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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study, GLP, japanese study, only abstract english

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD guideline 422
Deviations:
yes
Remarks:
, An old version of OECD 422 (not containing functional observation battery test) had been conducted.)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Methacrylic acid, monoester with propane-1,2-diol
EC Number:
248-666-3
EC Name:
Methacrylic acid, monoester with propane-1,2-diol
Cas Number:
27813-02-1
Molecular formula:
C7H12O3
IUPAC Name:
2-hydroxypropyl methacrylate
Details on test material:
- Name of test material (as cited in study report): Methacrylic acid (2 - hydroxypropyl)
Purity: 98 %
CAS: 923-26-2

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan
- Age at study initiation: 8 weeks
- Weight at study initiation: male 315 ~ 359 g; females 210 ~ 243 g,
- Fasting period before study: yes
- Housing: During the quarantine: suspended using a stainless steel cage type 1 with 5 per cage; Breeding: divided into separate rearing cages. Moved to a separate plastic cage, having had a natural birth .
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: five-day quarantine period and then set up a six-day acclimation period

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 deg C
- Humidity (%): 40-70%
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 hour light / 12 hour dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Concentration of samples was prepared by dissolving the required water for injection. The concentrations of preparation is protectedc from light at room temperature for 7 days to ensure that there were no stability issues. Preparation of 0.6% solution concentration is below the threshold level of determination, because we could not confirm the stability during the preparation for the 6% solution diluted with water for injection prepared in concentration.

VEHICLE
- Justification for use and choice of vehicle (if other than water): water
- Concentration in vehicle: 0.6, 0.8, 2.6 and 20%
- Amount of vehicle (if gavage): 5 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 14 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): moved to put a separate plastic cage, having had a natural birth and feeding.


Duration of treatment / exposure:
49 days
Frequency of treatment:
daily
Duration of test:
Exposure period: 49 days

No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: 2-week preliminary study
- Rationale for animal assignment (if not random): random by weight

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
- Cage side observations: general condition

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: twice a week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): 2 times per week
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood:day after treatment
- Anaesthetic used for blood collection: Yes (identity) : sodium pentobarbital
- Animals fasted: No data
- Parameters checked in table [No.1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day after treatment
- Animals fasted: No data
- Parameters checked in table [No.2] were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: sexual cycle until confirmation; status of delivery

GROSS PATHOLOGY: Yes; Males: Thymus, liver, kidney, testis and epididymis weight was measured after removal, adrenal gland, brain, heart and spleen and 10% neutral buffered formalin solution (However, testicular and epididymal fluid Buan) was fixed; Females: counting the number of corpora lutea and the number of implantation scars. Liver, kidney, ovary and thymus weight was measured after removal, adrenal gland, brain, heart and spleen with a fixed 10% neutral buffered formalin solution.

HISTOPATHOLOGY: Yes; Control group and 1000 mg / kg group of heart, liver, spleen, thymus, kidney, testis, epididymis, ovary, adrenal and brain for the Preparation HE staining of tissue was examined histologically.
Fetal examinations:
observed at birth
Mobilize the number of preterm birth and sex, number of stillborn children, the presence of abnormalities observed and the number of newborn.
(2) observation of the newborn
Newborns, the presence of daily survival and mortality in a general state who observed times.
(3) measurement of body weight
Weight, feeding 0 days (date of birth) and measured four days.

Autopsy performed after four days of feeding by exsanguination from the abdominal aorta under ether anesthesia.
Statistics:
In either test, significant risk factors were less than 5%.
1) multiple comparison test
Weight (the parent animals, babies), food consumption, number of estrus, days mating, pregnancy [Day delivery (feeding 0) - date confirmed mating, the number of implantation scars, the number of birth control mobilize (number of babies stillborn baby + ), the number of newborn, number of children born dead, birth rate [(number of birth control mobilize / number of implantation scars) × 100], rate of production of child [(number of infant feeding 0 days / number of implantation scars) × 100], corpus number, implantation rates [(number of implantation scars / number of corpora lutea) × 100], fertility [(number of infant feeding 0 day / mobilize all of birth control) × 100], feeding baby number four day, feeding 4 day survival rate [(number of newborn feeding 4 days / 0 Number of infant feeding day) × 100], unusual occurrence rate [(number of children with abnormal/ number of newborns) × 100], sex ratio (male / female), organ weights ( including the relative weight), results of blood tests, blood biochemistry test results for the mean and standard deviation were calculated for each group. Significant difference test, Bartlett's test and the homoscedasticity of Law, Law-way layout analysis of variance if the variance 1) and, if significant Dunnett method 2) or Scheff Method 3) were using. However, if the variance was not approved, the analysis method using centrally located position (Kruskal-Wallis test of 4)) and a significant if you use the ranking method or Dunnett Scheff Method was used.
2) χ ^ 2 test
Copulation rate [(number of established animal mating / number of live animals) × 100], fertility [(number of female fertility / Establishment of animal mating) × 100], the birth rate [(number of female newborns / number of female fertility) × 100] is, χ ^ 2 using the test.
Indices:
Reproductive indices
Estrus frequency, copulation index, number of days to conception, fertility index, length of gestation, number of corpora lutea or gestation index.

Offspring viability indices
Number of live pups born, birth index, number of dead pups, number of pups born, delivery index, live birth index, sex ratio, viability index

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
There were no effects of the test substance on the estrus frequency, copulation index, number of days to conception, fertility index, length of gestation, number of corpora lutea or gestation index.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
mortality

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no effects of the test substance on the number of live pups born, birth index, number of dead pups, number of pups born, delivery index, live birth index, sex ratio, viability index, external anomalies, body weight or necropsy findings.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In an OECD 422 study in rats, no effects in developmental toxicity related endpoints were seen up to 1000 mg/kg bw/d.
Executive summary:

The combined repeated dose toxicity study with the reproductive/developmental toxicity screening test [MHW Japan, 1996] was conducted by OECD TG 422 in compliance with GLP. SD (Crj: CD) rats (12 animals/dose/sex) were administrated with this substance by gavage at doses of 0 (vehicle; water for injection), 30, 100, 300, and 1,000 mg/kg bw/day (12 animal/dose/sex). Males were dosed for total of 49 days beginning 14 days before mating, and females were dosed for total of 41 to 48 days starting from 14 days before mating to day 4 of lactation throughout the mating and pregnancy period.

No adverse effects were observed in reproductive parameters such as estrous cyclicity, copulation index, fertility index, number of females with live pups, length of gestation, number of implantation sites, gestation index. Further, no adverse effects were found in developmental parameters such as number of live pups born, sex ratio, birth index, number of dead pups on day 0 of lactation, number of pups born, delivery index, live birth index, number of live pups on day 4 of lactation, viability index, number of external anomalies, body weight of pups, and autopsy findings of neonates. External examination of offspring revealed no morphological abnormality. In conclusion, no effects in developmental toxicity related endpoints were seen up to 1000 mg/kg bw/d.

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