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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline 422. GLP study.
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: 1.0% Methylcellulose
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
42 Days for males
14 Days before mating to day 4 of lactation for females
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
100 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
12 male animals per group
12 female animals per group
Control animals:
yes
Parental animals: Observations and examinations:
GENERAL STATE: Yes (appearance, behaviour, mortality)
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Before and after treatment, once a week.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: Weekly

Oestrous cyclicity (parental animals):
- Estrous cycle
Sperm parameters (parental animals):
- Number of cells in seminiferous epithelia, testis weight, seminal vesicle weight and epididymis weight.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in offspring:
number of pups born, delivery index (%), number of pups alive on Day 0 of lactation, live birth index (%), sex ratio, number of pups alive on Day 4 of lactation, viability index (%), body weight of live pups on Day 0.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: Yes

HISTOPATHOLOGY: Yes
Postmortem examinations (offspring):
GROSS NECROPSY: yes
Reproductive indices:
Copulation index
Fertility index
Implantation index
Gestation index
Offspring viability indices:
- Viability index
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
The parental animals exhibited no alterations in reproductive parameters.
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
>= 300 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Histopathology changes observed at 1000 mg/kg bw/day (forestomach)
Dose descriptor:
NOAEL
Remarks:
reproduction toxicity
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Description (incidence and severity):
99.5%
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
There were no significant differences in offspring parameters.
Dose descriptor:
NOAEL
Remarks:
offspring development
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Reproductive effects observed:
not specified
Conclusions:
The results were:
-NOAEL maternal toxicity >= 300 mg/kg bw /day
-NOAEL reproductive toxicity>= 1000 mg/kg bw/day
-NOAEL offspring development >= 1000 mg/kg bw/day
Executive summary:

The aim of the test was to study the reproductive and developmental toxicity in rats (12 males and 12 females) in a combined repeated dose toxicity study with the reproductive / developmental toxicity screening test at doses of 100, 300 and 1000 mg/kg bw/day.

The test was performed according to OECD Test Guideline 422.

The results were:

-NOAEL maternal toxicity >= 300 mg/kg bw /day

-NOAEL reproductive toxicity>= 1000 mg/kg bw/day

-NOAEL offspring development >= 1000 mg/kg bw/day

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:
The key study is GLP compliant and Klimisch score 1.
Additional information

Reproductive/Developmental toxicity screening test:

Key study. Study with 12 male/ 12 female rats at doses of 100, 300, 1000 mg/kg/day, according to OECD Test Guideline 422.

The result was as follows: fertility/reproductive toxicity NOAEL = 1000 mg/kg bw /day

Two-generation reproductive toxicity study:

In accordance with column 2 of REACH Annex IX, the two-generation reproductive toxicity study ( required in section 8.7.3) does not need to be conducted as the 28-day and 90-day study results do not indicate adverse effects on reproductive organs or tissues.


Short description of key information:
Fertility/ reproductive toxicity NOAEL= 1000 mg/kg bw , key study with 12 male/ 12 female rats, at doses of 100, 300, 1000 mg/kg/day, according to OECD Test Guideline 422.

Justification for selection of Effect on fertility via oral route:
Only one study available.

Effects on developmental toxicity

Description of key information
Developmental toxicity NOAEL= 1000 mg/kg bw , key study with  12 female rats,  at doses of 100, 300, 1000 mg/kg/day,  according to OECD Test Guideline 422.
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:
The key study is GLP compliant and Klimisch score 1.
Additional information

Reproductive/Developmental toxicity screening test:

Key study. Study with 12 female rats at doses of 100, 300, 1000 mg/kg/day, according to OECD Test Guideline 422.

The result was as follows: developmental toxicity NOAEL = 1000 mg/kg bw /day

Pre-natal developmental toxicity study: The study does not need to be conducted since based on the available data from the reproduction/developmental toxicity screening test, the test material did not cause any adverse effects.


Justification for selection of Effect on developmental toxicity: via oral route:
Only one study available. See the attachment above.

Justification for classification or non-classification

Based on the available information:

fertility/reproductive toxicity NOAEL = 1000 mg/kg bw /day

developmental toxicity NOAEL = 1000 mg/kg bw /day

the substance is not classified.

Additional information