Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

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

Referenceopen allclose all

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

Reference
Name:
Unnamed
Type:
Constituent
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 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..