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The substance chlorocresol is not toxic via oral and dermal route

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Toxicity of p-CHLORO-m-CRESOL was assessed in rats

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Sasco, Inc ,Omaha, Nebraska
- Age at study initiation: no data
- Weight at study initiation: Male: 221 to 331 g
Female: 170 to 216 g
- Fasting period before study: for 19 hrs
- Housing: stainless steel suspended cages with five rats to a cage
- Diet (e.g. ad libitum): Purina Lab Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: six days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 69-74 deg F
- Humidity (%): 35-55%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours of light
IN-LIFE DATES: From: To:

Route of administration:

oral: unspecified

Vehicle:

carbowaxe

Details on oral exposure:

The test material was administered orally at 1.0% of the animal’s body weight.

Doses:

Male: 2000, 2800, 3920, 5488 and 7683.2 mg/kg

Female: 1500, 2100, 2940, 4116 and 5762.4 mg/kg

No. of animals per sex per dose:

10/sex /dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 4 hours post treatment and at least twice daily for 14 days after treatment.
- Necropsy of survivors performed: yes
- Other examinations performed: mortality, clinical signs, body weight, organ weights, histopathology

Statistics:

The LD50 values were determined by probit analysis using an IBM 3.0 computer with the SAS Computer system (SAS Institute, Inc. Cary, Ne).

Sex:

male

Dose descriptor:

LD50

Effect level:

5 129 other: mg/kg

Based on:

test mat.

Sex:

female

Dose descriptor:

LD50

Effect level:

3 636 other: mg/kg

Based on:

test mat.

Mortality:

Rats that were found dead after treatment exhibited fluid in the stomach and/or intestines at gross necropsy

Clinical signs:

other: Symptoms of toxicity were observed in all treated rats, and included ataxia, wheezing. Muscle fasciculations, tremors, convulsions, salivation, diarrhea, lacrimation, bloody urine and urine stain, pilo-erection, decreased activity and immobilization

Gross pathology:

evidence of salivation was observed in some rats. One female that survived 4116 mg/kg exhibited a mass of about 6 mm on the left uterine horn; one male that survived 5488 mg/kg exhibited small testicles and seminal vesicles. These two findings were probably incidental. The remaining rats that survived the l4-day observation period exhibited no gross lesions.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Adult male and female Sprague-Dawley derived rats were treated orally with graded dosges of PCMC (p-chloro-m-cresol). The LD50 values of this compound were 5129 mg/kg (4432-6108 mg/kg in male rats and 3636 mg/kg (3105-4370 mg/kg in female rats.

Executive summary:

Adult male and female rats were used to test the acute oral toxicity of PCMC (p-chloro-m-cresol). Using Carbowax as the excipient, the test material was administered orally at graded dosages to groups of ten males and ten females. The rats were fasted for 19 hours prior to and at least one hour after dosing. The test material was administered at 2000, 2800, 3920, 5488 and 7683.2 mg/kg to male rats and at 1500, 2100, 2940, 4116 and 5762.4 mg/kg to female rats.

Symptoms of toxicity were observed in all treated rats. The incidence of mortality was dose-related. The most prominent finding at gross necropsy in rats that were found dead was fluid in the stomach and/or intestines. Rats that survived the l4-day observation period exhibited no gross lesions that could be related to treatment. The LD50 of PCMC was 5129 mg/kg (4432-6108 mg/kg) in male rats and 3636 mg/kg (3105-4370mg/kg) in female rats.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 129 mg/kg bw

Reference

Endpoint:: acute toxicity: inhalation
Data waiving:: study scientifically not necessary / other information available
Justification for data waiving:: other:

Endpoint conclusion:

no study available

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Institute for Industrial Research and Toxicology Ghaziabad
- Age at study initiation: 8 to 10 weeks
- Weight at study initiation: 200±20g
- Fasting period before study: Animals were fasted overnight prior to test and food was offered three hours after dosing
- Housing: Groups of two animals of same sex in polypropylene cages with stainless steel grill top, facilities for food and water bottle, and bedding of clean paddy husk
- Diet (e.g. ad libitum): Pelleted feed supplied by Pranav agro Industries Ltd., B7/6 Ramesh Nagar, Delhi, India
- Water (e.g. ad libitum): Fresh and clean water filtered through ‘Aqua Guard on line water filter’, was kept in glass bottles Ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25°C
- Humidity (%): 40-60%
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): Illumination cycle set to 12 hours artificial fluorescent light and 12 hours dark

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: The test substance was applied dermally at the dose level of 2000 mg/kg b.wt to each animal
- % coverage: Approximate 10 percent back skin of total body surface area was prepared 24 hrs prior to application of test compound
- Type of wrap if used: The test compound was held in contact with the skin with an impervious dressing secured in place with an adhesive tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the dressing was removed and the site of application was cleaned with lukewarm water wiping the test compound
- Time after start of exposure: After 24 hours

TEST MATERIAL
- Test substance was moistened with distilled water before application

Duration of exposure:

24 hours

Doses:

Group-I: 2000 mg/kg b.wt (limit test)
Group-II: 2000 mg/kg b.wt (confirmatory test)

No. of animals per sex per dose:

Group-I: 10 (5 male & 5 female)
Group-II: 10 (5 male & 5 female)

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes; Necropsy was carried out on all the animals that died during the study or surviving animals were sacrificed at the end of the study to observe any gross pathological changes.
- Other examinations performed:
Body weight:
The body weight of all the animals was observed weekly on day 0 (pre treatment), 7th and 14th (post treatment).
Clinical signs:
The treated animals were closely observed for clinical signs of intoxication, first 4 hours and thereafter for every 1 hrs interval for 24 hrs after dosing and twice a day for 14 days. All the rats were observed at least twice daily with the purpose of recording any symptoms of ill-health or behavioral changes. These observations included changes in skin and fur in the eyes and mucous membranes, respiratory, circulatory, central nervous and autonomous systems, somatomotor activity and behavior changes. The following clinical signs were observed in rats to characterize with erythema, hypersensitivity, edema etc. The clinical sign will be graded as 0 = Normal, + = Mild, ++= Moderate, +++ =High and ++++ = Severe.
Mortality:
All the animals were observed for mortality at 30 minutes time interval for first six hours on the day of test compound administration and thereafter twice a day for 14 days.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No incidence of mortality was observed in Wistar albino rats after application of test compound Chlorocresol (CAS No.-59-50-7). The period of application of test compound was 24 hours

Clinical signs:

other: The Wistar albino rats treated with the test compound did not show any clinical signs of intoxication throughout the period of observation

Gross pathology:

NECROPSY FINDING
EXTERNAL
i. Skin- Skin and hair coat was observed wet.
ii. All external orifices- Normal
B. INTERNAL
i. Subcutaneous- No changes were observed.
ii. Superficial and deep lymph nodes- No change in mesenteric lymph node
ABDOMINAL CAVITY
i. Opening and general examination- In the abdominal cavity all the organs were present in normal position.
ii. Spleen- No changes were recorded.
iii. Digestive system- No gross changes were observed in stomach and intestine.
iv. Liver and biliary ducts- No gross pathological changes were observed
v. Excretory system- No gross pathological changes were observed.
vi. Adrenal- Observed normal.
vii. Male/female genital organs – Showed normal colour, consistency and no inflammatory changes.
2. THORACIC CAVITY
i. Opening and general examination- Thoracic cavity was found to be normal without any fluid, mucous or blood etc.
ii. Lungs- No changes were recorded.
iii. Heart- No changes were observed in color and consistency. Heart found normal.
iv. Thyroid- Normal in shape, size and surface.
3. CRANIAL CAVITY
i. Brain- Normal in shape and size.

CLINICAL SIGNS AND MORTALITY

Group: I Limit test Dose: 2000 mg/kg b.wt

Parameters	Incidence of Clinical Signs Observed after Dosing on																			Mortality
	Day 0					DAY
	Min	Hour				DAY
	30	1	2	4	6	1	2	3	4	5	6	7	8	9	10	11	12	13	14	Total	%
Mortality (total)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0/10	0
Clinical Signs- Local
Redness	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Pain	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Swelling	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Systemic signs
	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Group: II Confirmatory test Dose: 2000 mg/kg b.wt

Parameters	Incidence of Clinical Signs Observed after Dosing on																			Mortality
	Day 0					DAY
	Min	Hour				DAY
	30	1	2	4	6	1	2	3	4	5	6	7	8	9	10	11	12	13	14	Total	%
Mortality (total)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0/10	0
Clinical Signs- Local
Redness	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Pain	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Swelling	-	-	-	-	-	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Systemic signs
Clinical signs	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

- =Observed after 24 hrs

0 = No clinical signs

+ = Mild

++ = Moderate

+++ = High

++++ = Severe

SUMMARY OF NECROPSY FINDINGS

S. No.	Fate	Wistar albino rats
		Dose (mg/kg b. wt)
		2000 (Limit test)	2000 (Confirmatory test)
1	Terminal sacrifice	10/10	10/10
2	Found Dead	0/10	0/10
3	Abnormalities detected	0/10	0/10

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LD50 value of chlorocresol in Wistar rats was found to be >2000 mg/kg body weight when applied dermally on the shaven back skin.

Executive summary:

Results obtained from present investigation indicate that the test compound Chlorocresol (CAS No.: 59-50-7) is acutely non toxic at the tested dose level of 2000 mg/kg b.wt in Wistar albino rats when applied by dermal route.

The acute dermal LD₅₀of test compound Chlorocresol (CAS No.: 59-50-7) was found to be more than 2000mg/kg b.wt. (> 2000 mg/kg b.wt.).

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: Oral -

Based on studies of target substance CAS NO 59-50-7 reviewed for acute oral toxicity from reliable sources having Klimisch rating 4 considering the weight of evidence approach.

The summary of the results are presented below

Sr. No	End point	Value	Species	Remark
1	LD50	5129 mg/kg 3636mg/kg	Rat (Male) Rat (Female)	Data from study report for target chemical
2	LD50	1830 mg/kgbw	Rat	Data from study report for target chemical
3	LD50	600 mg/kgbw	Mouse	Data from study report for target chemical

Based on above table, endpoint value was found to vary between 600 mg/kg bw to 5129 mg/kg bw which are much higher values. Since the LD50 for target chemical is greater than 2000 mg/kg bw/d which was the criteria for classification towards acute toxicity, it is concluded that the substance chlorocresol does not exhibits acute toxicity by the oral route.

Acute toxicity Inhalation:

The test substance chlorocresol has very low vapor pressure and high melting point, so the potential for the generation of inhalable vapours of chlorocresol is low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore this end point was considered for waiver.

Acute toxicity: Dermal -

Based on studies of target substance CAS NO 59-50-7 reviewed for acute dermal toxicity from reliable sources having Klimisch rating 1 and 4 considering weight of evidence approach

The summary of the results are presented below

Sr. No	End point	Value	Species	Remark
1	LD50	>2000 mg/kg bw	rat	Data from study report for target chemical
2	LD50	>5000 mg/kg bw	rat	Data from study report for target chemical

Based on the values summarized in above table, it was found that the endpoint values vary between 2000 mg/kg bw to 5000 mg/kg bw. Since the LD50 for target chemical is greater than 2000 mg/kg bw/d which was the criteria for classification towards acute toxicity, it is concluded that chlorocresol does not exhibits acute toxicity by the dermal route.However, since this chemical has a harmonized classification as "Acute tox.4 " category, for the pupose of chemical safety assessment, this classification shall be considered

Justification for selection of acute toxicity – oral endpoint

Adult male and female rats were used to test the acute oral toxicity of PCMC (p-chloro-m-cresol). Using Carbowax as the excipient, the test material was administered orally at graded dosages to groups of ten males and ten females. The rats were fasted for 19 hours prior to and at least one hour after dosing. The test material was administered at 2000, 2800, 3920, 5488 and 7683.2 mg/kg to male rats and at 1500, 2100, 2940, 4116 and 5762.4 mg/kg to female rats.

Symptoms of toxicity were observed in all treated rats. The incidence of mortality was dose-related. The most prominent finding at gross necropsy in rats that were found dead was fluid in the stomach and/or intestines. Rats that survived the l4-day observation period exhibited no gross lesions that could be related to treatment. The LD50 of PCMC was 5129 mg/kg (4432-6108 mg/kg) in male rats and 3636 mg/kg (3105-4370mg/kg) in female rats.

Justification for selection of acute toxicity – inhalation endpoint

The test substance chlorocresol has very low vapor pressure and high melting point, so the potential for the generation of inhalable vapours of chlorocresol is low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore this end point was considered for waiver

Justification for selection of acute toxicity – dermal endpoint

Results obtained from present investigation indicate that the test compound Chlorocresol (CAS No.: 59-50-7) is acutely non toxic at the tested dose level of 2000 mg/kg b.wt in Wistar albino rats when applied by dermal route.

The acute dermal LD50of test compound Chlorocresol (CAS No.: 59-50-7) was found to be more than 2000mg/kg b.wt. (> 2000 mg/kg b.wt.).

As per the end point results the substance, chlorocresol is considered to be non toxic via Oral and dermal route. However, since this chemical has a harmonized classification as "Acute tox.4 " category, for the pupose of chemical safety assessment, this classification shall be considered