Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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
Quality of whole database:
Guideline and GLP compliant study. Reliable without restriction.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The purpose of a reproduction/developmental toxicity screening test was to obtain initial information concerning the effect of the test item Incozol EH on male and female reproductive performance such as gonadal function, mating behavior, conception, pregnancy, parturition as well as on development of the F1 offspring from conception to day 4 post partum associated with oral administration to rats at repeated doses.

Four groups of Hsd.Brl.Han: Wistar rats (n=12/sex/group) were administered with the test item orally (by gavage) once a day at 0 (vehicle), 1000, 300 and 100 mg/kg bw/day corresponding to concentrations of 0, 200, 60 and 20 mg/mL. The application volume was 5 mL/kg bw. Control animals received the vehicle, Polyethylene glycol 400 (PEG 400). The suitability of the vehicle for the test item was analytically verified up front. The concentration of the test item in the dosing formulations was checked two times during the study. Incozol EH concentrations in the dosing formulations varied in the acceptable range between 91% and 106% of the nominal values and confirming the proper preparation of the dosing formulations.

All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before the necropsy (altogether for 41 days). Females were additionally exposed through the gestation period and up to lactation days 3 or 4, i.e. up to the day before necropsy (altogether for 41 – 44 days). Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of offspring. The dams were allowed to litter, and rear their offspring up to day 4 postpartum. Litters were weighed and offspring were observed for possible abnormalities and were euthanized on postnatal day 4. All parental animals were subjected to gross pathology one day after the last treatment. Histopathology examination was performed on reproductive organs (testes, epididymides and ovaries) in the control and high dose groups. The reproductive organs of cohabited males and non-pregnant females in the low dose group were also processed and evaluated histopathologically.

Results

Mortality

There was no mortality at any dose level (1000, 300 and 100 mg/kg bw/day).

Clinical observation

Adverse signs of systemic toxicity related to the test item were not detected at any dose level, neither at the daily nor the detailed weekly clinical observations. At the same intervals, the behavior and physical condition of the animals was not impaired at each dose level (1000, 300 or 100 mg/kg bw/day) during the entire treatment period.

Body weight and body weight gain

The mean body weight gain of male animals at 1000 mg/kg bw/day was in a varying degree slightly reduced during the treatment period. However, this slight change was not associated with relevant or significant changes in the mean body weight. Therefore, this observation was judged to be no toxicologically relevant adverse effect.

Food consumption

The mean daily food consumption was not affected by the test item in male or female animals at 1000, 300 and 100 mg/kg bw/day during the entire study (pre-mating, post-mating, gestation and lactation periods).

Reproduction

There were no test item related differences between the control and test item treated groups in delivery data of dams and in the reproductive performance of male and female animals.

Necropsy

Specific macroscopic alterations related to the test item were not found at necropsy.

Organ weight

There were no test item related changes in brain, testes and epididymides weights of male animals at any dose level.

Histopathology

Histopathological examinations of male and female genital organs (ovaries, testes and epididymides) did not reveal any test item related changes at any dose level.

Offspring

No adverse findings on offspring development (mortality, clinical signs, body weight) or at necropsy were detected in the offspring terminated as scheduled.

Conclusion

Under the conditions of the present study, Incozol EH administered at 1000, 300 or 100 mg/kg bw/day did not led to signs of systemic toxicity and did not adversely influence the reproductive performance (gonad function, mating behavior, conception, pregnancy, parturition) in parental male and female Hsd.Brl.Han: Wistar rats. The development of the F1 offspring from conception to day 4 postpartum after repeated oral administration was not impaired at any dose level. Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:

NOAEL for systemic toxicity of male/female rats: 1000 mg/kg bw/day

NOAEL for reproductive performance of male/female rats: 1000 mg/kg bw/day

NOAEL for F1 Offspring: 1000 mg/kg bw/day


Short description of key information:
The reproductive performance and developmental toxicity in F1 offspring of Incocol EH were assessed in a study performed according to OECD Guideline 421 in male and female Hsd.Brl.Han: Wistar rats. The No Observed Adverse Effect Levels (NOAEL) were determined as follows:  

NOAEL for systemic toxicity of male/female rats: 1000 mg/kg bw/day
NOAEL for reproductive performance of male/female rats: 1000 mg/kg bw/day
NOAEL for F1 Offspring: 1000 mg/kg bw/day

Justification for selection of Effect on fertility via oral route:
Reproduction/developmental toxicity screening test recommended to simulate likely route of exposure.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the results of the reproduction/developmental toxicity screening test (OECD 421), the test item was not classified and labelled according to Dierctive 67/548/EEC (DSD) and to Regulation EC (No) 1272/2008 (CLP).

Additional information