Registration Dossier

Administrative data

Description of key information

The substance chlorocresol is not toxic via oral and dermal route but is toxic  via inhalation route

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
Toxicity of chlorocresol was assessed in rats in 28 days study
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: soybean oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Rats were given Chlorocresol by gravage at concentrations of 0, 50, 200, or 400 mg/kg-day
VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0, 50, 200, or 400 mg/kg-day
- Amount of vehicle (if gavage): 5 ml/kg bw/day.
- Lot/batch no. (if required):no data
- Purity: no data




Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 50, 200, or 400 mg/kg-day
Basis:

No. of animals per sex per dose:
10 rats per sex per dose
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: no data

DETAILED CLINICAL OBSERVATIONS:no data

BODY WEIGHT: yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): no data

FOOD EFFICIENCY:
No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): no data

OPHTHALMOSCOPIC EXAMINATION: no data

HAEMATOLOGY: Yes
Blood samples were taken from eight males and eight females in each group after 21 days of dosing. Hematological analysis included hemoglobin, packed cell volume, total erythrocyte count, and glucose in whole blood.

CLINICAL CHEMISTRY: Yes
Plasma concentrations of creatinine and urea and activity of aspartate aminotransferase and alkaline phosphatase were determined.

URINALYSIS: no data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
The rats were killed by exanguination in CO2-anaesthesia after 4 weeks of dosing.
Upon necropsy, the kidneys, spleen, brain, adrenals, liver, and testes were weighed and examined microscopically along with tissue samples from the stomach, small intestine, pancreas, lung, aorta, heart, thymus, thyroid, and parathyroid. These tissues were fixed in 10% formalin and prepared for light microscopy by staining with hematoxin-eosin (all organs), PAS (liver), and Pearl (liver and spleen). Frozen sections of the liver and heart were stained with Oil red O. There were no clinical signs of toxicity in any of the treated groups.
Statistics:
Students t-test was performed on body weight and weight gain. Analysis of variance was performed on relative organ weights, hematological, and clinical chemical parameters. The statistical analyses were calculated for males and females separately.
Clinical signs:
no effects observed
Description (incidence and severity):
No other clinical signs of adverse effects were observed
Mortality:
no mortality observed
Description (incidence):
No other clinical signs of adverse effects were observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decrease in body weight
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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No significant alterations were noted in the relative organ weights.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Although not associated with pathological or biochemical changes the growth retardation of both males and females in the highest dosed group is considered a toxic effect of the test substance.
Dose descriptor:
NOAEL
Effect level:
200 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect observed on mortality, clinical signs, body weight, Gross pathology, hematology, histopathology
Dose descriptor:
LOAEL
Effect level:
400 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: decreases in body-weight gain
Critical effects observed:
not specified
Conclusions:
The NOAEL value of chlorocresol on rat in 28 days study was observed at dose concentration of 200 mg/kg bw/day

The LOAEL value of chlorocresol on rat in 28 days study was observed at dose concentration of 400 mg/kg bw/day
Executive summary:

4 groups of 10 male and 10 female rats were given 0, 50, 200 or 400 mg CMP/kg bw/day for 28 days. CMP was dissolved in soy bean oil (food grade),and dosed by gavage, 5 ml/kg bw/day. Body weight, clinical signs.organ weight, hematology, clinical chemistry and histopathology was observed.The animals in the highest dosed group exhibited a significant decrease in weight gain during the last week of dosing.No other clinical signs of adverse effects were observed.The hematological and clinical chemical parameters were found to be within the normal range in all groups.No significant alterations were noted in the relative organ weights. There were no pathological changes attributable to the dosing with 4-chloro-3-methylphenol. Although not associated with pathological or biochemical changes the growth retardation of both males and females in the highest dosed group is considered a toxic effect of the test substance. On this basis the no effect level in this 28-days oral toxicity study with CMP in rats was 200 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
K2 level data

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Remarks:
other: no data
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
The effect of exposure to chlorocresol was studied in 42 years old female
GLP compliance:
not specified
Limit test:
no
Species:
other: Human
Sex:
female
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
not specified
Vehicle:
other: water
Details on inhalation exposure:
A few drops of a 0-1% concentration of chlorocresol diluted in water was poured into a sink, the cold tap was turned on to ensure a water born aerosol and the patient was placed near the sink.
Duration of treatment / exposure:
3 min
Remarks:
Doses / Concentrations:
0.1%
Basis:

Control animals:
no
Observations and examinations performed and frequency:
NEUROBEHAVIOURAL EXAMINATION: Yes
Clinical signs:
not examined
Mortality:
not examined
Body weight and weight changes:
not examined
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:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
NEUROBEHAVIOUR
partial left-sided facial palsy occurred preceded by a feeling of pins and needles in the left cheek and temporal region. The weakness only affected the left orbicularis oris which was severely paretic. The philtrum was pulled 3-5 mms to the right (fig). There was no weakness of eye closure nor of the musculature of the forehead. The tear production of the left eye was unaffected. The rest of the neurological examination remained normal. After half an hour the facial palsy gradually resolved.
Dose descriptor:
LOAEL
Effect level:
1 other: %
Based on:
test mat.
Sex:
female
Basis for effect level:
other: partial left-sided facial palsy occured
Critical effects observed:
not specified
Conclusions:
The LOAEL value of chlorocresol in 42 years old human female was observed at dose concentration of 1%
Executive summary:

A few drops of a 0-1% concentration of chlorocresol diluted in water was poured into a sink, the cold tap was turned on to ensure a water born aerosol and the patient was placed near the sink. After approximately 3 minutes a partial left-sided facial palsy occurred preceded by a feeling of pins and needles in the left cheek and temporal region. Only muscles around the left side of the mouth were affected. On neurophysiological testing during chlorocresol provocation the only abnormality was a loss of motor units during maximal contraction of the left orbicularis oris muscle. This could be explained by a peripheral as well as a central effect. Extensive electrophysiological examination without chlorocresol provocation excluded a preexisting generalized nerve disorder and other diagnostic procedures did not give evidence of pathology involving the left facial nerve. A hyperreactive mechanism causing a transient block of the left facial nerve is proposed. Hence the LOAEL was considered to be 1%

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
1
Study duration:
subacute
Species:
other: Human
Quality of whole database:
K2 level data

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:
weight of evidence
Reliability:
4 (not assignable)
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
p-chloro-m-cresol was tested in a 21-day dermal study in New Zealand White rabbits
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
21days
Frequency of treatment:
5 days/wk for a total of 15 applications
Remarks:
Doses / Concentrations:
0, 10, 40 or 160 mg/kg/day
Basis:
no data
No. of animals per sex per dose:
10/sex/dose group
Control animals:
yes
Observations and examinations performed and frequency:
no data
Sacrifice and pathology:
no data
Other examinations:
Dermal effects were observed
Clinical signs:
not specified
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Dermal irritation was observed in all treated groups, which ranged from slight erythema and very slight edema (10 mg/kg/day) to severe erythema and slight edema (160 mg/kg/day).
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At 160 mg/kg/day, a compound related enhancing effect on nonsupporative pericholangitis (both sexes) and bile duct proliferation (females) in the liver were observed.
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Othereffects: Other dermal effects included skin thickening, scaling, blanching, raw areas, necrosis, brown scab-like areas, and sloughing. Fissuring occurred in one mid-dose female and in two high dose males.
Dose descriptor:
NOEL
Effect level:
40 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No systemic effect observed
Dose descriptor:
LOEL
Effect level:
160 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: severe erythema and slight edema
Critical effects observed:
not specified
Conclusions:
The NOEL of chlorocresol on New Zealand White in 21 days study was observed at dose concentration of 40 mg/kg/day
The LOEL of chlorocresol on New Zealand White in 21 days study was observed at dose concentration of 160 mg/kg/day
Executive summary:

p-chloro-m-cresol was tested in a 21-day dermal study in New Zealand White rabbits (10/sex/dose group) at the following dose levels: 0, 10, 40 or 160 mg/kg/day. The animals were dosed 5 days/wk for a total of 15 applications. It appears that the test material was applied without a vehicle. Dermal irritation was observed in all treated groups, which ranged from slight erythema and very slight edema (10 mg/kg/day) to severe erythema and slight edema (160 mg/kg/day). Other dermal effects included skin thickening, scaling, blanching, raw areas, necrosis, brown scab-like areas, and sloughing. Fissuring occurred in one mid-dose female and in two high dose males. No systemic effects were observed at either 10 mg/kg/day or 40 mg/kg/day. At 160 mg/kg/day, a compound related enhancing effect on nonsupporative pericholangitis (both sexes) and bile duct proliferation (females) in the liver were observed. The systemic NOEL is 40 mg/kg/day and the LOEL is 160 mg/kg/day based on enhanced liver pathology in both sexes.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subacute
Species:
mouse

Additional information

Repeated dose toxicity: oral-

Based on the various studies available with Klimish rating 2and 4 for the target chemical 59-50-7 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results is summarized as follows

 

Sr. No

End point

Value

Species

Route

Effects

Remarks

1

NOAEL

 

 

 

 

 

 

 

LOAEL

200 mg/ kg/day

 

 

 

 

 

 

 

400 mg/ kg/day

rat

Oral

No adverse effect observed on mortality, clinical signs, body weight, Gross pathology, hematology, histopathology

 

decreases in body-weight gain

 

Data from publication for Target chemical

2

NOAEL

 

 

 

 

 

 

LOAEL

100 mg/Kg bw/d

 

 

 

 

 

 

500 mg/Kg bw /d

 

Rat

Oral

No adverse effect observed on mortality, clinical signs, body weight, Gross pathology, hematology, histopathology

 

Urinalyses, organ weight determinations, gross pathological and histopathological investigations revealed damage to kidney

Data from study report for Target chemical

3

NOAEL

125mg/ kg bw /day

 

rat

oral

Change in body weight

Predicted data of target chemical

 

Based on the studies summarized in the above table it can be observed that a NOAEL value varies from 100 - 200 mg/Kg bw/ d. whereas the lowest effect observed value (LOEL) values varies from 400 -500 mg/kg bw/d. The effects observed on these doses was listed as follows

·        No adverse effect observed on mortality, clinical signs, body weight, Gross pathology, hematology, histopathology

·        decreases in body-weight gain

 

·        Urinalyses, organ weight determinations, gross pathological and histopathological investigations revealed damage to kidney.

Thus based on above values it can be concluded that substance CAS NO 59-50-7 is expected to show the similar toxicological effect. Since no effective dose value (NOAEL) is 100 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 59-50-7 is considered to be not toxic to repeated dose via oral route for the above mentioned dose. Also there are no known evidence of adverse effect to Human of CAS NO 59-50-7 as well as mechanistic trigger does not indicates any concern of CAS NO 59-50-7 on toxicity to human.

 

Repeated dose Inhalation:

A few drops of a 0-1% concentration of chlorocresol diluted in water was poured into a sink, the cold tap was turned on to ensure a water born aerosol and the patient was placed near the sink. After approximately 3 minutes a partial left-sided facial palsy occurred preceded by a feeling of pins and needles in the left cheek and temporal region. Only muscles around the left side of the mouth were affected. On neurophysiological testing during chlorocresol provocation the only abnormality was a loss of motor units during maximal contraction of the left orbicularis oris muscle. This could be explained by a peripheral as well as a central effect. Extensive electrophysiological examination without chlorocresol provocation excluded a preexisting generalized nerve disorder and other diagnostic procedures did not give evidence of pathology involving the left facial nerve. A hyperreactive mechanism causing a transient block of the left facial nerve is proposed. Hence the LOAEL was considered to be 1%.

Repeated dose toxicity: dermal-

Based on the various studies available with Klimish rating 2and 4 for the target chemical 59-50-7. The results for target are summarized as follows

 

Sr. No

End point

Value

Species

Route

Effects

Remarks

1

NOEL

 

 

 

 

 

LOEL

160 mg/kg

 

 

 

 

 

500 mg/kg

guinea pig

Dermal

No effect observed at this challenge concentration

 

sensitization observed at this challenge concentration

 

Data from publication for Target chemical

2

NOEL

 

 

LOAEL

40 mg/Kg d

 

 

160 mg/Kg d

 

Rabbit

Dermal

No systemic effect observed

 

severe erythema and slight edema

Data from study report for Target chemical

 

Based on the studies summarized in the above table it can be observed that a NOAEL value varies from 40 -160 mg/Kg bw/ d. whereas the lowest effect observed value (LOEL) values varies from 160 -500 mg/kg bw/d. The effects observed on these doses was listed as follows

·        No effect observed at this challenge concentration

·        sensitization observed at this challenge concentration

·        No systemic effect observed

·        

 

Thus based on above values it can be concluded that substance CAS NO 59-50-7 is expected to show the similar toxicological effect. Since no effective dose value (NOAEL) is 40 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 59-50-7 is considered to be not toxic to repeated dose via dermal route for the above mentioned dose. Also there are no known evidence of adverse effect to Human of CAS NO 59-50-7 as well as mechanistic trigger does not indicates any concern of CAS NO 59-50-7 on toxicity to human.

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

4 groups of 10 male and 10 female rats were given 0, 50, 200 or 400 mg CMP/kg bw/day for 28 days. CMP was dissolved in soy bean oil (food grade),and dosed by gavage, 5 ml/kg bw/day. Body weight, clinical signs.organ weight, hematology, clinical chemistry and histopathology was observed.The animals in the highest dosed group exhibited a significant decrease in weight gain during the last week of dosing.No other clinical signs of adverse effects were observed.The hematological and clinical chemical parameters were found to be within the normal range in all groups.No significant alterations were noted in the relative organ weights. There were no pathological changes attributable to the dosing with 4-chloro-3-methylphenol. Although not associated with pathological or biochemical changes the growth retardation of both males and females in the highest dosed group is considered a toxic effect of the test substance. On this basis the no effect level in this 28-days oral toxicity study with CMP in rats was 200 mg/kg bw/day.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

A few drops of a 0-1% concentration of chlorocresol diluted in water was poured into a sink, the cold tap was turned on to ensure a water born aerosol and the patient was placed near the sink. After approximately 3 minutes a partial left-sided facial palsy occurred preceded by a feeling of pins and needles in the left cheek and temporal region. Only muscles around the left side of the mouth were affected. On neurophysiological testing during chlorocresol provocation the only abnormality was a loss of motor units during maximal contraction of the left orbicularis oris muscle. This could be explained by a peripheral as well as a central effect. Extensive electrophysiological examination without chlorocresol provocation excluded a preexisting generalized nerve disorder and other diagnostic procedures did not give evidence of pathology involving the left facial nerve. A hyperreactive mechanism causing a transient block of the left facial nerve is proposed. Hence the LOAEL was considered to be 1%.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

p-chloro-m-cresol was tested in a 21-day dermal study in New Zealand White rabbits (10/sex/dose group) at the following dose levels: 0, 10, 40 or 160 mg/kg/day. The animals were dosed 5 days/wk for a total of 15 applications. It appears that the test material was applied without a vehicle. Dermal irritation was observed in all treated groups, which ranged from slight erythema and very slight edema (10 mg/kg/day) to severe erythema and slight edema (160 mg/kg/day). Other dermal effects included skin thickening, scaling, blanching, raw areas, necrosis, brown scab-like areas, and sloughing. Fissuring occurred in one mid-dose female and in two high dose males. No systemic effects were observed at either 10 mg/kg/day or 40 mg/kg/day. At 160 mg/kg/day, a compound related enhancing effect on nonsupporative pericholangitis (both sexes) and bile duct proliferation (females) in the liver were observed. The systemic NOEL is 40 mg/kg/day and the LOEL is 160 mg/kg/day based on enhanced liver pathology in both sexes.

Justification for classification or non-classification

The substance chlorocresol is not toxic via oral and dermal route but is toxic via inhalation route.