Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Reproductive toxicity

No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 20 mg/kg/day ,When female CF1 mice were treated with test chemical orally.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from peer reviewed journal
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive toxicity study of test chemical was performed on CF1 mice.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
CF-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: (P) Females: 30 g
- Fasting period before study:No data available
- Housing:No data available
- Use of restrainers for preventing ingestion (if dermal):No data available
- Diet (e.g. ad libitum):No data available
- Water (e.g. ad libitum):No data available
- Acclimation period:No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C):No data available
- Humidity (%):No data available
- Air changes (per hr):No data available
- Photoperiod (hrs dark / hrs light):No data available
IN-LIFE DATES: From: To:
Route of administration:
oral: unspecified
Vehicle:
not specified
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS: No data available
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: 0, 20, 50 or 100 mg/kg bw/day
- Amount of vehicle (if gavage): No data available

- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
- M/F ratio per cage:2:1
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancyNo data available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol:The males were rotated every 7 days to eliminate infertility. After three weeks the males were removed
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 weeks
Frequency of treatment:
daily
Details on study schedule:
No data available
Remarks:
0,20,50 or 100 mg/kg bw/day
No. of animals per sex per dose:
Total:24
0 mg/kg bw/day:6
20 mg/kg bw/day:6
50 mg/kg bw/day:6
100 mg/kg bw/day:6
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule:

BODY WEIGHT: No data
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OTHER:All the females were observed for % pregnancy and mortality.
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: [no]
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded. No data available

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups, other:], number of live births, deaths and birth weights were noted. Four weeks after birth the pups weight, % survival and sex were noted for each group.


GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]No data available

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:No data available

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY:No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
All of the female mothers died at dose concentration 100mg/kg bw /day
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
The % pregnancy was reduced at dose concentration 20 mg/kg/day and 50 mg/kg/day compared to control . Also the number of foetuses /litter was reduced at 20 mg/kg/day from 9.33 to 7.75.
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
mortality
reproductive performance
Remarks on result:
other: no effect was observed at given dose level
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
The survival of the fetuses was not affected at 20 mg/kg but was reduced from 10.6 at birth to 7.75 after four weeks at 50 mg/kg/day treatment of the mother
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The average weight of the fetuses after four weeks was elevated in the treated groups.The average weight of the fetuses at birth was reduced from
1.6 g to 1.37 g at 50 mg/kg/day.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
The percentage of male/litter was lower in the treated groups
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
LOAEL
Generation:
F1
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
mortality
body weight and weight gain
Remarks on result:
other: Adverse effects was observed at dose related manner
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Reproductive effects observed:
no
Treatment related:
not specified
Conclusions:
No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 20 mg/kg/day ,When female CF1 mice were treated with test chemical orally.
Executive summary:

Reproductive toxicity study of test chemical was performed on female CF1 mice.24 mice were divided as 6 mice /dose group. The test material in dose concentration 0, 20, 50 or 100 mg/kg bw/day was administered by oral route for 3 weeks.While continuing dosing the females were exposed to males (2:1 ) for another three weeks. The males were rotated every 7 days to eliminate infertility. After three weeks the males were removed.All the animals were observed for %pregnancy, numberoflive births, deaths and birth weights .Four weeks after birth the pups weight,%survival and sex were noted for each group.

All of the female mothers died at dose 100 mg/kg/day, the number of foetuses/litter was reduced at 20 mg/kg from 9.33 to 7.75 was noted. The average weight of the fetuses at birth was reduced from 1.6 g to 1.37 g at 50 mg/kg/day. In 50 mg/kg /day dose group, the survival of the foetuses reduced from 9.20 at birth to 7.66 after four weeks while was not affected at 20 mg/kg dose group. The percentage of males/litter was lower in the treated groups and the average weight of the fetuses after four weeks was elevated in the treated groups. As adverse effect on fetus was observed at all dose level NOAEL value could not be determined .Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 20 mg/kg/day,when femaleCF1 mice were treated with test chemical orally.

 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Data is Klimicsh 2 and from peer reviewed journal
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity

In given experimental study,test chemical and read across chemical has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments:

2. Groups of Sprague–Dawley Rats (13/sex/dose) were administered thiophene via gavage at dose levels of 0, 25, 100 or 400 mg/kg bw per day. No adverse effects on copulation, ovulation or fertility in treatment groups were observed when compared with the control groups. However, in each group, abnormal parturition was found. Females in the 100 or 400 mg/kg bw per day group, showing evidence of histopathological change in the cerebellum, exhibited abnormal lactation. Pups born to the 400 mg/kg bw per day group showed reduced birth weights and viability decreased at postnatal day 4. No morphological abnormalities associated with the administration of thiophene were found in any pups. With respect to effects on reproduction, the NOAEL was suggested by the authors to be 400 mg/kg bw per day for males and 25 mg/kg bw per day for females (Nagao, 2006).

3. Groups of Guinea pigs were administered Fumaric acid vid Oral feed at dose concentration on 1.0% for 52 weeks. There were too few female animals in each group to give a significant average value but fumaric acid does not appear to exert any detectable effect on the growth of guinea pigs. Average growth values for male rats, though quite irregular, are more or less coincident. No evidence of toxicity was found in offspring of guinea pigs fed a 1% fumaric acid diet from birth. There were no effects on reproduction or lactation. No evidence of toxicity was found in F1 generation guinea pigs fed a 1.0% fumaric acid diet from birth (400 mg/kg bw/day).

4.Reproductive toxicity study of test chemicalwas performed on female CF1 mice.24 mice were divided as 6 mice /dose group. The test material in dose concentration 0, 20, 50 or 100 mg/kg bw/day was administered by oral route for 3 weeks.While continuing dosing the females were exposed to males (2:1 ) for another three weeks. The males were rotated every 7 days to eliminate infertility. After three weeks the males were removed.All the animals were observed for %pregnancy, numberoflive births, deaths and birth weights .Four weeks after birth the pups weight,%survival and sex were noted for each group. All of the female mothers died at dose 100 mg/kg/day, the number of foetuses/litter was reduced at 20 mg/kg from 9.33 to 7.75 was noted. The average weight of the fetuses at birth was reduced from 1.6 g to 1.37 g at 50 mg/kg/day. In 50 mg/kg /day dose group, the survival of the foetuses reduced from 9.20 at birth to 7.66 after four weeks while was not affected at 20 mg/kg dose group. The percentage of males/litter was lower in the treated groups and the average weight of the fetuses after four weeks was elevated in the treated groups. As adverse effect on fetus was observed at all dose level NOAEL value could not be determined .Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 20 mg/kg/day,when femaleCF1 mice were treated with test chemical orally.

 

 So, based on the above mentioned study for target chemical it was considered that no adverse effects on fertility was observed. Thus,comparing this value with the criteria of CLP regulation test chemical can be "Not classified" for reproductive toxicity.

 

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

Thus,comparing this value with the criteria of CLP regulation test chemical can be "Not classified" for reproductive toxicity.

 

Additional information