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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: TSCA Health Effect Guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA 1984, 1987)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
IUCLID4 Test substance: other TS: o-cresol, purity: 99.8 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston N
- Weight at study initiation: 228-230 g
- Housing: after mating singly
- Diet :. ad libitum
- Water : ad libitum
- Acclimation period: 2 week

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 40-60
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing formulations were prepared by weighing the amount of test chemical into a volumetric flask and diluting to volume with certified corn oil. The resulting solutions were mixed by repeated inversions and stored at room temperature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A standard stock solution (1 mg/ml) was prepared as needed by weighing 50 mg o-cresol into a 50 ml volumetric flask and diuting to volume with propanol. Standards ranging vrom 10 to 100 ng/ml were prepared by diluting the stock solution with propanol. 10 µl of each standard was injected onto the HPLC . The actual concentration of each dosing solution was calculated from the equitation for the standard curve developed by linear regression.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
10 d (gd 6-15)
Frequency of treatment:
once daily
Duration of test:
gd 21 (scheduled sacrifice)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30.0, 175.0, 450 mg/kg bw/d in corn oil
Basis:
actual ingested
No. of animals per sex per dose:
25 females /group, 50 control females
Control animals:
yes, concurrent vehicle
Details on study design:
mo further data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations : mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 11, 15, 21


FOOD CONSUMPTION Yes
- Food consumption for each animal determined throughout gestation gd 0-21


WATER CONSUMPTION No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: body weight, liver, gravid uterine weight, number of corpora lutea, number and status of implantation sites:



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 all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
Statistics:
Levene's test for equal variances, ANOVA, pooled t-test with Bonferroni probabilities for pairwise comparison , Kruskal-Wallis test, Mann-Whitney U-test, Fisher's exact test
Indices:
no data
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
see section " remarks on results"

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
ca. 175 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
ca. 175 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
see section"remarks on results"

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

RS-Freetext:
---Maternal toxicity:
450 mg-group:
4/25 died,
significant reduction in periodic maternal body weight and
weight gain during dosing,
reduction of food consumption,
clinical signs: at 450 mg/kg bw
hypoactivity, ataxia, tremor, twitches, prone positioning,
audible respiration, perioral wetness,

for all groups: gestational parameters uneffected, no early
delivery, no abortion;

---Evaluation of offspring:
450 mg/kg bw: slight fetotoxicity:
one visceral variation: dileted lateral ventricles of the
brain with no tissue compression;
NOEL (maternal): 175.0 mg/kg bw/day
NOEL (developmental): 175.0 mg/kg bw/day

Applicant's summary and conclusion

Executive summary:

Developmental toxicity study according to TSCA Health Effect Guidelines for Specific Organ/Tissue Toxicity - Developmental Toxicity (EPA 1984, 1987):

Administration of o-cresol by gavage to time-pregnant Sprague-Dawley rats during organogenesis at 0.0, 30.0, 175.0, 450.0 mg/kg bw/d resulted in significant maternal toxicity at 450 mg/kg bw/d including treatment related clinical signs (hypoactivity, ataxia, tremor, twitches, prone positioning, audible respiration, perioral wetness), mortality of 4 dams, statistically significant reduction in body weights and body weight gain (NOAEL (maternal toxicity) 175 mg/kg bw/d). Slight fetotoxicity only at 450 mg/kg bw/d as one visceral variation (dilateted lateral ventricles of the brain with no tissue compression). Thus the NOAEL (developmental toxicity) is 175 mg/kg bw/d.