o-cresol

Endpoint summary

Description of key information

Subchronic inhalational exposure (4 months) of rats to o-cresol causes reduced locomotor activity, inflammation of respiratory tissues and changes in the liver. No NOAEL could be determined for this route. Oral exposure of up to 13 weeks of mice and rats resulted in mortality, tremors, reduced body weights, hematologic effects and increase in organ weights. An overall subchronic NOAEL of 50 mg/kg bw/day can be derived (OECD SIDS for o-Cresol, CAS N°: 95-48-7, UNEP publication).

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: comparable to a guideline study

Qualifier:

according to guideline

Guideline:

other: Sontag JM, Page NP, Saffotti U, NCI, DHEW Publication No (NIH)78-ß01Guidelines for Carcinogen Bioassay in small rodents

Principles of method if other than guideline:

Method: see section" any other information of materials and methods".

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
- Source: Charles River Breeding Laboratories
- Age at study initiation: 5-6 weeks
- Fasting period before study: 24 hours
- Housing: individually
- Diet : ad libitum):
- Water : ad libitum):
- Acclimation period: 16 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 50
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
test solution was produced on a weekly basis

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

during test week 1, 2, 4, 8 and 13 by
Enseco Inc, Cambridge MA and additionally by American BiogenicsCorporation, Decatur IL

Duration of treatment / exposure:

13 w

Frequency of treatment:

once daily

Remarks:

Doses / Concentrations:
50, 175, 600 mg/kg bw/day in corn oil
Basis:
actual ingested

No. of animals per sex per dose:

30 animals /sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Positive control:

no data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and clinical signs

BODY WEIGHT: Yes
- Time schedule for examinations: day 1 and then weekly

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption
and body weight gain data: Yes , weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during quarantine period and in test week 13

HAEMATOLOGY: CLINICA CHEMISTRY : Urinalysis Yes
- Time schedule for collection of blood: as baseline clinical pathology, at test week 7 (interim kill) at study termination
- How many animals: 10 rats/sex/dose
- Parameters checked : see section "additional iformation on materials and methods"


NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see section " any other information on materials and method"
HISTOPATHOLOGY: Yes (see section"Any other information on materials and method"

Other examinations:

no data

Statistics:

One-Way Analysis of Variance tests, Dunnett's t 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):

no effects observed

Food efficiency:

not specified

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:

600 mg/kg bw/day: mortality 19/30 females and 9/30 males,
Body weight:
reduction
body weight of females were unaffected
600 mg/kg bw/d, males: significant during week 2 through 10
175 mg/kg bw/d, males: significant during week 2
Body weight gain
175 and 600 mg/kg bw/d
reduction in body weight gain (males), slight decrease in food intake;
600 mg/kg bw/day, males and females,
175 mg/kg bw/d: 1 female d23 and 1 female d27
Treatment-related depression of the central nervous system: lethargy, dyspnoe, tremor and/or convulsions, recovering within 1 h after dosing
No effects on clinical chemistry, hematology, urinalyses parameters,
No treatment-related ophthalmic lesions,
No effects on organ weights,
No treatment-related gross and histomorphologic lesions;

Key result

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/day animals revealed central nervous system depression and showed statistically significant reduction in body weight and body weight gain

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

175 mg/kg bw/day (nominal)

System:

other: central nervous system depression and statistically significant reduction in body weight and body weight gain.

Organ:

other: central nervous system

Treatment related:

yes

Dose response relationship:

yes

600 mg/kg bw/day:
Mortality 19/30 females and 9/30 males.
Body weight: reduction body weight of females were unaffected 600 mg/kg bw/d, males: significant during week 2 through 10, 175 mg/kg bw/d, males: significant during week 2. Body weight gain 175 and 600 mg/kg bw/d reduction in body weight gain (males), slight decrease in food intake.
600 mg/kg bw/day, males and females, 175 mg/kg bw/d: 1 female d 23 and 1 female d 27.
Treatment-related depression of the central nervous system: lethargy, dyspnoe, tremor and/or convulsions, recovering within 1 h after dosing.
No effects on clinical chemistry, hematology, urinalyses parameters, no treatment-related ophthalmic lesions, no effects on organ weights, no treatment-related gross and histomorphologic lesions.

Conclusions:

The NOAEL is 50 mg/kg bw/day based on adverse effects from 175 mg/kg bw /day onwards.

Executive summary:

According to Sontag JM, Page NP, Saffotti U, NCI, DHEW Publication No (NIH)78-ß01 Guidelines for Carcinogen Bioassay in small rodents) male and female rats were applied with 0, 50,175, 600 mg/kg bw/day by gavage for 13 weeks. The NOAEL is 50 mg/kg bw/day based on adverse effects from 175 mg/kg bw /day onwards including central nervous system depression and statistically significant reduction in body weight and body weight gain (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:

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

According to Sontag JM, Page NP, Saffotti U (NCI, DHEW Publication No (NIH)78-ß01 Guidelines for Carcinogen Bioassay in small rodents) male and female rats were applied with 0, 50, 175, 600 mg/kg bw/day by gavage for 13 weeks. The NOAEL is 50 mg/kg bw/day based on adverse effects from 175 mg/kg bw/day onwards including central nervous system depression and statistically significant reduction in body weight and body weight gain (RTI 1988).

Additionally, in feeding studies according to OECD TG 408 male and female F344 rats were fed 0, 1880, 3750, 7500, 15000, 30000 ppm o-cresol and. male and female B6C3F1 mice were fed 0, 1250, 2500, 5000, 10000, 20000 ppm o-cresol (US Department of Health and Human Services 1991). The NOAEL is 3750 ppm for males and females rats (247 and 256 mg/kg bw/d, respectively) based on increased relative kidney and liver weights from 7500 ppm onwards but no histopathological changes were reported. For male and female mice the NOAEL is 1250 ppm (199 and 237 mg/kg bw/d, respectively) based on increased relative and absolute liver and kidney weights without histopathological correlate from 2500 ppm onwards.

DERMAL APPLICATION

There is no valid dermal repeated dose toxicity study available. o-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 o-cresol might be absorbed across the 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 informacion on systemic tocicity is needed for risk assessment. Due to the corrosive properties of o-cresol it is not appropriate to conduct route to route extrapolation for local effects. The available data for o-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 informationrequirements and chemical safety assessment R.8: Characterisation of dose [concentration]-exposure for human health (version 2.1), November 2012. Due to the corrosive properties of o-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 into account animal welfare reasons.

INHALATION EXPOSURE

There is no adequate inhalation study available.

o-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, o-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 o-cresol it is not appropriate to conduct a route-to-route extrapolation for local effects. The available data for o-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), November 2012.

Due to the corrosive properties of o-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 reasons

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
key study used

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: hematopoiesis; neurologic: behaviour; other: all gross lesions and masses.

Justification for classification or non-classification

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.