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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study

Data source

Referenceopen allclose all

Reference Type:
other: microfiche
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:
th Toxicologists 7, 246 No.982

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Method: other: 30 rats/sex/dose, add.10 rats/sex for baseline clin. Pathol., interim kill at week 7, terminal kill at week 14, blood samples for hematology, clin.chemistry; urinalysis; gross and microsc. pathology; stat. anal.: Dunnett's t-t
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
IUCLID4 Test substance: other TS: purity: 98.6 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5-6 weeks
- Housing: 2or 3 per cage during pretest, individually following randomization to groups
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air change: at least 12-15 per hour
- 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:
the test chemical was diluted in corn oiil on a weekly basis to achieve the respective test concentrations
which allowed for a dosing volume 5 ml/kg

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gas chromatography: m-cresol was found to be stable for at least 14 days at the concentration tested. Additionally the analyses of the dosage form
preparations used during test week 1, 2, 4, 8, and 13 indicated that target concentrations were generally within an acceptable range.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
once daily for 13 consecutive weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 150 or 450 mg/kg bw/d in corn oil (m/f)
Basis:
actual ingested
No. of animals per sex per dose:
30 rats/sex/dose group; 10 of each group for interim kill at day 45
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure period: 1 w
- Dose selection rationale: doses were chosen based on the results of a range-finding study
Positive control:
not relevant

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: for moribundity/mortality: twice daily
- for clinical signs: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: at initiaation and weekly thereafter

FOOD CONSUMPTION:
Time schedule: weekly


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretreatment and at termination
- Dose groups that were examined: at termination on all animals designated to be terminated at 13-weeks

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals:
10 males and 10 females for baseline examination
10 rats/sex/dose group at interim kill
10 rats/sex/group at termination of the study
- Parameters checked in table were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
for details see above
- Parameters checked in table were examined.


URINALYSIS: Yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: No data
for details see above
- Parameters checked in table were examined.


NEUROBEHAVIOURAL EXAMINATION: No data



OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see section: any other information on materials and methods incl. tables)
HISTOPATHOLOGY: Yes
Other examinations:
no
Statistics:
One-way analysis of Variance tests with Dunnett's test: body weight, food consumption, clinicla chemistry, hematology and organ weights data

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):
effects observed, treatment-related
Food efficiency:
not examined
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:
MORTALITY/CLINICAL OBSERVATIONS: 450 mg/kg: one high dose male was found dead on day 5 (cause not evident), signs of intoxication: 450 mg/kg bw, male, female: lethargy, tremors, hunched posture, rough hair coats post dosing
BODY WEIGHT was sign reduced (p female, week 11 at 450 mg/kg bw
body weight gain was reduced (p female, week 1 at 450 mg/kg bw FOOD CONSUMPTION was sign. reduced (p female: 50 mg/kg bw, week 4, 150 mg/kg bw, week 4, 11, 450 mg/kg bw, week1, 4, 6 CLINICAL PATHOLOGY clinical chemistry, haHematology and urinalyses parameters were not affected by treatment
OPHTHALMOLOGY treatment related lesions were not seen ORGAN WEIGHTS organ weights were not affected by treatment PATHOLOGY treatment-related gross and histomorphology lesions were not in evidence
NOAEL (female) = 150 mg/kg bw/day NOAEL (male) = 50 mg/kg bw/da

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: dose-dependant body weight reduction and at450 mg/kg bw, lethargy, tremors, hunched posture, rough hair coats post dosing
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: decrease in body weight gain and at 450 mg/kg bw, lethargy, tremors, hunched posture, rough hair coats post dosing

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

RS-Freetext:
MORTALITY/CLINICAL OBSERVATIONS:
450 mg/kg: one high dose male was found dead on day 5 (cause not evident),
signs of intoxication:
450 mg/kg bw, male, female:
lethargy, tremors, hunched posture, rough hair coats post dosing
BODY WEIGHT
was sign reduced (p</=0.05): male, week 2-5, 13 at 450 mg/kg bw and week 6 -12, 14 from 150 mg/kg bw; female, week 11 at 450 mg/kg bw
body weight gain was reduced (p</=o.05): male, week 1-3 at 450 mg/kg bw and week 4 -13 from 150 mg/kg bw; female, week 1 at 450 mg/kg bw
FOOD CONSUMPTION
was sign. reduced (p</=0.05): male: 50 mg/kg bw, week 1, 2, 9, 11, 12; 150 mg/kg bw week 3, 6, 8, 12, 13; 450 mg/kg bw week 1 -4, 6 -9, 11; female: 50 mg/kg bw, week 4, 150 mg/kg bw, week 4, 11, 450 mg/kg bw, week1, 4, 6
CLINICAL PATHOLOGY
clinical chemistry, haematology and urinalyses parameters were not affected by treatment
OPHTHALMOLOGY
treatment related lesions were not seen
ORGAN WEIGHTS
organ weights were not affected by treatment
PATHOLOGY
treatment-related gross and histomorphology lesions were not in evidence
NOAEL (female) = 150 mg/kg bw/day
NOAEL (male) = 50 mg/kg bw/day

Applicant's summary and conclusion

Executive summary:
In a study according to OECD 408 , male and female Sprague-Dawley rats received 0, 50, 150, 450 mg/kg bw/day diluted in corn oil feor 13 weeks by gavage at 450 mg/kg bw male and female rats displayed lethargy, tremors, hunched posture and rough fur post dosing. Dose-dependant body weight decrease resulted in a NOAEL (male rat ) of 50 mg/kg bw/day. The NOAEL (female rat) was 150 mg/kg bw/day based on reduced body weight gain in the highest dose