m-cresol

Endpoint summary

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).

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

Qualifier:

according to guideline

Guideline:

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

Principles of method if other than guideline:

30 rats/sex/dose, add.10 rats/sex for baseline clin. Pathol., interim kill at week 7, terminal kill at week 14, blood samples for hematology, clin.chemistry; urinalysis; gross and microsc. pathology; stat. anal.: Dunnett's t-t.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 5-6 weeks
- Housing: 2or 3 per cage during pretest, individually following randomization to groups
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air change: at least 12-15 per hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
the test chemical was diluted in corn oiil on a weekly basis to achieve the respective test concentrations
which allowed for a dosing volume 5 ml/kg

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Gas chromatography: m-cresol was found to be stable for at least 14 days at the concentration tested. Additionally the analyses of the dosage form preparations used during test week 1, 2, 4, 8, and 13 indicated that target concentrations were generally within an acceptable range.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Once daily for 13 consecutive weeks.

Remarks:

Doses / Concentrations:
0, 50, 150 or 450 mg/kg bw/d in corn oil (m/f)
Basis:
actual ingested

No. of animals per sex per dose:

30 rats/sex/dose group; 10 of each group for interim kill at day 45.

Control animals:

yes, concurrent vehicle

Details on study design:

- Post-exposure period: 1 w
- Dose selection rationale: doses were chosen based on the results of a range-finding study.

Positive control:

not relevant

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: for moribundity/mortality: twice daily
- for clinical signs: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: at initiaation and weekly thereafter

FOOD CONSUMPTION:
Time schedule: weekly


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretreatment and at termination
- Dose groups that were examined: at termination on all animals designated to be terminated at 13-weeks

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals:
10 males and 10 females for baseline examination
10 rats/sex/dose group at interim kill
10 rats/sex/group at termination of the study
- Parameters checked in table were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
for details see above
- Parameters checked in table were examined.


URINALYSIS: Yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: No data
for details see above
- Parameters checked in table were examined.


NEUROBEHAVIOURAL EXAMINATION: No data



OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see section: any other information on materials and methods incl. tables)
HISTOPATHOLOGY: Yes

Other examinations:

no

Statistics:

One-way analysis of Variance tests with Dunnett's test: body weight, food consumption, clinicla chemistry, hematology and organ weights data

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 examined

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

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

MORTALITY/CLINICAL OBSERVATIONS: 450 mg/kg: one high dose male was found dead on day 5 (cause not evident), signs of intoxication: 450 mg/kg bw, male, female: lethargy, tremors, hunched posture, rough hair coats post dosing
BODY WEIGHT was sign reduced (pbody weight gain was reduced (pFOOD CONSUMPTION was sign. reduced (pCLINICAL PATHOLOGY clinical chemistry, haHematology and urinalyses parameters were not affected by treatment
OPHTHALMOLOGY treatment related lesions were not seen ORGAN WEIGHTS organ weights were not affected by treatment.
PATHOLOGY treatment-related gross and histomorphology lesions were not in evidence
NOAEL (female) = 150 mg/kg bw/day NOAEL (male) = 50 mg/kg bw/day.

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: dose-dependant body weight reduction and at 450 mg/kg bw, lethargy, tremors, hunched posture, rough hair coats post dosing

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: decrease in body weight gain and at 450 mg/kg bw, lethargy, tremors, hunched posture, rough hair coats post dosing

Critical effects observed:

yes

Lowest effective dose / conc.:

150 mg/kg bw/day (nominal)

System:

other: dose-dependant body weight reduction and at450 mg/kg bw, lethargy, tremors, hunched posture, rough hair coats post dosing.

Organ:

other: dose-dependant body weight reduction and at450 mg/kg bw, lethargy, tremors, hunched posture, rough hair coats post dosing

Treatment related:

yes

Dose response relationship:

yes

MORTALITY/CLINICAL OBSERVATIONS:
450 mg/kg: one high dose male was found dead on day 5 (cause not evident).
Signs of intoxication:
450 mg/kg bw, male, female: lethargy, tremors, hunched posture, rough hair coats post dosing
BODY WEIGHT
was sign reduced (p</=0.05): male, week 2-5, 13 at 450 mg/kg bw and week 6 -12, 14 from 150 mg/kg bw; female, week 11 at 450 mg/kg bw
body weight gain was reduced (p</=o.05): male, week 1-3 at 450 mg/kg bw and week 4 -13 from 150 mg/kg bw; female, week 1 at 450 mg/kg bw
FOOD CONSUMPTION
was sign. reduced (p</=0.05): male: 50 mg/kg bw, week 1, 2, 9, 11, 12; 150 mg/kg bw week 3, 6, 8, 12, 13; 450 mg/kg bw week 1 -4, 6 -9, 11; female: 50 mg/kg bw, week 4, 150 mg/kg bw, week 4, 11, 450 mg/kg bw, week1, 4, 6
CLINICAL PATHOLOGY
clinical chemistry, haematology and urinalyses parameters were not affected by treatment
OPHTHALMOLOGY
treatment related lesions were not seen
ORGAN WEIGHTS
organ weights were not affected by treatment
PATHOLOGY
treatment-related gross and histomorphology lesions were not in evidence
NOAEL (female) = 150 mg/kg bw/day
NOAEL (male) = 50 mg/kg bw/day

Conclusions:

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.

Executive summary:

In a study according to OECD 408 , male and female Sprague-Dawley rats received 0, 50, 150, 450 mg/kg bw/day 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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

scientifically acceptable and sufficient documented

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 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, showed 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 2.1), December 2012.

Due to the corrosive properties of m-cresol 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 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 2.1), December 2012.

Due to the corrosive properties of m-cresol to the skin 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

According to Regulation (EC) No. 1272/2008 no classification /labelling is required.