MP99

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

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: comparable to a guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Reference 2

Reference Type:

publication

Title:

Comparative toxicity of cresol isomers

Author:

Dietz DD, Levine BS, Sonawane RB, Rubenstein R, DeRosa C

Year:

1987

Bibliographic source:

the Toxicologists 7, 246 No.982

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Sontag JM, Page NP, Saffotti U, NCI, DHEW Publication No (NIH)78-ß01Guidelines for Carcinogen Bioassay in small rodents

Principles of method if other than guideline:

Method: see section" any other information of materials and methods"

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:

2-methyl-phenol

Details on test material:

IUCLID4 Test substance: other TS: o-cresol purity 99.5%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 5-6 weeks
- Fasting period before study: 24 hours
- Housing: individually
- Diet : ad libitum):
- Water : ad libitum):
- Acclimation period: 16 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
test solution was produced on a weekly basis

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

during test week 1, 2, 4, 8 and 13 by
Enseco Inc, Cambridge MA and additionally by American BiogenicsCorporation, Decatur IL

Duration of treatment / exposure:

13 w

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
50, 175, 600 mg/kg bw/day in corn oil
Basis:
actual ingested

No. of animals per sex per dose:

30 animals /sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Positive control:

no data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and clinical signs

BODY WEIGHT: Yes
- Time schedule for examinations: day 1 and then weekly

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption
and body weight gain data: Yes , weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during quarantine period and in test week 13

HAEMATOLOGY: CLINICA CHEMISTRY : Urinalysis Yes
- Time schedule for collection of blood: as baseline clinical pathology, at test week 7 (interim kill) at study termination
- How many animals: 10 rats/sex/dose
- Parameters checked : see section "additional iformation on materials and methods"


NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see section " any other information on materials and method"
HISTOPATHOLOGY: Yes (see section"Any other information on materials and method"

Other examinations:

no data

Statistics:

One-Way Analysis of Variance tests, Dunnett's t test

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

see section: "Remarks on results "

Effect levels

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: >= 175 mg/kg bw/day animals revealed central nervous system depression and showed statistically significant reduction in body weight and body weight gain

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

RS-Freetext:
600 mg/kg bw/day: 
mortality 19/30 females and 9/30 males, 
Body weight:
reduction  
body weight of females were unaffected
600 mg/kg bw/d, males: significant during week 2 through 10
175 mg/kg bw/d, males: significant during week 2
Body weight gain
175 and 600 mg/kg bw/d
reduction in body weight gain (males), slight decrease in food intake;

600 mg/kg bw/day, males and females, 
175 mg/kg bw/d: 1 female d23 and 1 female d27
Treatment-related depression of the central nervous system:
lethargy, dyspnoe, tremor and/or convulsions, recovering
within 1 h after dosing 

no effects on clinical chemistry, hematology, urinalyses parameters, 
no treatment-related ophthalmic lesions, 
no effects on organ weights, no treatment-related gross and  histomorphologic 
lesions;

Applicant's summary and conclusion

Executive summary:

According to Sontag JM, Page NP, Saffotti U, NCI, DHEW Publication No (NIH)78-ß01 Guidelines for Carcinogen Bioassay in small rodents) male and female rats were applied with 0, 50,175, 600 mg/kg bw/day by gavage for 13 weeks. The NOAEL is 50 mg/kg bw/day based on clinical signs and effects on body weights from 175 mg/kg bw /day onwards..