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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
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

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1996

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Early version of guidance for OECD 422 not containing functional observation battery test 
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:
1-hydroxypropan-2-yl 2-methylprop-2-enoate; 2-hydroxypropyl 2-methylprop-2-enoate
Details on test material:
- Name of test material (as cited in study report): 2-Hydroxypropyl methacrylate
Purity: 98 %
CAS: 923-26-2

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
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 oral 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
Duration of treatment / exposure:
Males :49 days
Females: from 14 days before mating to day 3 of lactation
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (vehicle), 30, 100, 300 and 1000 mg/kg/ day
Basis:
nominal in water
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
- Terminal kill: Males, day 50; Females, day 4 of lactation
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
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

Sacrifice and pathology:
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.
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.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
For the males, salivation, decrease in locomotor activity and ptosis were found in the 1000 mg/kg group, and 2 animals of the group died. Decrease in hematocrit, tendencies for decrease in RBC and hemoglobin, and increase in the relative liver weights were also found in the 1000 mg/kg group. 
For the females, salivation, decrease in locomotor activity and ptosis were found in the 1000 mg/kg group, and 1 animal died.

Effect levels

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
clinical signs
haematology
mortality
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In an OECD 422 study in rats, the oral repeated dose NOAEL was determined to be 300 mg/kg based on body weights.
Executive summary:

According to the OECD test guidelines for combined repeated dose toxicity study with the reproductive/developmental toxicity screening test [OECD TG 422], 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 a 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.

At 1000 mg/kg bw/day for males, two of the 12 animals died. Salivation, decreases in locomotor activity, ptosis were observed. The decrease in hematocrit and the tendencies for decrease in erythrocyte (RBC) and hemoglobin were found in haematological examination. The statistically significant increase in the relative liver weights was observed in organ weight. At that for females, one of the 12 animals died. Salivation, decreases in locomotor activity, ptosis were observed. The other significant toxicological changes were not observed. 

At 0, 30, 100 and 300 mg/kg bw/day for both sexes, no animals died and no abnormal clinical changes were observed. Moreover, significant toxicological changes were not observed in body and organ weight, food consumption, haematological examination, blood chemical examination, necropsy, and histopathological examination. Therefore, no adverse effect was observed in both sexes. 

The NOAELs for the repeated dose toxicity are considered to be 300 mg/kg bw/day for both sexes.