEL for reproductive performance and fertility was 1000 mg/kg bw/day for the F0 parental rats.

The NOAEL for developmental toxicity in the F1 progeny was found to be 1000 mg/kg bw/day.

Short description of key information:
OECD 422 (BASF SE, 2013): NOAEL (reproductive preformance, fertility and developmental toxicity) = 1000 mg/kg bw/day

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

Based on the available data, the test substance is not classified with regard to toxicity to reproduction according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), respectively.