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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:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study

Data source

Referenceopen allclose all

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:
Chemical Investigation Promoting Council
Reference Type:
secondary source
Title:
Phthalimide - CAS No: 85-41-6
Author:
OECD SIDS
Year:
2005
Bibliographic source:
SIDS Initial Assessment Report for 20th SIAM, UNEP Publications

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD 422
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Phthalimide
- Analytical purity: 99.9%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals 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% (w/v) methylcellulose-sodium
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Males, 46 days
Females, from 14 days before mating to day 3 post parturition
Frequency of treatment:
one administration per day
Duration of test:
Duration of test: Males, 46 days
Females, from 14 days before mating to day 3 p.p.
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

Maternal examinations:
CAGE 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

-NECROPSY: autopsy: to all animals

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

Fetal examinations:
-CLINICAL AND PATHOLOGICAL OBSERVATIONS FOR PUPS
general appearance: every day
-MORTALITY: every day
-BODY WEIGHT: on day 0, 1, 4
-AUTOPSY: on day 4 or when died on major organs by gross observation

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
One female in the 500 mg/kg bw/day dose group did not deliver until day 26 of gestation. Autopsy of the females revealed dilatation of the uterus and vagina, and five implantation 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.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
other: NOEL maternal
Effect level:
500 mg/kg bw/day
Dose descriptor:
other: NOEL teratogenicity
Effect level:
250 mg/kg bw/day
Basis for effect level:
other: effect type not specified

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Eight of its pups were dead or cannibalized, and the surviving nine pups showed body weight loss. Male and female pups of the 500 and 1000 mg/kg bw/day groups showed lower body weights or body weight gains in the lactation period at day 4 (not at day 0, and 1). No pups with malformation were found in any group. No changes in pathological findings were observed in offspring

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Tab1 Developmental performance and observation on pups F1 after exposure to phthalimide

 Dose (mg/kg bw)  0  250  500  100
 No. of pregnant animals  12  12  12  12
 No. of corpora lutea 17±2  18±3  18±2  18±2
 No. of implantation sites 16±2  17±2  16±4  16±3
 Implantation index (%)  93±8  96±7  94±11  86±19
 No. of pups born  14±2  16±2  14±5  15±3
 Delivery index (%)  91±7  94±7  86±27  98±3**
 Live pups born  14±2  15±2  16±3  15±3
 Live birth index (%)  100±0  99±3  100±2  99±2
 Sex ratio (M/F)  1.2±0.6  1.4±0.6  1.1±0.8  1.2±0.6
 Gestation length (day)  23±1  23±1  23±1  22±1
 Gestation index (%)  100  100  91.7  100
Body weight of pups (g)
 Male Day 0  6.9±0.4  6.8±0.7  6.7±0.5  6.4±0.6
 Male Day 4  11±0.9  11±1.6  10±0.8*  10±1.9*
 Female Day 0  6.6±0.4  6.4±0.6  6.3±0.5  6.1±0.6
 Female Day 4  10±0.8  10±1.5  9±0.7**  9±1.7*

Values are expressed as mean ± SD. Significantly different from 0 mg/kg group; *:p<0.05, **:p<0.01

The influence of phthalimide on developmental performance was as follows: no influence on no. of dead pups, no. of pups born, sex ratio, gestation length, gestation index, nursing index, live pups on day 4. Male and female pups of the 500 and 1000 mg/kg bw/day groups showed lower body weights or body weight gains in the lactation period

Applicant's summary and conclusion