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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Han Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Number of animals: 40 males: 10 per group; 40 females: 10 per group
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
First Test Item Administration: Males and Females: Day 1 of pre-pairing
Frequency of Administration: Once daily (oral, gavage)
Analytical verification of doses or concentrations:
yes
Details on study design:
Target dose levels:
Group 1: 0 mg/kg/day (control group)
Group 2: 100 mg/kg/day
Group 3: 300 mg/kg/day
Group 4: 1000 mg/kg/day
Duration of Treatment Period: Males: Minimum 4 weeks; Females: Approximately 7 weeks
The reproduction parameters investigated did not give any indication of any test item-related effects. Mating performance, fertility and duration of gestation were not affected by the treatment with the test item. Relevant reproduction parameters such as mean number of corpora lutea, mean number of implantations per dam, post-implantation losses and litter size were also not affected by the treatment with the test item.
Gross pathology findings were considered to be within the range of normal background lesions. Only findings common in rats of this strain and age have been noted during gross pathology. All of them were within the range of historical control and are reflecting the usual individual variability. No significant findings for organ weights.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL for general toxicity
Remarks on result:
other: Generation not specified (migrated information)
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOEL for reproduction/developmental toxicity
Remarks on result:
other: Generation not specified (migrated information)
Viabilitiy index was 100% in the control group and at the dose levels 300 and 1000 mg/kg bw/day and 94.5% at the dose level of 100 mg/kg bw/day. This difference in viability index in the 100 mg/kg bw/day was due to five pups which were missing on day 2 post partum. All these pups were from one litter. No further posnatal loss was noted at any dose level. No findings were noted in pups at first litter check or during the first 4 days post partum. Pups sex ratio was not affected by the treatment with the test item at any dose level. No effects were observed on pup body weight and body weight gain during the first four days post partum at any dose level. No findings were noted during macroscopic examination of pups at any dose level.
Reproductive effects observed:
not specified

The only effect seen under the conditions of this test was the discoloration of feces occurring in all animals which received the test item. The NOAEL (No Observed Adverse Effect Level) for general toxicity was established at 1000 mg/kg/bw/day (the highest dose level used in the study).

The NOEL (No Observed Effect Level) for reproduction/developmental toxicity was established at 1000 mg/kg bw/day (the highest dose level used in the study).

Conclusions:
The NOAEL (general toxicity) as well as the NOEL (reproduction/developmental toxicity) was determined to be 1000 mg/kg/bw/day.
Executive summary:

The only effect seen under the conditons of this test was the discoloration of feces occurring in all animals which received the test item. The NOAEL (No Observed Adverse Effect Level) for general toxicity was established at 1000 mg/kg/bw/day (the highest dose level used in the study).

The NOEL (No Observed Effect Level) for reproduction/developmental toxicity was established at 1000 mg/kg bw/day (the highest dose level used in the study).

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:
Kimisch 1 rated experimental study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A valid OECD 421 reproduction/development toxicity screening study has been conducted with the registered substance. The substance proved to be not reprotoxic up to a dose level of 1000 mg/kg bw/d.

The reproduction parameters investigated did not give any indication of any test item-related effects. Mating performance, fertility and duration of gestation were not affected by the treatment with the test item. Relevant reproduction parameters such as mean number of corpora lutea, mean number of implantations per dam, post-implantation losses and litter size were also not affected by the treatment with the test item.

Additional information with regard to this endpoint is available from a vlaid OECD 407 oral subacute toxicity study, in which the following fertility related endpoints were monitored:

- Organ weights: epididymes, testes, ovaries

- Gross pathology: epididymes, testes, prostate gland incl. coagulating glands, ovaries, uterus, vagina, mammary gland.

Findings were considered to be within the range of normal background lesions. Only findings common in rats of this strain and age have been noted during gross pathology. All of them were within the range of historical control and are reflecting the usual individual variability. No significant findings for organ weights.

Overall, no indication of a reproductive toxic potential exist for the registration substance, neither from a reproductive screening study according to OECD 421 nor from additional data on reproductive organs from a repeated dose toxicity study. The NOAEL of 1000 mg/kg body weight with regard to developmental toxicity was established at the highest dose tested.


Justification for selection of Effect on fertility via oral route:
In order to assess the effects of the test substance on fertility via oral route, a valid OECD 421 study from 2011 in rats is available. Further a subacute 28-day oral gavage study in rats provides some information on effects on reproductive organs.

Effects on developmental toxicity

Effect on developmental toxicity: 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:
Kimisch 1 rated experimental study
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

A Klimisch-1-rated OECD 421 reproduction/development toxicity screening study has been conducted in the year 2011 on the registration substance. The substance proved to be not reprotoxic up to a dose level of 1000 mg/kg bw/day. Viabilitiy index was 100% in the control group and at the dose levels 300 and 1000 mg/kg bw/day and 94.5% at the dose level of 100 mg/kg bw/day. This difference in viability index in the 100 mg/kg bw/day was due to five pups which were missing on day 2 post partum. All these pups were from one litter. No further posnatal loss was noted at any dose level. No findings were noted in pups at first litter check or during the first 4 days post partum. Pups sex ratio was not affected by the treatment with the test item at any dose level. No effects were observed on pup body weight and body weight gain during the first four days post partum at any dose level. No findings were noted during macroscopic examination of pups at any dose level.


Justification for selection of Effect on developmental toxicity: via oral route:
In order to assess the effects of the test substance on development toxicity via oral route, a valid OECD 421 study from 2011 in rats is available. No other studies are available.

Justification for classification or non-classification

The registered substance proved to be not toxic on reproduction up to a dose level of 1000 mg/kg bw/d, thus no classification of the test item is required.

Additional information