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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:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
No analysis of dose levels. No individual data. Compared to OECD 414, the following parameters were not examined: gravid uterus weight, number of corpora lutea, foetal sex., only gestation days 6 to 15

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Doses administered from day 6 of pregnancy instead of day 5 post mating to day 15 instead of until birth. Uteri were not weighted and corpora lutea not counted. The sex of the fetuses was not determined.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Substance type: Organic
- Physical state: Solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Closed SPF breeding colony
- Weight at study initiation: females: 240 g
- Housing: Throughout the experiment the successfully mated females were kept in groups of 5 in Macrolon cages
- Diet (e.g. ad libitum): Standard diet Nafag No.890
- Water (e.g. ad libitum): Ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 0.5
- Humidity (%): 56 ± 5
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Substance in 2 % CMC (acqueous solution)

VEHICLE
- Justification for use and choice of vehicle (if other than water): Substance insoluble in water
- Amount of vehicle (if gavage): 1 mL/100 g bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/3
- Length of cohabitation: Overnight
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 days, from day 6 to 15 of gestation
Frequency of treatment:
Daily
Duration of test:
21 days
Doses / concentrationsopen allclose all
Dose / conc.:
150 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
25 dams for the test substance and 30 dams for the control
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: During the period of treatment daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: During the period of treatment daily

BODY WEIGHT: Yes
- Time schedule for examinations: During the period of treatment daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: dam's organs, especially ovaries and uterus (mucosa and contents, including amniotic fluid and placentae)
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
At the 150 and 500 mg/kg dose level the feed consumption was increased when compared with controls. The mean body-weight gain, however, appeared to be comparable in all groups.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
At the 150 and 500 mg/kg dose level the feed consumption was increased when compared with controls. The mean body-weight gain, however, appeared to be comparable in all groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
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:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Description (incidence and severity):
The rates of implantation and embryolethality (resorptions) as well as the average weights of the foetuses were comparable for all groups.

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: no adverse effects reported

Results (fetuses)

External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Skeletal assessment revealed a decrease in the numbers of not yet ossified phalangeal nuclei of the hind-limb and calcanei in the 150 mg/kg and 500 mg/kg dose group, No further clear-cut deviations from the control group were found.
Visceral malformations:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: no adverse effects reported

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. Skeletal assessment (figures in brackets refer to %)

Dose group (mg/kg/day) No. of skeletons examined Phalangeal nucleia Calcaneusa Sternebraed Vertebraee
Fore-limbb Hind-limbc
150 193 2 (1.0) 17 (8.8) 9 (4.7) 49 (25.4) 1 (0.5)
500 177 2 (1.1) 31 (17.5) 20 (11.3) 41 (23.2) 0
1000 157 5 (3.2) 45 (28.7) 45 (28.7) 44 (28.0) 0
CMC control 205 6 (2.9) 61 (29.6) 43 (20.9) 63 (30.6) 1 (0.5)
99 % Confidence limits 0.69 21.95 14.48 23.46 0.00
of the CMC control -7.57 -38.99 -29.84 40.81 -3.66

a) Ossification still absent. b) Proximal phalanges. c) Proximal phalanges. d) Particularly ossification centers of the 5th sternebra still incompletely ossified (bipartite). e) Centres of some thoracic vertebrae still dumbbell-shaped. f) Centres displaced and irregularly ossified. g) Centres of some thoracic vertebrae bipartite.

Applicant's summary and conclusion

Conclusions:
Embryonic development was not adversely affected by the treatment. No teratogenic effects were noted.