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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
Study period:
September 1990 - June 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-(n-octyl)-2-pyrrolidinone
EC Number:
403-700-8
EC Name:
N-(n-octyl)-2-pyrrolidinone
Cas Number:
2687-94-7
Molecular formula:
C12 H23 N O
IUPAC Name:
N-(n-octyl)-2-pyrrolidinone
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): SURFADONE LP 100
- Physical state: liquid
- Analytical purity: 99.7 %
- Lot/batch No.: 238106
- Expiration date of the lot/batch: 1991-01-13
- Stability under test conditions: stable in the vehicle at least 2 h
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL, Fuellinsdorf/CH
- Age at study initiation: 11 weeks, minimum (age at pairing)
- Weight at study initiation: 179-225 g (d0 post coitum)
- Fasting period before study:
- Housing: individually in Makrolon cages
- Diet (ad libitum): Kliba (Klingentalmuehle AG, Kaiseraugst/CH)
- Water (ad libitum): tap water
- Acclimation: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 40-70 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: bi-distilled water with 0.5% Cremophor
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- daily before administration
- amount: 10 ml/kg bw (daily adjustment)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During the dosing period of this study, samples were taken for confirmation of concentration, homogeneity and stability on two occasions. Analyses were performed by the RCC Analytlcal Chemistry Laboratory using a method supplied by the Sponsor.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Proof of pregnancy: [sperm in vaginal smear] referred to as [day 0] of pregnancy
Duration of treatment / exposure:
day 6 - 15 post coitum
Frequency of treatment:
daily in the morning
Doses / concentrations
Remarks:
Doses / Concentrations:
50, 200, 800
Basis:
nominal conc.
No. of animals per sex per dose:
25 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: range-finding study (RCC project 277896)

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, twice daily
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes, daily from day 0 - 21 post coitum
FOOD CONSUMPTION: Yes (day0-6, 6-11, 11-16, 16-21)
WATER CONSUMPTION: No data
POST-MORTEM EXAMINATIONS: Yes, gross macroscopic examination
- Sacrifice on gestation day 21
- Organs examined: all internal organs, with emphasis on the uterus, uterine contents, position of fetuses in the uterus and number of corpora lutea
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of pre- and post-implantation loss: Yes


Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [about half per litter]
- Skeletal examinations: Yes: [about half per litter]
- Head examinations: Yes
Statistics:
For analysis of body weights, food consumption, reproduction and skeletal examination data:
Univariate one-waY analysis of variance was used to assess the significance of intergroup differences. If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-one t- test) , based on a pooled variance estimate, was applied for the comparison between the treated groups and the control group. The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information. Individual values, means, standard deviations and t - statistics were rounded off before printing.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
HIGH DOSE GROUP (800 mg/kg bw/d):
- 2 females were found dead of day 16 or 12 post coitum, respectively (observed toxic effects noted during the days prior to death)
- ruffled fur, ventral recumbency. somnolence, apathy, dyspnea, comatose state were note during the dosing period

MID DOSE GROUP (200 mg/kg bw):
- 1 incidental death in the mid dose group
- no clinical signs of reaction to treatment

LOW DOSE GROUP (50 mg/kg bw):
- no clinical signs of reaction to treatment

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: fetal effects at maternal toxic doses

Details on embryotoxic / teratogenic effects:
- At 800 mg/kg, mean fetal body weight was statistical significantly reduced in comparison with the control group. This finding which was combined with a delay in skeletal ossification correlated with the severe maternal toxicity observed at this dosage. At 50 or 200 mg/kg, no effects of treatment with the test article on the mean fetal body weights were evident.
- At external, visceral or skeletal examination of the fetuses, no test article related abnormal findings were noted in any group.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
800 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:
No teratogenic potenial of Surfadone LP 100 (= NOP, CAS 2687-94-7) was found in this study. The fetotoxicity (reduced mean fetal body weight, combined with delay in skeletal ossification) correlated with the severe maternal toxicity at 800 mg/kg bw exposure.
Executive summary:

SURFADONE LP 100 (N-octyl-pyrrolidone, CAS 2687-94 -7) was administered orally by gavage, once daily, to pregnant female Wistar rats from day 6 through to day 15 post coitun, at dosages of 50, 200 or 800 mg/kg bw/d in order to assess the effects on embryonic and fetal development (OECD guideline 414, GLP; Bayer AG 1991).

At 800 mg/kg, one dam died after the 7th and one after the 10th test article administration. The females of this group had marked clinical signs of reaction to treatment, reduced food consumption, slight body weight loss during the first day of dosing and reduced corrected body weight gain. The mean fetal body weight was reduced at this dosage, combined with a delay of skeletal ossification.

At 50 or 200 mg/kg, no effects of treatment with the test article on the a maternal or fetal parameters were evident.

Based on the results of this study, the NOAEL for the maternal and fetal parameters was considered to be 200 mg/kg bw/d. SURFADONE LP 100 did not reveal any teratogenic potential up to and including the highest dose level of 800 mg/kg bw/d when administered to pregnant Wistar rats under the conditions described for this study.