p-cresol

Repeated dose toxicity: oral

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 for cross-reference:

reference to same 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:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

p-cresol

EC Number:

203-398-6

EC Name:

p-cresol

Cas Number:

106-44-5

Molecular formula:

C7H8O

IUPAC Name:

p-cresol

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 or test system 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).