Phthalimide

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1999

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

Test material information

Constituent 1

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)

1

Dose descriptor:

NOEL

Effect level:

500 mg/kg bw/day

Sex:

female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

histopathology: non-neoplastic

reproductive performance

2

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day

Sex:

male

Basis for effect level:

clinical signs

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

Basis for effect level:

mortality

body weight and weight gain

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