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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guidelline Study

Data source

Reference
Reference Type:
publication
Title:
Toxicity Testing Reports of Environmental Chemicals
Author:
MHW Japan (1999). Toxicity Testing Reports of Environmental Chemicals 7, 97-124.
Year:
1999
Bibliographic source:
Chemicals Investigation Promoting Council, 7:97-124.

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)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Phthalimide
EC Number:
201-603-3
EC Name:
Phthalimide
Cas Number:
85-41-6
Molecular formula:
C8H5NO2
IUPAC Name:
1H-isoindole-1,3(2H)-dione
Details on test material:
- Name of test material (as cited in study report): phthalimide
- Analytical purity: 99%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 weeks for males and females
- Weight at study initiation: 350-402 g for male, 195-257 g for female
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24°C
- Humidity (%): 45-61%

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1% Carboxymethylcellulose sodium
Details on mating procedure:
- M/F ratio per cage: one by one in each cage
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Exposure period: Males, 46 days
Females, from 14 days before mating to day 3 of lactation
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Frequency of treatment:
one administration per day
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250, 500, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CCAGE SIDE OBSERVATIONS: Yes
- Time schedule: every day


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: every day


BODY WEIGHT: Yes
-Time schedule for examinations: male animals´ body weight was recorded on day 1, 2, 5, 7, 10, 14, 21, 28, 35, 42, 46; female animals´ body weight was recorded: before mating on day 1, 2, 5, 7, 10, 14; during gestation on day 0, 1, 3, 5, 7, 10, 14, 17, 20 after parturition on day 0, 1, 4


FOOD CONSUMPTION:
- At every body weight check (24hr consumption), except day 0 of gestation and day 0 of parturition for female


-Regarding to urinalysis, hematology, blood chemical and organs, please refer to endpoint summary 7.5.1

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

open allclose all
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day
Sex:
female
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Sex:
male

Results: F1 generation

Details on results (F1)

No effects were observed in any dose levels in male. One female in the 500 mg/kg bw/day dose group did not deliver until day 26 of gestation. Autopsy of the female revealed dilatation of the uterus and vagina, and five implatation sites. Body weights and food consumption were decreased in one female dosed with 1000 mg/kg bw/day which demonstrated abnormal findings on histopathological examination. Eight of its pups were dead or cannibalized, and the surviving nine pups showed body weight loss.

Effect levels (F1)

Dose descriptor:
NOEL
Generation:
F1
Effect level:
250 mg/kg bw/day
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Tab1 Reproductive performance after exposure to phthalimide

 Dose (mg/kg bw)  0  250  500  100
 No. of animals examined  12  12  12  12
 No. of pairs mated 12   12  12  12
 No. of pairs with successful copulation  12  12  12  12
 Duration of mating (days, mean±SD)  3.3±1.1  2.9±1.2  3.7±3.4  3.6±2.5
 No. of pregnant females  12  12  12  10
 Fertility index (%)  100.0  100.0  100.0  83.3
 Weight of testes (g)  3.4±0.2  3.3±0.2  3.2±0.3  3.2±0.3
 Weight of Epididymides (g)  1.3±0.1  1.3±0.1  1.3±0.1  1.3±0.1
 Weight of Ovaries (mg)  160±10  111±13  111±15  115±18

Historical control data on reproductive outcome in this strain of rats in the Laboratory that performed this Screening Reproductive Toxicity Study are as follows: dilatation of the uterine horn: 0-4.2% (average=0.6%), dilatation of the uterine cervix: 0-4.0% (average= 0.3%); dilatation of the vagina: 0%.

One female did not deliver at 500 mg/kg. No offspring were found in this female on gestation day 2. Only 5 implantation sites were found in this female. Historical control data on reproductive outcome in this strain of rats in the Laboratory performed this Screening Reproductive Toxicity Study are follows: fertility index (No. of pregnant animals/no. of pairs with successful copulation) x 100: 91.7-100% (average=96.5%); gestation index (No. of females with live pups delivered/no.of pregnant females) x 100: 95.5-100% (average=99.0%); fertility index at 1000 mg/kg was 83.3% in this study. This value was not within the range of the historical control data, but this value is not significantly different from the control value of this study

Applicant's summary and conclusion