o-cresol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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

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

Test material information

Constituent 1

Reference substance name:

o-cresol

EC Number:

202-423-8

EC Name:

o-cresol

Cas Number:

95-48-7

Molecular formula:

C7H8O

IUPAC Name:

o-cresol

Details on test material:

Test substance: o-cresol, purity: 99.8 %

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system 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)

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)

1

Dose descriptor:

NOAEL

Effect level:

ca. 175 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Remarks on result:

other:

Remarks:

450 mg/kg bw/day: treatment related clinical signs including hypoactivity, ataxia, tremor, twitches, prone positioning, audible respiration, perioral wetness, mortality of 4 dams, statistically significant reduction in body weights and body weight gain.

2

Dose descriptor:

NOAEL

Effect level:

ca. 175 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

Remarks on result:

other:

Remarks:

450 mg/kg bw: slight fetotoxicity: one visceral variation: dileted lateral ventricles of the brain with no tissue compression.

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
see section "Remarks on result"

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

ca. 175 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: 450 mg/kg bw: slight fetotoxicity: one visceral variation: dilated lateral ventricles of the brain with no tissue compression.

Fetal abnormalities

Abnormalities:

not specified

Localisation:

other: 450 mg/kg bw: slight fetotoxicity: one visceral variation: dilated lateral ventricles of the brain with no tissue compression.

Description (incidence and severity):

450 mg/kg bw: slight fetotoxicity: one visceral variation: dilated lateral ventricles of the brain with no tissue compression.

Overall developmental toxicity

Developmental effects observed:

yes

Lowest effective dose / conc.:

450 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Any other information on results incl. tables

---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

Conclusions:

The NOAEL (developmental toxicity) is 175 mg/kg bw/d.

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.