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Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Screening for reproductive / developmental toxicity:

The NOAEL of the test substance was 800 mg/kg feed in female rats and 800 mg/kg feed in male rats. Converted into average daily intake of the sample, the NOAEL was 91.38 mg/kg bw/day in female rats and 80.74 mg/kg bw/day in male rats.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2015-02-25 to 2015-06-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
1995
Deviations:
no
GLP compliance:
no
Remarks:
non GLP, but in compliance with China National Metrology Accreditation
Limit test:
no
Specific details on test material used for the study:
Batch No.: 141104
Purity: 95.4%
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8-9 weeks old
- Weight at study initiation: Males: 291 - 350 g, Females: 210 - 243 g, not exceed ±20 per cent of the mean weight.
- Housing: housed in suspended, wire bottom, stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: More than 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 °C ± 3 °C
- Humidity (%): 40 - 70%
- Photoperiod (hrs dark / hrs light): 12-hour light / dark crycle
- Air changes / hour: 12
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
Weighed test substance required, take a small amount of blank feeds mixed with test substance and then mixed with the blank feed gradually expand to reach the designed concentration and to have better exposure to the homogeneity of the test substance, formed different concentrations of powdered feed.
Details on mating procedure:
- M/F ratio per cage: 1 to 1
- Length of cohabitation:14 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Male rats were exposed more than 2 weeks before mating and 2 weeks during mating, the total exposure time should not be less than 4 weeks; female rats were exposed more than 2 weeks before mating, 2 weeks during mating, and the period of gestation, and lactation , and finished on 4th days of the lactation.
Dose / conc.:
0 mg/kg diet
Dose / conc.:
50 mg/kg diet
Dose / conc.:
200 mg/kg diet
Dose / conc.:
800 mg/kg diet
No. of animals per sex per dose:
12
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based upon repeated dose 28-day oral toxicity study NOAEL values (147 mg/kg) on female rats and 316 mg/kg on male rats), SD rats were randomly assigned to four groups: one control group, one low dose level group, one intermediate dose level group and one high dose level group. The dosages of the groups were 0, 50, 400 and 800 mg/kg feed respectively.
- Rationale for animal assignment (if not random): Random
Parental animals: Observations and examinations:
Observation period: Males were observed for a minimum of four weeks, including prior to mating (a minimum of two weeks), mating and post-mating period; females were observed for a minimum of two weeks prior to mating, during the mating, the duration of pregnancy and at least four days after delivery.

GENERAL CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once a day, and more frequently when signs of toxicity were observed.

BODY WEIGHT: Yes
- Time schedule for examinations: each animal should be weighed on the first day of dosing, once per week thereafter and at termination. Pregnant females should be weighed on days 0, 7, 14, and 20 during pregnancy and on days 0, 4 after delivery.

FOOD CONSUMPTION:
- Time schedule: measured at least weekly
Sperm parameters (parental animals):
Parameters examined in male parental generations:
Detailed histological examination should be performed on the testes and epididymides (with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure)
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
Pups in each litter were weighed on day 0 and 4 post-partum. Each litter should be examined as soon as possible after delivery to establish the number and sex of pups, stillbirths, live births, runts (pups that significantly smaller than corresponding control pups) and the presence of gross abnormalities. The stillbirths and pups at the time of sacrifice should be examined for gross abnormalities.
Postmortem examinations (parental animals):
GROSS NECROPSY:
The adult animals should be examined macroscopically for any abnormalities or pathological changes. Special attention should be paid to the organs of the reproductive system. The number of implantation sites and corpora lutea should be recorded. The testes and epididymides of all male adult animals should be weighed. The ovaries, testes, epididymides, accessory sex organs and all organs showing macroscopic lesions of all adult animals should be preserved in Bouin's fixative.
HISTOPATHOLOGY:
Detailed histological examination should be performed on the ovaries, testes and epididymides (with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure) and all organs showing macroscopic lesions.
Reproductive indices:
Rate of mating success (%) = (number of successful mating animals / number of female animal for mating) x 100 %
Rate of pregnancy (%) = (number of pregnant animals / number of female animal for mating) x100 %
Offspring viability indices:
Rate of live birth (%) = (number of female animals producing live offspring / number of pregnant animals) x 100 %
Rate of birth livability (%) = (number of offspring survived on day 4 post-partum / number of offspring survived on day 0 post-partum) x100 %
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The body weight changes of parental rats during periods of pre-mating and mating: There were no significant differences in the body weight of parental rats during periods of pre-mating and mating between the control group and the dose groups.
The body weight changes of pregnant rats: There were no significant differences in the body weight on day 0, 7, 14, 20 and the body weight gain during pregnancy between the control group and the dose groups.
The body weight changes of maternal rats during lactation period: There were no significant differences in the body weight changes of the maternal rats during lactation period between the control group and the dose groups.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Compared with the control group, in the low and intermediate dose level groups, the average food consumption of parental rats were reduced, the differences were significant, but no dose-effect relationship was investigated.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no significant differences between control group and dose groups.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Mating and gestation:
12 pairs were arranged for mating in control, low, intermediate and high dose groups, respectively, in which 12,12,12,12 pairs were successful mating, 12, 11 ,12,12 females were pregnant, respectively. The date of pregnancy was in the first estrous period after mating, and the most duration of gestation was 22-23 days. There were no significant differences in above parameters.
Analysis of offspring loss:
There were no significant differences in offspring 10ss in different period between control group and dose groups.
Propagation index:
There were no significant differences in the ratios of successful mating, pregnancy, live birth and birth livability between control group and dose groups.
Gross necropsy:
There were no abnormality in gross necropsy on parental rats of each group.
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg diet
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No obvious reproductive and developmental toxicity was observed in the dose groups.
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg diet
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No obvious reproductive and developmental toxicity was observed in the dose groups.
Key result
Dose descriptor:
NOAEL
Effect level:
91.38 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No obvious reproductive and developmental toxicity was observed in the dose groups.
Key result
Dose descriptor:
NOAEL
Effect level:
80.74 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No obvious reproductive and developmental toxicity was observed in the dose groups.
Key result
Critical effects observed:
no
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
The number of corpora lutea and implantation sites, litter weight and situation of pups:
Compared with the control group, there were no significant differences in the average numbers of corpus luteum, implantations, the average number of surviving pups at day 0 and 4, the litter weight at day 0 and 4, average weight of pups at day 0 and 4 in each group.
The abnormalities of pups:
There were no abnormalities on appearance of pups and short stature pups.
Key result
Generation:
F1
Remarks on result:
not measured/tested
Key result
Reproductive effects observed:
no
Conclusions:
The NOAEL of the test substance was 800 mg/kg feed in female rats and 800 mg/kg feed in male rats. Converted into average daily intake of the sample, the NOAEL was 91.38 mg/kg bw/day in female rats and 80.74 mg/kg bw/day in male rats.
Executive summary:

The evaluation of possible effects on reproduction and / or development in male and female Sprague-Dawley (SD) rats was conducted on the test substance using reproduction and developmental toxicity screening test according to OECD Guideline 421.

96 SD rats of 8-9 weeks old were randomly divided into the 4 groups using mixed feed method with the concentration of 0, 50, 200, 800 mg/kg feed. Male rats were exposed to a minimum of 4 weeks, the exposure time of female rats includes the pre-mating period (2 weeks), mating, gestation and lactation period (4 days). Rats were mated by one male to one female after two weeks of exposure. The test was finished on day 4 post partum. At the time of sacrifice or death during the study, the adult animals were examined macroscopically for any abnormalities or pathological changes and detailed histological examination were performed on the organs of the reproductive system. The numbers of implantation sites and corpora lutea were recorded.

 

Results showed that compared with the control group, there were no significant abnormalities in the body weight and in the food consumption in each exposure groups. There were no abnormalities in the coefficients of testis and epididymis of parental male rats. No clinical signs and death of parental rats were observed in each treated group. No significant abnormality was found in dose groups on parental gross anatomy and histopathology compared with the control group.

Compared with the control group, there were no significant differences in the average numbers of corpus luteum, implantations, the average number of surviving pups at day 0 and 4, the litter weight at day 0 and 4, average weight of pups at day 0 and 4 in each group. There were no abnormalities on appearance of pups in each group, no runts were found in each group. There were no significant differences in propagation indexes such as the ratios of successful mating, pregnancy, live birth and birth livability between control group and dose groups. In this test, no obvious reproductive and developmental toxicity was observed in the dose groups.

 

The NOAEL of the test substance was 800 mg/kg feed in female rats and 800 mg/kg feed in male rats. Converted into average daily intake of the sample, the NOAEL was 91.38 mg/kg bw/day in female rats and 80.74 mg/kg bw/day in male rats.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
80.74 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Guideline study, non GLP, but in compliance with China National Metrology Accreditation
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Screening for reproductive / developmental toxicity:

The evaluation of possible effects on reproduction and / or development in male and female Sprague-Dawley (SD) rats was conducted on the test substance using reproduction and developmental toxicity screening test according to OECD Guideline 421.

96 SD rats of 8-9 weeks old were randomly divided into the 4 groups using mixed feed method with the concentration of 0, 50, 200, 800 mg/kg feed. Male rats were exposed to a minimum of 4 weeks, the exposure time of female rats includes the pre-mating period (2 weeks), mating, gestation and lactation period (4 days). Rats were mated by one male to one female after two weeks of exposure. The test was finished on day 4 post partum. At the time of sacrifice or death during the study, the adult animals were examined macroscopically for any abnormalities or pathological changes and detailed histological examination were performed on the organs of the reproductive system. The numbers of implantation sites and corpora lutea were recorded.

 

Results showed that compared with the control group, there were no significant abnormalities in the body weight and in the food consumption in each exposure groups. There were no abnormalities in the coefficients of testis and epididymis of parental male rats. No clinical signs and death of parental rats were observed in each treated group. No significant abnormality was found in dose groups on parental gross anatomy and histopathology compared with the control group.

Compared with the control group, there were no significant differences in the average numbers of corpus luteum, implantations, the average number of surviving pups at day 0 and 4, the litter weight at day 0 and 4, average weight of pups at day 0 and 4 in each group. There were no abnormalities on appearance of pups in each group, no runts were found in each group. There were no significant differences in propagation indexes such as the ratios of successful mating, pregnancy, live birth and birth livability between control group and dose groups. In this test, no obvious reproductive and developmental toxicity was observed in the dose groups.

 

The NOAEL of the test substance was 800 mg/kg feed in female rats and 800 mg/kg feed in male rats. Converted into average daily intake of the sample, the NOAEL was 91.38 mg/kg bw/day in female rats and 80.74 mg/kg bw/day in male rats.

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

Reproductive toxicity:

According to CLP Regulation (Commission Regulation 1272/2008), table 3.7.1 (a), Substances should be classified for reproductive toxicity when there is clear evidence from humans or experimental animals, of an adverse effect on sexual function and fertility, or on development.

As no toxicologically significant effects on sexual function and fertility, or on development in reproductive-developmental screening study, the substance does not meet the criteria for classification as toxic to reproduction or development.

 

Effects on or via lactation:

According to CLP Regulation (Commission Regulation 1272/2008), table 3.7.1 (b), substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies.

As no toxicologically significant effects were noted in reproductive-developmental screening study, the substance does not meet the criteria for classification.

Additional information

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