Registration Dossier

Administrative data

Description of key information

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 (RTI 1988). 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
Due to the corrosive properties of p-cresol to the skin (R34) it will be allocated to the moderate hazard category for local effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
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

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
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
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"
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"
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
Critical effects observed:
not specified
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
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)

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The materials/methods and results are described in detail und are sufficient for evaluation.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

ORAL APPLICATION

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 (RTI 1988). 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/day

In 2007, US Health and Human services published a Toxicity and Carcinogenicity Study in which only male rats or only female mice were fed with a diet containing m/p-Cresol mixture (60:40) over a period of two years. Only gross and microscopic anatomical lesions were reported. Obviously, no organ weights, no clinical chemistry , no hematology and no urinalysis were done to evaluate general toxicity. Based on these limitations these toxicity and carcinogenicity studies were not chosen as key studies. Nevertheless , the reported histopathological changes are consistent with the observed effects of cresols in general::

Male F344/N rats, fed with 0, 1500, 5000 or 15000 ppm in diet , shoed increased incidences of non -neoplastic lesions in the kidney (hyperplasia); nose (inflammation, hyperplasia and metaplasia) and liver (eosinophilic focus). A NOAEL could not be derived; the LOAEL (male rat) is 1500 ppm (equivalent to average daily dose of approximately 70 mg/kg bw/day).

From female B6C3F1 mice, fed 0, 1000, 3000 or 10000 ppm in diet , increased incidences in lesions in the respiratory tract (hyperplasia in the nose and lung), thyroid gland (follicular degeneration)and liver (eosinophilic foci were reported with a LOAEL of 1000 ppm (equivalent to average daily doses of approximately 100 mg m/p cresol / kg bw/day).

DERMAL APPLICATION

There is no valid dermal repeated dose study available. p-Cresol shall be registered according to REACH Article 10 and a reliable oral sub-chronic study in male and female rats (rodent) is available. Based on toxicokinetic information p-cresol might be absorbed across gastrointestinal tract and through the intact skin Therefore, systemic toxicity after dermal exposure can be covered by the available robust oral study (route to route extrapolation) and no additional information on systemic toxicity is needed for risk assessment.

Due to the corrosive properties of p-cresol it is not appropriate to conduct a route-to-route extrapolation for local effects. The available data for p-cresol in animals are not sufficiently robust to derive a clear threshold value and to calculate a DNEL for local effects after dermal exposure. Based on the available data a qualitative risk assessment approach will be followed as outlined in the REACH “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (Version 2), December 2010.

Due to the corrosive properties of p-cresol to the skin (R34) it will be allocated to the moderate hazard category.

No additional animal experiments are necessary in the course of a qualitative risk assessment and, consequently, further animal testing on vertebrates should be omitted for this endpoint, taking also into account animal welfare reasons

INHALATION EXPOSURE

There is no adequate inhalation study available. p-cresol shall be registered according to REACH Article 10 and the required reliable oral sub-chronic study in male and female rats (rodent) is available. Based on the toxicokinetic information discussed in the respective section, p-cresol is well absorbed across the respiratory tract and the gastrointestinal tract. Therefore, systemic inhalation toxicity can be covered by the available robust oral study (route to route extrapolation) and no additional information on systemic toxicity is needed for risk assessment.

Due to the corrosive properties of p-cresol it is not appropriate to conduct a route-to-route extrapolation for local effects. The available data for p-cresol in animals are not sufficiently robust to derive a clear threshold value and to calculate a DNEL for local effects at the respiratory tract. Based on the available data a qualitative risk assessment approach will be followed as outlined in the REACH “Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health” (Version 2), December 2010.

Due to the corrosive properties of p-cresol (R34) it will be allocated to the moderate hazard category. Thus, according to ANNEX XI of REACH Regulation further testing does not appear scientifically justified based on the reliable occupational historical human data.

No additional animal experiments are necessary in the course of a qualitative risk assessment and, consequently, further animal testing on vertebrates should be omitted for this endpoint, taking also into account animal welfare reasons


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The most reliable study was used as key study and for classification.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

Based on the available data, no classification is required.