4-chlororesorcinol

Endpoint summary

Description of key information

Repeated dose : Oral
In subchronic toxicity study of 4-Chlororesorcinol on male and female HanBrl: Wistar(SPF) rats, the NOAEL was considered to be 70 mg/kg bw/day.
Repeated Dose: Inhalation
Vapour pressure of test substance 4-Chlororesorcinol is found to be 0.0012 mm Hg at 25 °C. This value is equivalent to 0.1599 Pascal at 25°C. Thus, exposure by the inhalation route is not likely considering this low vapour pressure of the chemical. Thus, repeated dose toxicity by the inhalation route is highly unlikely.
Repeated dose: Dermal
In subchronic toxicity study of 4-Chlororesorcinol on New Zealand white male and female rabbits, the NOAEL was considered to be 340 mg/kg bw/day

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:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Data is from review article

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

not specified

Species:

rat

Strain:

other: HanBrl : Wistar (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: Yes, duration not mention

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES:
From: 7 September 2004
To: 7 February 2005

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

Bi-distilled water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Test substance was dissolved in 10 ml/kg bw of distilled water in the concentration of 0, 35, 70 and
210 mg/kg bw for 91 days.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 35, 70 and 210 mg/kg bw
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

91 days

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 35, 70 and 210 mg/kg bw/day
Basis:
no data

No. of animals per sex per dose:

Group A
0mg/kg/day: 10 male, 10 female
35 mg/kg/day: 10 male, 10 female
70 mg/kg/day: 10 male, 10 female
210 mg/kg/day: 10 male, 10 female

Group A
For recovery Period
0mg/kg/day: 5 male, 5 female
210 mg/kg/day: 5 male, 5 female

Reserve animals: 2 male, 2 female

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Aliquots of 10 ml/kg bw of 4-Chlororesorcinol were administered in a single dose by gavage and on the basis of results of a dose range finding study 0, 35,70 and 210 mg/kg/bw /day dose were selected for present study.
- Rationale for animal assignment (if not random): No data available
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included: Mortality was observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

FOOD EFFICIENCY: No data available
- 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: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: During acclimatization, at the end of treatment and recovery.
- Dose groups that were examined: All the 100 animals were examined.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the termination of study.
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: All the 100 animals were examined.
- Parameters checked in table [No.?] were examined. Red blood cell count, reticulocyte count and/or maturity index were observed.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the termination of study.
- Animals fasted: No data available
- How many animals: All the 100 animals were examined.
- Parameters checked in table [No.?] were examined: Lipid metabolism parameters and electrolyte parameters Na+, K+, Cl- and PO4- were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: At the termination of study.
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined: Color and appearance were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: At the termination of study.
- Dose groups that were examined: All the 100 animals were examined.
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Functional observational battery, locomotor activity and grip strength were examined.

OTHER:
Absolute and relative organ weight were examined

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
All the animals were sacrificed, necropsied and examined after post mortem.
HISTOPATHOLOGY: Yes
Histological examinations were performed on animals which died spontaneously and in all gross lesions.
Organs and tissues from all control and high dose (210 mg/kg/day) group animals were examined.

Other examinations:

No data available

Statistics:

No data available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

In 210 mg/kg/bw/day treated rat, Four female rats died as compared to control. Clinical signs: In 210 mg/kg/bw/day treated male and female rat spasm/tremor, hunched posture, abnormal gait, and salivation were observed approximately 10 to 60 minutes post dosing followed by rapid recovery as compared to control

Mortality:

mortality observed, treatment-related

Description (incidence):

In 210 mg/kg/bw/day treated rat, Four female rats died as compared to control. Clinical signs: In 210 mg/kg/bw/day treated male and female rat spasm/tremor, hunched posture, abnormal gait, and salivation were observed approximately 10 to 60 minutes post dosing followed by rapid recovery as compared to control

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significant changes were observed in treated and control group.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No significant changes were observed in treated and control group.

Food efficiency:

not specified

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

no effects observed

Description (incidence and severity):

No significant changes were observed in treated and control group.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

Opthalmoscopic investigations revealed no evidence of eye toxicity.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Depressed red blood cell count, effect on reticulocyte count and/or maturity index was observed in 210 mg/kg bw/day treated female rat as compared to control.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In 210 mg/kg bw/day treated male rat effect on lipid metabolism parameters was observed. In 35, 70 and 210 mg/kg bw/day treaded male and female rats, effects on the electrolyte parameters Na+, K+, Cl- and PO4 - were observed in minimal extent.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

In male rat treated with 210 mg/kg bw/day yellow-brown discoloration and cloudy appearance of the urine were observed as compared to control. The effect disappeared after treatment.

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Reduced forelimb grip strength was recorded in high dose (210 mg/kg/day) males.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

No change in absolute and relative weight of organs was observed in treated rat. Minimal changes of liver-to-body weight and thymus to body weight in males in 210 mg/kg bw/day were associated with a minimally depressed body weight.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No significant changes were observed in treated and control group.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant changes were observed in treated and control group.

Dose descriptor:

NOAEL

Effect level:

70 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effect on survival, body weight, food consumption, hematology, clinical chemistry, urinalysis, neurobehaviouraL, organ weight, gross pathology and histopathology.

Critical effects observed:

not specified

Conclusions:

NOAEL was found to be 70 mg/kg bw/day for 4 -Chlororesorcinol in male and female HanBrl: Wistar (SPF) rats when exposed by oral (gavage) route.

Executive summary:

In a chronic toxicity study,male and female HanBrl: Wistar(SPF) rats were exposed to 4-Chlororesorcinol in the concentration of 0, 35, 70 and 210 mg/kg bw/day for 91 days.  The results showed that 4-Chlororesorcinol is toxic. Toxic changes were observed as four female rats died, clinical signs such as spasm/tremor, hunched posture, abnormal gait, and salivation and hematological changes depressed red blood cell count, effect on reticulocyte count and/or maturity index in 210 mg/kg bw/day treated rat was observed as compared to control. Changes in the electrolye parameters Na⁺, K⁺, Cl^-(both sexes) and PO₄^–were also observed but the effect is on all doses. Therefore, NOAEL was considered to be 70 mg/kg bw/day for male and female HanBrl: Wistar (SPF) rats as no adverse effects were seen at this dose. This indicates that the substance does not exhibit repeated dose toxicity by the oral route at a dose level of 70 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

70 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The data is of K4 level and is obtained from Scientific Committee on Consumer Safety (SCCS) report.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from peer reviewed journal

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Subchronic dermal toxicity study of 4-Chlororesorcinol (as part of mixture 7406) in rabbits

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Housing: Animals was housed in cages

Type of coverage:

open

Vehicle:

other: Hydrogen peroxide

Details on exposure:

TEST SITE
- Area of exposure: Dorsolateral aspects of thoracic-lumbar area (one on each side of the midline) were exposed.
- % coverage: No data available
- Type of wrap if used: No data available
- Time intervals for shavings or clipplings: The hair at the site of application on the back and sides of each rabbit was clipped short throughout the study.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The rabbits were shampooed, rinsed and dried
- Time after start of exposure: 1 hr

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1 ml/kg
- Concentration (if solution): 1 ml/kg of 1:1 oxidation mixture were used.
- Constant volume or concentration used: yes
- For solids, paste formed: yes

VEHICLE
- Justification for use and choice of vehicle (if other than water): Hydrogen peroxide was used
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): 6% hydrogen peroxide.
- Lot/batch no. (if required): No data available
- Purity: No data available

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
The rabbits were restrained in holding stocks for 1 hr following each application

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Twice weekly (The application sites on three animals of each sex in each group were abraded on the first treatment day of each week).

Remarks:

Doses / Concentrations:
1 ml/kg (equivalent to 340 mg/kg)
Basis:
no data

No. of animals per sex per dose:

Control 1 : 6 male, 6 female
Control 2 : 6 male, 6 female
Control 3 (combined control) : 6 male, 6 female
1 ml/kg : 6 male, 6 female

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: 1 ml/kg dose were applied as it was the maximum dose that could be applied on the side of the rabbits without runoff.
- Rationale for animal assignment (if not random): No data available
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked: Mortality was observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data available.

DERMAL IRRITATION (if dermal study): No data available.
- Time schedule for examinations: No data available.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: No data available
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available

FOOD EFFICIENCY: No data available
- 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: No data available

WATER CONSUMPTION: No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected on day 0, 3, 7and 13 of study.
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: All 48 animals were examined.
- Parameters checked in table [No.?] were examined: Blood count, methemoglobin, fasting blood sugar, HCT, Hb, RBC, WBC and Met-Hb were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was collected on day 0, 3, 7and 13 of study.
- Animals fasted: No data available
- How many animals: All 48 animals were examined.
- Parameters checked in table [No.?] were examined: Glucose, BUN, Alkaline Phosphatase and SGOT were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected on day 0, 3, 7and 13 of study.
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined: Color, pH, albumin, glucose, occult blood, and microscopic elements were examined.

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: Organ weight was examined.

Organ weighed: Liver, kidneys, adrenals, heart, thyroid, spleen, brain, stomach, duodenum, colon, gall bladder, adrenals, eyes, pancreas, kidneys, urinary bladder, ovaries, testes, bone, bone marrow and lung were examined.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Gross abnormalities were examined by sacrificing all the treated animals at the termination of study.

HISTOPATHOLOGY: Yes
Organ was stained with hematoxylin and eosin and examined microscopically.
Organs examined: Skin from treated and untreated areas, lymph nodes (mesanteric, axillary, and cervical), spleen, stomach, duodenum, colon, liver, gall bladder, adrenals, nerve with adjacent muscle, eyes, pancreas, kidneys, urinary bladder, ovaries, testes, bone, bone marrow, heart, lung, thyroid, brain and skeletal muscle under the site of application and elsewhere (thigh) were examined

Other examinations:

No data available

Statistics:

Statistical analysis was performed using the analysis of variance F test and Student's t test for body weight gains, hematology, clinical chemistries, and absolute and relative organ weights. When variances differed significantly, Student's t test was modified (t’) and Cochran's approximation was used.

Clinical signs:

no effects observed

Description (incidence and severity):

No mortality were observed in treated rabbits as compared to control. Five control and five treated animals died during the study due to complications resulting from cardiac puncture while collecting blood for blood investigations. Clinical signs: No sign of toxicity was observed in treated rabbits as compared to control.

Dermal irritation:

not examined

Mortality:

no mortality observed

Description (incidence):

No mortality were observed in treated rabbits as compared to control. Five control and five treated animals died during the study due to complications resulting from cardiac puncture while collecting blood for blood investigations. Clinical signs: No sign of toxicity was observed in treated rabbits as compared to control.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No body weight and weight gain was observed in treated rabbits as compared to control.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

In treated female rabbits, there was significant increase in RBC and significant decreased in Met-Hb and in male, significant decreased in Met-Hb was observed. However, these differences were not considered to be of toxicological significance.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Scattered statistically significant differences were observed in treated rabbits but were not considered to be of significance because of either the direction or continuity of the differences or because they fell in the range of historical control values.

Urinalysis findings:

no effects observed

Description (incidence and severity):

No effect was observed in urine of treated rabbits as compared to control.

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

In treated rabbits, statistically significant differences in relative organ weight were observed as compared to combined control but the difference was not significant when compared with control.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No gross abnormalities were observed in treated animals

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No microscopic lesions were observed in treated rabbits as compared to control.

Histopathological findings: neoplastic:

no effects observed

Details on results:

No gross abnormalities were seen at necropsy and no microscopic examination that were judged to be due to the administration of the test compound. The incidence and severity of disease processes common to laboratory rabbits was not affected by the experimental treatments.

Dose descriptor:

NOAEL

Effect level:

340 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect on survival, clinical sign, body weight, hematology, clinical chemistry, urine analysis, organ weight, gross pathology and histopathology

Critical effects observed:

not specified

Conclusions:

NOAEL was considered to be 340 mg/kg bw/day for New Zealand white male and female rabbits when treated with 4-Chlororesorcinol (as part of mixture 7406).

Executive summary:

In subchronic dermal repeated dose toxicity study, male and female New Zealand white rabbits were exposed to 4–Chlororesorcinol in the concentration of 0 and 1 ml/kg (equivalent to 340 mg/kg bw/day).

The results showed that 4 -Chlororesorcinol was not toxic. No effect were observed on survival, no evidences of percutaneous toxicity, no changes in body weight, hematology, clinical chemistry and absolut and relative organ weight of treated animals. In addition, no gross pathological and histopathological changes were observed in treated rabbits.

Therefore, NOAEL was considered to be 340 mg/kg bw/day when New Zealand white male and female rabbits were exposed to 4-Chlororesorcinol (as part of mixture 7406) dermally for 13 weeks.

This value indicates that the substance is unlikely to exhibit repeated dose toxicity by the dermal route at the above mentioned dose level.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

340 mg/kg bw/day

Study duration:

subchronic

Species:

rabbit

Quality of whole database:

The data is of K2 level and from peer reviewed journal.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose : Oral

In subchronic toxicity study, male and female HanBrl: Wistar(SPF) rats were exposed to 4-Chlororesorcinol in the concentration of 0, 35, 70 and 210 mg/kg bw/day for 91 days. 

The results showed that 4-Chlororesorcinol is toxic to the animals. Toxic changes were observed as four female rats died, clinical signs such as spasm/tremor, hunched posture, abnormal gait, and salivation and hematological changes depressed red blood cell count, effect on reticulocyte count and/or maturity index in 210 mg/kg bw/day treated rat as compared to control.

Changes in the electrolyte parameters Na⁺, K⁺, Cl^-(both sexes) and PO₄^–were also observed but the effect is on all doses.Therefore, NOAEL was considered to be 70 mg/kg bw/day when male and female HanBrl: Wistar (SPF) rats.This indicates that the substance does not exhibit repeated dose toxicity by the oral route at a dose level of 70 mg/kg/day.

Repeated dose: Dermal

In subchronic dermal repeated dose toxicity study, male and female New Zealand white rabbits were exposed to 4–Chlororesorcinol in the concentration of 0 and 1 ml/kg (equivalent to 340 mg/kg bw/day).

The results showed that 4 -Chlororesorcinol was not toxic. No effect were observed on survival, no evidences of percutaneous toxicity, no changes in body weight, hematology, clinical chemistry and absolut and relative organ weight of treated animals. In addition, no gross pathological and histopathological changes were observed in treated rabbits.

Therefore, NOAEL was considered to be 340 mg/kg bw/day when New Zealand white male and female rabbits were exposed to 4-Chlororesorcinol (as part of mixture 7406) dermally for 13 weeks.

This value indicates that the substance does not exhibit repeated dose toxicity by the dermal route at the above mentioned dose level.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
NOAEL was found to be 70 mg/kg bw/day for 4 -Chlororesorcinol in male and female HanBrl: Wistar (SPF) rats when exposed by oral (gavage).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Vapour pressure of test substance 4-Chlororesorcinol is found to be 0.0012 mm Hg at 25 °C. This value is equivalent to 0.1599 Pascal at 25°C.
Thus, exposure by the inhalation route is not likely considering the low vapour pressure of the chemical. Thus, repeated dose toxicity by the inhalation route is unlikely.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
NOAEL was considered to be 340 mg/kg bw/day for New Zealand white male and female rabbits when treated with 4-Chlororesorcinol (as part of a mixture).

Justification for classification or non-classification

Based on the available studies, the substance 4 -Chlororesorcinol is likely to be non-toxic on repeated exposure by oral, inhalation and dermal route.