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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:
1983-04-25 to 1983-10-25
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report date:
1984

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
N,N-dibutylformamide
EC Number:
212-090-0
EC Name:
N,N-dibutylformamide
Cas Number:
761-65-9
Molecular formula:
C9H19NO
IUPAC Name:
N,N-dibutylformamide
Test material form:
liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 82/330
- Purity test date: 1982-10-26

Test animals

Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr . K . THOMAE GmbH, Biberach, Germany
- Age at study initiation: 27-69 weeks
- Weight at study initiation: Mean body weight of the animals: 2.55 kg
- Housing: Singly housing in stainless steel cages (area: 2860 cm2).
- Diet: standardized animal laboratory diet (about 130 g/animal/day)
- Water: tap water (about 500 mL/animal/day).

ENVIRONMENTAL CONDITIONS
- Temperature: 20-24°C
- Humidity: 30-70%
- Air changes: air-conditioned rooms
- Photoperiod: 12 h light and 12 h darkness

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was emulgated in CMC (basis: weight/volume). During the period of treatment the suspensions were prepared daily, shortly before the beginning of treatment.
The concentration of the suspensions was 3.1% for the 62 mg/kg bw/day dose, 6.25% for the 125 mg/kg bw/day dose and 12.5% for the 250 mg/kg bw/day dose.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration of the emulsion was tested twice.
Details on mating procedure:
- Impregnation procedure: artificial insemination

One hour prior to insemination 40 I.U. of Primogonyl R (= chorionic gonadotropin, trade product of SCHERING AG, Berlin/Bergkamen, FRG, dissolved in 1 mL of physiological saline solution) were injected intravenously (ear vein) into each animal. The day of insemination was designated day 0 of pregnancy, the following day the first day post insemination (p.i.).
Duration of treatment / exposure:
13 successive days (from the 6th -18th day post insemination)
Frequency of treatment:
daily at the same time of day (in the morning). The amount of test substance to be administered at each dose level per kg body weight was contained in a volume of 2 mL.
Duration of test:
from the 6th -18th day post insemination
Doses / concentrationsopen allclose all
Dose / conc.:
62 mg/kg bw/day
Dose / conc.:
125 mg/kg bw/day
Dose / conc.:
250 mg/kg bw/day
No. of animals per sex per dose:
62 mg/kg bw/day; 22
125 mg/kg bw/day: 14
250 mg/kg bw/day: 22
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In a preliminary study (doses: 31, 62, 125 and 250 mg/kg bw/day), rabbits were orally administered from day 6 - 18 p.i. Only at a dose of 250 mg/kg bw/day a slight till questionable embryolethality was demonstrated. Thus, 250 mg/kg was selected as the high dose for the main study. Supportingly, the acute oral LD50 in rats is about 1050 mg/kg bw/d (BASF SE, 1979), and mortality of pregnant rats is described after single dermal appllication of 1200 mg/kg DBF at GD10 (Stula et al., 1977). Therefore, the MTD after repeated exposure for rats is expected to be well below 500 mg/kg.
- Details on control animals: A further group of animals was treated with a 0.5% aqueous CMC formulation and treated and investigated in the same way

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Three times in the week

FOOD CONSUMPTION AND COMPOUND INTAKE : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: Ovaries and uterine

Animals were sacrificed by rapid intravenous administration (ear vein) of 1 mL/kg + 1 mL Nembutal R (= pentobarbital sodium, 60 mg/mL, trade product of ABBOTT GmbH).
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
Fetal examinations:
- External examinations: Yes, on day 29
- Soft tissue examinations: Yes
- Skeletal examinations: Yes

The length and weight of the fetuses as well as the weight of the placentas were determined.
All fetuses were eviscerated, their sex was determined, and the organs were examined macroscopically. Subsequently the fetuses were X-rayed for the evaluation of the skeletons. After being X-rayed, the heads were fixed in BOUIN's solution, and after fixation they were processed and evaluated according to the method of WILSON.
Statistics:
method of WILSON

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
62 and 125 mg/kg bw /day: non-treatment related diarrhoe and conjunctivitis
The dose of 250 mg/kg bw/day showed symptoms, which were related to the test substance administration. Following symptoms were oberseved: Mydriasis, tachycardia, uncertain gait, apathy.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
From days 5 to 6 post insemination a significant increase in food consumption was observed for the highest dose group compared to the control group.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
no significant differences in weight of uteri
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
control: one animal with changes in liver morphology, 4 animals with cysts in uterine horns
62 mg/kg bw/day: 5 animals with cysts in uterine horns
125 mg/kg bw/day: 2 animals with cysts in uterine horns
250 mg/kg bw/day: 4 animals with cysts in uterine horns
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
No changes in numbers of corpora lutea, dead or alive implants, preimplantative lost of eggs was observed. The conception rate was between 77.78 and 92.86 %.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Abnormalities:
not examined

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: prenatal developmental toxicity including teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion