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Key value for chemical safety assessment

Effects on fertility

Description of key information

OECD 422 study (GLP) with rats (administration of the test substance via diet)

-->       NOAEL for fertility and reproductive performance = about 54 mg/kg bw/d (male); about 78 mg/kg bw/d (female) (highest concentration tested)

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
54 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

In an OECD 422 study, the test compound was administered daily as a constant homogeneous addition to the food in different concentrations to groups of 10 male and 10 female Wistar rats to screen for potential systemic, reproductive and developmental toxicity. After a two-week premating period, these parental animals were mated and the females were allowed to give birth and bring up the offspring until sacrifice on PND 4 or PND 13.

Analyses confirmed the overall accuracy of the prepared concentrations and the homogeneity of the test substance in the diet. The stability of these preparations was also demonstrated over a period of 8 days under ambient conditions.

In the clinical examinations of the parental animals F0 no clinical symptoms were caused by the test compound up to the high concentration of 1000 ppm. In the subsequent investigations including the detailed clinical observation (DCO), the functional observational battery (FOB) and the measurement of motor activity (MA) no treatment related differences to control were observed at any concentration.

Food consumption of the high-dose F0 males was statistically significantly below the concurrent control values during the entire premating period (up to 11%) and in the high-dose females during premating days 0 - 7 (about 10%).

The mean body weights of the high-dose parental males were statistically significantly below the concurrent control values during the mating and postmating period as well as the terminal body weights (up to 6%).

Additionally, the mean body weight change of the high-dose parental males was statistically significantly below the concurrent control values during premating (up to 38%).

In summary the affected food consumption and body weight parameters of the rats of the high dose group point to systemic toxicity. This trend is only borderline; however, the total of minor changes is considered as an adverse effect of treatment.

Concerning clinical pathology, no treatment-related, adverse effects were observed up to a concentration of the compound of 1000 ppm in the diet. Regarding pathology all findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

Regarding fertility and reproductive performance, no signs of toxicity were observed in male or female parental animals of all test groups (100, 300, and 1000 ppm) during the entire study. All F0 parental animals proved to be fertile. Mating behavior, conception, implantation and parturition were not influenced.

Under the conditions of the present OECD 422 combined repeated dose toxicity study with the reproductive/developmental screening test in Wistar rats the NOAEL for fertility and reproductive performance was 1000 ppm for male (about 54 mg/kg bw/d) and female (about 78 mg/kg bw/d) Wistar rats, the highest concentration tested.

Effects on developmental toxicity

Description of key information

OECD 422 study (GLP) with rats (administration of the test substance via diet)

-->       NOAEL for developmental toxicity in the offspring = about 17 mg/kg bw/d (male); about 23 mg/kg bw/d (female) (based on decreased pup body weights and an increased number of areolae in male pups at PND 13)

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
17 mg/kg bw/day
Study duration:
subacute
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

In the OECD 422 study described in the section "Effects on fertility", regarding developmental toxicity, the mean body weights of the high-dose (1000 ppm) male and female pups were statistically significantly below the concurrent control values on PND 1. Additionally, lower weights were noted in male pups and both sexes combined on PND 7 (about 15%) as well as in male pups on PND 10 (about 13%). The mean body weight change of the high-dose (1000 ppm) female pups and both sexes combined was statistically significantly below the concurrent control values during PND 4 - 7 (about 15%).

In summary, the decreased pup body weight parameters in the high-dose group are considered as an adverse effect of treatment. One high-dose female (1000 ppm) delivered very small pups (all pups are runts at PND 1) and had a complete litter loss on PND 3 due to an insufficient maternal care. Between PND 1 and PND 3 ten pups of this high-dose female where cannibalized and two pups died. At necropsy the two died pups had an empty stomach.

In test group 3 (1000 ppm) the number of runts was increased (18 vers. 3 runts in the control group), the viability index indicating pup mortality during lactation (PND 0 - 4) was decreased (89.1% vers. 99.2% in control) and the number of cannibalized/dead pups was increased during PND 1 - 4. Although a complete litter loss as finding (with a low incidence) was present in the historical control data of the facility, a treatment related cause of these changes cannot be excluded.

The percentage (97.2% vers. 63.3% in control) of male pups having areolae on PND 13 was statistically significantly increased in test group 3 (1000 ppm). The percentages of the historical controls range between 0% and 81.7%. This finding was assessed as an adverse treatment related change.

All other findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

Under the conditions of the present OECD 422 combined repeated dose toxicity study with the reproductive/developmental screening test in Wistar rats the NOAEL for developmental toxicity in the offspring was 300 ppm, based on decreased pup body weights and an increased number of areolae in male pups at PND 13.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result, the substance has to be classified as Repro Cat. 2, H361d under Regulation (EC) No. 1272/2008 due to the observed questionable developmental toxicity (mortality, body weight effects and areolae in the pups) in the OECD 422 study. As these effects might partially be attributable to residual levels of CAS # 68814 -95 -9 of about 0.1 % which is classified as Repro Cat. 1B, H360FD and as general toxicity observed in the study might have also contributed to the developmental toxicity, a classification with Repro Cat. 2, H361d is considered sufficient. Furthermore, the body weight effects are expected to disappear during further growth of the pups but this can not be confirmed as the pups were sacrificed as required by the guideline on PND 13. Areolae normally also disappear during further growth of the pups after PND13, thus in order to make a proper assessment, a re-check would be required on PND 20 which is not possible as the pups are sacrificed on PND 13.