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Diss Factsheets

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:
From 14 June 1983 to 16 February 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to 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)
Deviations:
yes
Remarks:
Treatment was performed during the day 5 to 16 instead of until the day scheduled for caeserian section. However, this old study had a method equivalent to the OECD guideline of 1981. This study was not up to modern standard but was still reliable.
GLP compliance:
no
Remarks:
Not GLP compliance but reviewed with a statement of quality assurance
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
5-amino-o-cresol
EC Number:
220-618-6
EC Name:
5-amino-o-cresol
Cas Number:
2835-95-2
Molecular formula:
C7H9NO
IUPAC Name:
5-amino-2-methylphenol
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2155/19/11
- Expiration date of the lot/batch: not specified
- Purity test date:not specified

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: stored at room temperature in a dark area away from heat
- Stability under test conditions: not specified
- Solubility and stability of the test substance in the solvent/vehicle: not specified

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test article was prepared as suspension. For preparation and during administration to the animals, each formulation mixed using a magnetic stirrer. Separate preparations were made for each dose level.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: not specified
- Weight at study initiation: 170 to 230g
- Fasting period before study: not specifed
- Housing: solid floor macrolone cages type II with stainless steel lids (dimensions 260 x 200 mm)
- Diet and water (e.g. ad libitum): Throughout the study the rats were allowed free access to food. The basic diet used was obtained in pelleted form, Ssniff R. Tap water was available ad libitum from plastic water bottles attached to each cage.
- Acclimation period: seven days prior the start of mating

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 23°C
- Humidity (%): 40 to 70%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light):12 hours / 12 hours

IN-LIFE DATES: From: 14 June 1983 To: 1 August 1983

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% CMC
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test article was prepared as suspension. For preparation and during administration to the animals, each formulation mixed using a magnetic stirrer. Separate preparations were made for each dose level.

VEHICLE
- Justification for use and choice of vehicle (if other than water): no specified
- Concentration in vehicle: 2, 6, 18 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 Male for 4 females
- Length of cohabitation: overnight
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
From the day 6 to 15
Frequency of treatment:
once daily
Duration of test:
until the day 20 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
20 mg/kg bw/day (nominal)
Dose / conc.:
60 mg/kg bw/day (nominal)
Dose / conc.:
180 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 animals were used per condition (expet for positive control : 23 animals)
Control animals:
yes
yes, concurrent vehicle
other: positive control
Details on study design:
- Dose selection rationale: not specified
- Rationale for animal assignment (if not random): randomly

Examinations

Maternal examinations:
APPEARANCE, BEHAVIOUR AND GENERAL OBSERVATIONS All animals were examined at least once daily for signs of ill-heath, toxicity and behavioural change. Daily mortality checks were also performed.
BODYWEIGHT: The bodyweight of each mated female rat was recorded on days 0, 6, 15 and 20 (respectively 19) of gestation.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- 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: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
Statistics:
WHere appropriate the data were analysed using Kruskal Wallis test, Wilcoxin's test, Fisher's randomisation testn Analysis of Variance and the Chi-square method

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical changes during gestation were observed in all groups
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No difference was observed between tested and control group.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There was no treatment related changes in all groups. Dilatations of the renal pelvis were observed in all groups including control.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
In treated groups, the mean number of corpora lutea and the mean number of implantations per dam were comparable with the control group. The incidence of intra-uterine deaths was not affected by treatment with the test substance.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Both litter was comparable to all groups including the control

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
180 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
gross pathology
maternal abnormalities

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
no difference between treated and control groups was observed.
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Visceral variations (dilatation of the renal pelvis) were observed in group II (five fetuses), group III (five fetuses) and group IV (two fetuses). The occurence of these visceral variations was considered to be unrelated to treatment with test substance, because dilatations of renal pelvis were also observed in the control group and in historical groups of similar studes with the same strain of rats.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Positive Control : Vitamin A Acid was sued as positive control. Administration of 15 mg/kg produced a marked teratogenic effect. The majority of malformed foetuses showed exencephaly.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
180 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In this rat teratogenicity study, no treatment-related changes were noted in any of the dose groups of 20, 40 and 180 mg /kg bw/day administered from day 6 to day 15 post coitum. Consequently, a NOAEL of 180 mg/kg bw for maternal and embryo-foetal effects is determined for 4-amino-2-hydroxytoluene
Executive summary:

The present study was performed in order to assess the potential teratogenicity effect when administered orally to female pregnant rats. The method was similar to OECD 414 guideline.

Mature male and female Sprague-Dawley rats were housed together, and day 0 of pregnancy was defined as the day on which vaginal sperm were detected. Females were then housed separately and dosed by gavage during the embryonic period GD 6 -15. Treated rats were observed daily and weighed on GD 0, 6, 15 and 20. On GD 20, dams were euthanized with CO2, the uterine horns were removed and numbers and conditions of foetuses recorded Half the foetuses were fixed in Bouin’s solution for examination of soft tissue, and the other half were fixed in ethanol and stained with Alizarin Red S for examination of skeletal effects.

In this rat teratogenicity study, no treatment-related changes were noted in any of the dose groups of 20, 40 and 180 mg /kg bw/day administered from day 6 to day 15 post coitum. Consequently, a NOAEL of 180 mg/kg bw for maternal and embryo-foetal effects is determined for 4-amino-2-hydroxytoluene