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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:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Study not available for review

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 Effects Test 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
Type:
Constituent
Details on test material:
IUCLID4 Test substance: other TS: m-cresol, purity: 99.4 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding labarotory, Kingston, NY
- Age at study initiation: 56 days at arrival
- Weight at study initiation: 228-231g
- Housing: after mating: singly
- Diet : ad libitum
- Water : ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 40 - 60
- 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 m-cresol into a 50 ml volumetric flask and
diluting to volume with propanol. Standards ranging from 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 conentration 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:
day 6 through day 15 of gestation
Frequency of treatment:
daily
Duration of test:
gd 21 (scheduled sacrifice)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 175 or 450 mg/kg bw/d dissolved 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:
no 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 implantaion sites


OTHER:
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: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Levene's test, ANOVA, t-test with Bonferroni prohabilities, Kruskal-Wallis test, Mann-Whitney U test, Fishers 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:
no mortality,
no treatment-related abortions or early delivery,
no treatment related lesions in dams at scheduled sacrifice

450 mg/kg bw/day (significant canges only)
significant reduction in mean maternal body weights:
gd 11: 261 g versus 276 g in controls
gd 15: 281 g versus 300 g in controls
reduction in mean weight gain during dosing
reduced mean gestational weight gain
gd 0-21: 145 g versus 163 g in controls
clinical signs of toxicity :
predominantly hypoactivity, ataxia, tremors, twitches, prone positioning, audible rtespiration, perioral wetness
reduction inmean food consumption
pretratment period: day 6-9: 15 g versus 21 g of controls
treatment period gd 6-15 : 19 g versus 22 g of controls
relative (not absolute) liver weight was increased
4.9 % versus 4.52 % in controls

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:
> 450 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

RS-Freetext:

maternal toxicity: no deaths, no abortions or early deliveries

 

450 mg/kg:

significant reduced food consumption, reduced maternal body weights and weight gain during dosing period; reduced gestational weight gain (day 0-21);

 

clinical signs of toxicity: hypoactivity, ataxia, tremors, audible respiration, perioral wetness; increased relative but not absolute liver weights no embryotoxicity or teratogenicity was observed at any dosage level

Applicant's summary and conclusion

Executive summary:

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

Administration of m-cresol by gavage to time-pregnant-Sprague Dawley rats during organogenesis at 0.0, 30, 175, 450 mg/kg bw/d resulted in maternal toxicity at 450 mg/kg bw/day including significant reduction in periodic maternal body weights and weight gain during the dosing period in addition with clinical signs of toxicity (NOAEL (maternal toxicity) 175 mg/kg bw/d). m-Cresol did not induce fetotoxicity or malformations at any dose level tested. (NOAEL (developmental toxicity) >450 mg/kg bw).