Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to reproduction - Fertility

A GLP study according to OECD Guideline 421 was performed to characterize the reproductive and developmental toxicity of the test substance (Schleh, 2012). Groups of 10 animals per sex were exposed daily to 100, 300 or 1000 mg/kg bw/day via gavage for a time period of 14 days prior to and 14 days during mating. Afterwards, exposure to females was continued during gestation until post-natal day 3. Control animals received aqua ad injectionem. Males and females were sacrificed on day 29 and on postnatal day 4, respectively. Non-pregnant females were sacrificed on their respective gestation day 26 after completion of the mating period. Over the whole study period, no mortalities or moribund deaths were recorded at any dose level. Clinical symptoms like salivation and moving of the bedding was observed in 4/10 females and 1/10 males of the high-dose group. Additional clinical symptoms are reported in few animals of the high-dose group including swollen cheek, swollen chin, bluish skin, piloerection, red nasal discharge and alopecia. Precoital intervals and duration of gestation did not reveal differences between the test and control groups. No treatment-related effects on body weight development or food consumption were observed. At gross pathology, several tissues and organs of the high-dose animals showed a blue colour due to the colour of the test item. In parental animals, no alteration in absolute or relative organ weights was determined. In testis, greyish pigment was observed in 8/10 high-dose animals related to pigment accumulation in interstitial macrophages. As no further test item-related histological findings were observed in the testes, this effect is not considered adverse. No further histological findings were noted in the male or female reproductive organs. A slight but not statistically significant increase in the number of corpora lutea was observed in mid- and high-dose females whereas the number of implantations sites and post-implantation loss were unremarkable compared to the control group. A significant increase in the percentage of pre-implantation loss in the high-dose group of 29.85% compared with 8.75% in the control group was determined. However, it has to be considered that the number of corpora lutea was increased about 19% in high-dose females without affecting the number of implantation sites or the number of post-implantation loss. Further, no effects were observed on the number of born pups and their viability. Thus, the biological significance of the observed pre-implantation loss is questionable. Furthermore, data on corpora lutea, pre- and post implantation loss generated in a reproductive /developmental toxicity screening assays do not provide sufficient evidence for classification in general due to the relatively small low number of test animals involved in the study, the selectivity of endpoints and short duration of the test. No alterations were determined for copulation, delivery and viability index. In conclusion, a NOAEL≥ 1000 mg/kg bw/day was determined for fertility and parental toxicity.


Short description of key information:
Oral (OECD 421), rat: NOAEL (fertility): ≥ 1000 mg/kg bw/day
Oral (OECD 421), rat: NOAEL (maternal): ≥ 1000 mg/kg bw/day

Justification for selection of Effect on fertility via inhalation route:
Study not required according to Annex VIII of Regulation (EC) No. 1907/2006.

Justification for selection of Effect on fertility via dermal route:
Study not required according to Annex VIII of Regulation (EC) No. 1907/2006.

Effects on developmental toxicity

Description of key information
Oral (OECD 421), rat: NOAEL (developmental): ≥ 1000 mg/kg bw/day
Oral (OECD 421), rat: NOAEL (maternal): ≥ 1000 mg/kg bw/day
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1) and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7, of Regulation (EC) No 1907/2006).
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

Developmental Toxicity

A GLP study according to OECD Guideline 421 was performed to characterize the reproductive and developmental toxicity of the test substance (Schleh, 2012b). Groups of 10 animals per sex were exposed daily to 100, 300 or 1000 mg/kg bw/day via gavage for a time period of 14 days prior to and 14 days during mating. Afterwards, exposure to females was continued during gestation until post-natal day 4. Control animals received aqua ad injectionem. Males and females were sacrificed on day 29 and on postnatal day 4, respectively. Non-pregnant females were sacrificed on their respective gestation day 26 after completion of the mating period. The total number of pups born, the sex ratio, litter weight and the number of viable pups on postnatal day 0 or 4 were comparable among the groups. The significant increase in litter weight in the mid-dose group is considered as incidental as no dose-response is present. Further effects observed in the parental generation are described above under “Effects on fertility”. In summary, as no adverse effects were observed on the litter data, a NOAEL ≥ 1000 mg/kg bw/day is derived for developmental toxicity.

 


Justification for selection of Effect on developmental toxicity: via oral route:
There is only one study available.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Study not required according to Annex VIII of Regulation (EC) No. 1907/2006.

Justification for selection of Effect on developmental toxicity: via dermal route:
Study not required according to Annex VIII of Regulation (EC) No. 1907/2006.

Justification for classification or non-classification

The available data on reproductive and developmental toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.