Xylenol

Developmental toxicity / teratogenicity

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

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

Test material information

Constituent 1

Reference substance name:

m-cresol, purity: 99.4 %

IUPAC Name:

m-cresol, purity: 99.4 %

Constituent 2

Reference substance name:

m-cresol

EC Number:

203-577-9

EC Name:

m-cresol

Cas Number:

108-39-4

IUPAC Name:

m-cresol

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 or test system 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)

1

Dose descriptor:

NOAEL

Effect level:

ca. 175 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

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).