Registration Dossier

Administrative data

Description of key information

In a study according to OECD TG 408, male and female Sprague Dawley rats received 0, 50, 150, 450 mg/kg bw/day m-cresol diluted in corn oil for a period of 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 group (RTI 1988).
Due to the corrosive property of m-cresol to the skin (R34) it will be allocated to the hazard category for local effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
50 mg/kg bw/day

Additional information

ORAL APPLICATION

In a study according to OECD 408 , male and female Sprague-Dawley rats received 0, 50, 150, 450 mg/kg bw/day m-cresol diluted in corn oil for 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 group.

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).

INHALATION EXPOSURE

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

Due to the corrosive properties of m-cresol it is not appropriate to conduct a route-to-route extrapolation for local effects. The available data for m-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 m-cresol (R34) it will be allocated to the moderate hazard category. Thus, according to ANNEX XI of REACH Regulationfurther testing does not appear scientifically justified based on the reliable occupational historcal 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 reason.

DERMAL APPLICATION

There is no valid dermal repeated dose study available. m-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 m-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 m-cresol it is not appropriate to conduct a route-to-route extrapolation for local effects. The available data for m-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 m-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.

Justification for classification or non-classification

No classification /labelling is required