Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

In a GLP conform study according to OECD guideline 422, the test item was given daily as an aqueous solution to groups of 10 male and 10 female Wistar rats (F0 animals) by gavage at doses of 100, 300 and 1000 mg/kg body weight/day (mg/kg bw/d) (BASF SE, 2010f). Control animals (10 male and 10 female Wistar rats) were dosed daily with the vehicle only (drinking water). The duration of treatment covered a 2-week pre-mating and a 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 approximately 1 week thereafter in females.

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 determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females. 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. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on 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 with CO2, under isoflurane anesthesia, and examined macroscopically for external and visceral findings.

Clinicochemical and hematological examinations as well as urinalyses were performed in 5 parental animals of either sex towards the end of the administration period. At the end of the administration period a functional observational battery was performed and motor activity was measured in 5 parental males and females per 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 various analytical analyses confirmed compound identity using IR- UV- and NMR-spectroscopic methods, demonstrated the stability of the test substance solutions in drinking water at room temperature for a period of 7 days and confirmed the overall accuracy of the prepared concentrations

The following test substance-related adverse effects/findings were noted:

 

Test group 3 (1000mg/kg bw/d)

F0/ Parental animals: No test substance-related adverse findings

F1/ Pups:No test substance-related adverse findings

 

Test group 2 (300 mg/kg bw/d)

F0/ Parental animals: No test substance-related adverse findings

F1/ Pups: No test substance-related adverse findings

 

Test group 1 (100 mg/kg bw/d)

F0/ Parental animals: No test substance-related adverse findings

F1/ Pups: No test substance-related adverse findings


Conclusion

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Wistar Rats Golpanol ALS wasserfrei had no adverse effects on fertility of the F0 parental animals of both sexes at 100; 300 and 1000 mg/kg bw/d.

The test substance caused also no impairments of the reproductive performance. Mating behaviour, conception, gestation, parturition, as well as sexual organ weights and gross and histopathological findings of these organs were not influenced up to 1000 mg/kg bw/d.

 

No general systemic toxicity was noted in the F0 parental animals at all dose levels tested. Golpanol ALS wasserfrei caused no indicationsof test substance-induced effects in low-, mid- and high-dose rats regarding considering food consumption and body weights/ body weight gain as well asdetailed clinical examinations in an open field, in a functional observational battery (FOB) and measurements of motor activity.

 

Concerning clinical and gross pathology as well as histopathology all findingsoccurred either singly or were biologically equally distributed over the control group and the treatment groups. They are considered to be incidental or spontaneous in origin and without any relation to treatmentup to 1000 mg/kg bw/d.

 

Up to 1000 mg/kg bw/dGolpanol ALS wasserfrei caused no developmental toxicity. No alteration of the pre-/postnatal development of the F1 offspring was indicated in number of delivered, liveborn and stillborn pups as well as survival, weight/weight gain, and sex ratio of pups.

Thus, under the conditions of the screening test the NOAEL (no observed adverse effect level) for reproductive performance and fertility as well as for general, systemic toxicity was ≥ 1000 mg/kg bw/d for the F0 parental rats, the highest dose tested.


Short description of key information:
oral
rat, screening test, gavage: NOAEL parental >= 1000 mg/kg bw/d; NOAEL fertility >= 1000 mg/kg bw/d (no adverse effects observed; GLP, OECD 422, BASF SE 2010f)

Effects on developmental toxicity

Description of key information
oral
rat, screening test: NOAEL maternal >= 1000 mg/kg bw/d; NOAEL developmental toxicity >= 1000 mg/kg bw/d (no adverse effects observed; GLP, OECD 422, BASF SE 2010f)
Additional information

In a GLP conform study according to OECD guideline 422 as described above, the NOAEL for developmental toxicity as well as for general, systemic toxicity was ≥ 1000 mg/kg bw/d for the F0 parental rats, the highest dose tested (BASF SE, 2010f). One control and one low-dose F1 pup showed post mortem autolysis, a spontaneous finding, at gross necropsy. No malformations were observed, indications for embryotoxic/teratogenic effects were not noted (for details see discussion of effects on fertility).

Justification for classification or non-classification

Concerning fertility and developmental toxicity, there were no adverse effects observed in a screening test. Therefore, no classification is warranted for the toxicity to reproduction of the test substance according to the criteria of DSD (67/548/EEC) and CLP (1272/2008/EC), respectively.