p-cresol

Carcinogenicity

Description of key information

There is no carcinogenicity bioassay or other chronic study available to assess the carcinogenic potential of p-cresol.
However, the recently published studies on carcinogenicity with m/p-cresol mixture (60:40; US Department of Health and Human services 2007) is considered.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: only male rats in test

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Principles of method if other than guideline:

Groups of 50 male rats were fed diets containing 0, 1,500, 5,000 or 15,000 ppm m-/p-cresol (equivalent to average daily doses of approximately 70, 230, or 720 mg cresols/kg body weight) for 105 weeks.
All animals were observed twice daily. Body weights were recorded at the beginning of the study, weekly for the first 13 weeks, at 4-week intervals thereafter, and at study termination. Clinical findings
were recorded during week 5 of the study, at 4-week intervals thereafter, and at study termination.
Complete necropsies and microscopic examinations were performed on all rats. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major tissues were fixed and preserved in 10% neutral buffered formalin (eyes were first placed in Davidson’s solution), processed and trimmed, embedded in paraffin, sectioned to a thickness of 4 to 6 μm, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (e.g., adrenal gland, kidney, ovary), samples from each organ were examined. For extended evaluation of renal proliferation lesions, additional sections of both kidneys from the residual formalin-fixed wet tissues were obtained for each male rat, imbedded in separate paraffin blocks, and step sectioned at 1 mm intervals. Three (left kidney) or four (right kidney) sections were examined for each rat.

GLP compliance:

yes

Species:

rat

Strain:

other: Fisher 344/N

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Laboratory Animals and Sevices, Germantown, NY
- Age at study initiation: 6 weeks
- Housing: 2-3 rats/cage
- Diet: ad libitum
- Water: ad libitum):
- Acclimation period: 11 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): monthly
- Mixing appropriate amounts with NTP-2000 food
- Storage temperature of food: at 25 °C in the dark

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Periodic analyses of the dose formulations were conducted by the study laboratory usinng GC. The dose formulations were analyzed
approximately every 3 months.All of the dose formulations analyzed for rats were within 10 % of the target concentration.

Duration of treatment / exposure:

105 weeks

Frequency of treatment:

daily

Post exposure period:

no

Remarks:

Doses / Concentrations:
0, 1500, 5000 or 15000 ppm = equivalent to average daily doses of approx. 0, 720, 230, or 720 mg/kg bw/day
Basis:
nominal in diet

No. of animals per sex per dose:

50 male rats per dose

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: the highest exposure concentrations was based on the minimal toxicity observed at this level
in the 13 week study with m/p-cresol mixture

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: yes
- Time schedule:
Clinical findings were recorded during week 5 of the study, at 4 week intervallsthereafter and at terminiation

BODY WEIGHT: Yes
- Time schedule for examinations:
at the beginning of the study weekly for the first 13 weeks, at 4 week intervals thereafter and at study termination

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined Yes
at the beginning of the study weekly for the first 13 weeks, at 4 week intervals thereafter:
Food consumption calculated as mean g/day
Compound consumption calculated as mean mg/kg bw/day

OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
was performed on all rats
HISTOPATHOLOGY: Yes
complete histopathology was performed on all rats. In addition to gross sessions and tissue masses, the following tissues were examined:
adrenal gland, none with marrow, brain, esophagus, eye, hardrian gland, heart and aorta, large
intestine, small intestin kidney, liver, lung, mainstem bronchi, lymph nodes (mandibular and mesenteric), mammary gland, nose, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea and urinary bladder.

For all paired organs samples from each organ were examined.

For extended evaulation of renal proliferation lesions, additional sections of both kidneys from the residual formalin-fixed wet tissues were obtained for each male rat. 3 sections of the left kidney and 4 sections of the right kidney were examined for each rat.

Other examinations:

no

Statistics:

Kaplan Meier, Cox-method, Tarone's life-table test, Poly-k-test,

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 specified

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

at 15000 ppm in 4/50 rats renal tubular adenomas ; increase not significant but exceeding historical controls of the laboratory [1/297 [feed studies])

Details on results:

see section "remarks on results"
mean body weights of the 15000 ppm group were less than those of the controls throughout the study and decreased to 15 % less than that of the controls by the end of the study
There were no clinical findings related to exposure to cresols.
Equivocal finding :
The incidence of renal tubule adenomas was increased in the 15000 ppm group and the incidence exceeded the historical range for controls in feed studies (0-2 %).

Dose descriptor:

LOAEL

Effect level:

720 mg/kg diet

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Under the conditions of these 2-year studies, there was equivocal evidence of carcinogenic activity of 60:40 m-/p-cresol in male F344/N rats based on the marginally increased incidence of renal tubule adenoma.

Remarks on result:

other: Effect type: carcinogenicity

Dose descriptor:

NOAEL

Effect level:

230 mg/kg diet

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity

Concentration in feed

0, 1,500, 10,000 or 15,000 ppm

equivalent to average daily doses of approximately 0, 70, 230, 720 mg/kg bw/day

Body weights

15,000 ppm group: less than the control group

Survival rates : 33/50, 34/50, 33/50, 31/50

Nonneoplastic effects

----Kidney

pelvis, transitional epithelium, hyperplasia (0/50, 0/50, 2/50, 8/50);

severity of nephropathy (1.4, 1.4, 1.7, 2.1)

----Nose:

goblet cell, hyperplasia (23/50, 40/50, 42/50, 47/50);

respiratory epithelium, hyperplasia (3/50, 17/50, 31/50, 47/50)

respiratory epithelium, metaplasia, squamous (0/50, 1/50, 8/50, 40/50);

inflammation (17/50, 19/50, 19/50, 28/50)

----Liver:

eosinophilic focus (14/50, 14/50, 13/50, 23/50)

Neoplastic effects

-----None

Equivocal findings:

---- Kidney:

renal tubule adenoma

--standard evaluation - 0/50, 0/50, 0/50, 3/50;

--standard and extended evaluations combined - 0/50, 0/50, 0/50, 4/50(8%)

Level of evidence of carcinogenic activity : equivocal evidence

Executive summary:

Under the conditions of these 2-year studies (oral feed, 0, 1500, 5000 or 15000 ppm = equivalent to average daily doses of approx. 0, 720, 230, or 720 mg/kg bw/day), there was equivocal evidence of carcinogenetic activity of 60:40 m/p-cresol in male F344/N rats based on the marginally increased incidence of renal tubule adenoma. The LOAEL(male rats) is therefore 720 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

230 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The materials/methods and results are described in detail und are sufficient for evaluation.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

No classification is required

Additional information

There is no carcinogenicity bioassay or other chronic study available to assess the carcinogenic potential of p-cresol.

However, for read across purposes, the recently published studies on carcinogenicity with m/p-cresol mixture (60:40; US Department of Health and Human services 2007) is considered.

In 2007, US Health and Human Services published a Toxicity and Carcinogenicity Study in which only male rats or only female mice were fed m/p-cresol mixture over a period of two years without interim kill. Neither absolute/relative organ weights nor blood biochemistry data were reported so far. The report contains only histopathological data.

Rat study

Male F344/N rats received in feed 0, 1500, 5000, or 15000 ppm (= equivalent to daily doses of approx. 0, 70, 230 or 720 mg/kg bw/day) for 105 weeks. Under the condition of these 2-year studies, there was equivocal evidence of carcinogenic activity on m/p-cresol based on the 4/50 male rats with renal tubular adenomas. The incidence of these neoplasms was not significant but exceeded the historical control data of the laboratory (1/297 [feed studies]).

Mouse study

Female B6C3F1 mice received in feed 0, 1000, 3000, 10000 ppm (= equivalent to dailydoses of approx. 0, 100, 300 or 1040 mg(kg bw/day) for 104-105 weeks. Under the conditions of these 2-year studies there was some evidence of carcinogenic activity of m/p-cresol mixture based on the increased incidence of forestomach squamous cell papillomas. However, there is no human counterpart for the rodent forestomach (Proctor et al., Toxicol Sci 98, 313 -326, 2007). Therefore, the forestomach squamous cell paplillomas are of minor significance for the human situation. In addition, due to the corrosive property of the test substance, chronic irritation is expected to be the mode of action.

Justification for selection of carcinogenicity via oral route endpoint:
A NTP technical report on the toxicology and carcinogenesis studies of cresols (CAS no. 1319-77-3) in male F344/N rats and female B6C3F1 mice (feed studies). The most reliable study concernig effects relevant for humans is used as key value and for classification.

Carcinogenicity: via oral route (target organ): urogenital: kidneys