Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

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
Cross-reference
Reason / purpose:
reference to same 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:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: p-cresol, purity: 99.9 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Ladeview,NY
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 152-233 g
- Housing: individually
- Water ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air changes (per hr): 12-17
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Dosage formulations were prepared fresh weekly throughout the study and stored protected from light at room temperature.


DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:


VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
the concentration of p-cresol in corn oil was analyzed in week 1, 2, 4, 8 and 13
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
once daily, 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 175, 600 mg/kg bw/day dissolved in corn oil
Basis:
actual ingested
No. of animals per sex per dose:
30 rats/sex/dose, for baseline examinations additionally 10 rats/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Interim kill at week 7
Post-exposure period: no
Positive control:
no

Examinations

Observations and examinations performed and frequency:
yes, see section "any other information on materials and method"
Sacrifice and pathology:
yes, see section "any other information on materials and method"
Other examinations:
yes, see section "amy other information on materials and method"
Statistics:
yes, see section "any other information on materials and method"

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:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
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/d: increased mortality, clinical signs including lethargy, excessive salivation, tremor and occasional convulsions and comas, hepatotoxicity and nephrotoxicity

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

600 mg/kg: 3 females died within the first 3 days of dosing.  

Overt signs  of toxicity at this dose included lethargy, tremors, convulsions and coma.

BODY WEIGHT was sign. reduced (p</=0.05):
50 mg/kg bw: female, at week 1, 2, 3, 4, 5, and 7 175 mg/kg bw: male, at week 2, 3, and 4 600 mg/kg bw: male, except week 1 in all weeks; female, week 2, 3, 4, 5,  6, 7, 8, 9, and 14  
BODY WEIGHT GAIN was sign. reduced (p</=0.05):
50 mg/kg bw: female, week 2, and 3
175 mg/kg bw: male, week 1, 2, and 3; female, week 1 and 2
600 mg/kg bw: male, all weeks; female, week 1, 2, 3, 4, 5, 6, 7, 10, 13
FOOD CONSUMPTION data was sign. reduced (p</=0.05):
50 mg/kg bw: male, week 5, 9; female, week 1 and 2
175 mg/kg bw: male, week 1, and 5
600 mg/kg bw: male, week 1, 2, 3, 4, 5, 6, 7, and 9; female, week1, 2,  and 5  
CLINICAL PATHOLOGY, only sign. changes (p</=0.05):
Male: 
APTT, 600 mg/kg bw, increased; total protein from 175 mg/kg bw increased;  Ca, at 175 mg/kg bw increased; phosphate, 600 mg/kg bw, increased 
Female: 
RBC, HGB, HCT, from 175 mg/kg bw, decreased; CO2, at 175 mg/kg bw,  decreased;  SGPT, SGOT, Cholesterin, at 600 mg/kg bw increased;  
OPHTHALMOLOGY:
Treatment related changes were not seen.
ORGAN WEIGHTS (rel. and abs., only sign. changes, p</=0.05):
Male:
Heart, rel., at 600 mg/kg bw increased; liver, 600 mg/kg bw, abs.  decrease,  rel. increase; spleen, 600 mg/kg bw, absol. decreases; right  and left kidney,  from 175  mg/kg bw, rel. increased; right and left  testis, at 600 mg/kg bw, rel. increased; brain, at 600 mg/kg bw, abs.  decreased, rel. increased; 
Female:
spleen, at 50 mg/kg bw, rel. increased (no histopathologic correlate);  right kidney, at 600 mg/kg bw, rel. increased; right ovary, at 600 mg/kg  bw, ovary and brain, abs. decreased
PATHOLOGY: 
Gross necropsy examinations did not detect treatment- related changes.
Histological examination:
male: 
chronic nephropathy in all rats including controls:
a slight increased incidence in all dosed males when compared to the  controls. The increased incidence was significantly greater (p</=0.05) at  the low and the high dose but not at the middle dose. The proportion of  rats with minimal and mild nephropathy was generally similar for all male  rats including controls:
controls: 4/20 = 20%, severity(s): minimal 3/4, mild 1/4; 
50 mg-gr.:  11/20 = 55%, s: minimal: 3/11, mild: 2/11
175 mg-gr.:  7/20 = 35%, s: minimal: 7/7, mild:0/7
600 mg-gr.: 12/20 = 60%, s: minimal: 9/12, mild: 3/12
(no dose-response relationship, controls also affected, no increase in  percentage of severity in dosed rats when compared to the controls)
male, female:
epithelial metaplasia of the trachea:
sign, at 600 mg/kg bw (p</=0.05), 10/20 males, 9/19 females
The incidence of this lesions was similiar for low dose, mid dose and  control

Applicant's summary and conclusion

Executive summary:

In a subchronic toxicity study according to OECD TG 408 p-cresol was administered daily to male and female Sprague-Dawley rats by gavage at dose levels of 0, 50, 175 , 600 mg/kg bw/day diluted in corn oil. Based on increased mortality, clinical signs including lethargy, exessive salivation, tremor and occasional convulsions and comas, hepatotoxicity and nephrotoxicity from 175 mg/kg bw/d onwards. The NOAEL is 50 mg/kg bw/d (RTI 1988)