Chlorocresol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

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 chlorocresol was assessed in pregnant female in 10 days study

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Route of administration:

oral: gavage

Vehicle:

other: aqueous methyl cellulose

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0, 30, 100, or 300 mg/kg
- Amount of vehicle (if gavage): 0.5%
- Lot/batch no. (if required): no data
- Purity: no data

Details on mating procedure:

Pregnant females were used

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Days 6–15 of gestation

Frequency of treatment:

Once daily

Remarks:

Doses / Concentrations:
0, 30, 100, or 300 mg/kg
Basis:
nominal conc.

No. of animals per sex per dose:

25 female rats

Control animals:

yes

Parental animals: Observations and examinations:

Clinical examinations were performed daily, food and water intake were noted and body weights were recorded on gestation days (GD) 0, 6–15, and 20.

Oestrous cyclicity (parental animals):

no data

Sperm parameters (parental animals):

no data

Litter observations:

Uterine and fetal weights were recorded

Postmortem examinations (parental animals):

Gross pathological examinations were performed on GD 20, at which time uteri were removed and examined for numbers of corpora lutea, implantations, live fetuses, and live fetuses per sex.

Postmortem examinations (offspring):

Fetuses were examined for signs of external malformations. Half of the fetuses were examined for gross and skeletal malformations; the other half were prepared for visceral examination.

Statistics:

no data

Reproductive indices:

no data

Offspring viability indices:

no data

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Clinical signs of toxicity, including prostration and convulsions, were observed in high-dose dams on Day 6 of gestation. From GD 8 onward, clinical signs of toxicity became increasingly apparent and included labored breathing and bloody nasal exudate.
Between GD 12 and 18, five of the high-dose dams died and another was sacrificed after being found in a moribund state.


BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Mean maternal body-weight gain in high-dose dams was decreased by 96%, relative to controls
Food intake in the high-dose dams was significantly lower than that of controls throughout the treatment period
Decreased water intake was also noted in high-dose dams

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No significant treatment-related effects were found for number of corpora lutea, implantations, live fetuses, and live fetuses per sex in any of the dose groups

GROSS PATHOLOGY (PARENTAL ANIMALS)
Preliminary pathological findings in these dams included gas-filled intestines and vaginal bleeding in 3/6

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: labored breathing and decreased body weight

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: labored breathing and decreased body weight

Critical effects observed:

not specified

Clinical signs:

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

BODY WEIGHT (OFFSPRING)
significantly decreased mean fetal weight was observed

SEXUAL MATURATION (OFFSPRING)
Signs of fetotoxicity were observed only in the high-dose group and included significantly increased early resorptions (a mean of 1.8/dam in the high-dose group compared with 0.6/dam in controls)

OTHER FINDINGS (OFFSPRING)
There was a significant skewing of the normal sex ratio from 55.6% males to 45.6% males at the Mid-dose.
There were no treatment-related fetal malformations at any dose level

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Reproductive effects observed:

not specified

Conclusions:

The maternal NOAEL and LOAEL (labored breathing and decreased body weight) for the study are 30 and 100 mg/kg-day, respectively

Executive summary:

Groups of 25 pregnant Wistar rats were given 0, 30, 100, or 300 mg/kg of Preventol CMK (p-chloro-m-cresol) by gavage in 0.5% aqueous methyl cellulose, once per day on Days 6–15 of gestation. Clinical examinations were performed daily, food and water intake were noted and body weights were recorded .Gross pathological examinations were performed on GD 20, at which time uteri were removed and examined for numbers of corpora lutea, implantations, live fetuses, and live fetuses per sex. Uterine and fetal weights were recorded and fetuses were examined for signs of external malformations. Half of the fetuses were examined for gross and skeletal malformations; the other half were prepared for visceral examination. Clinical signs of toxicity, including prostration, convulsions and labored breathing, were observed in high-dose dams. Decrease in body weight, food intake and water consumption was observed in high dose dams. No significant treatment-related effects were found for number of corpora lutea, implantations, live fetuses, and live fetuses per sex in any of the dose groups. Pathological findings in these dams included gas-filled intestines and vaginal bleeding. Hence, the maternal NOAEL and LOAEL was considered to be 30 and 100 mg/kg-day, respectively.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Toxicity to Reproduction:

Based on the various studies available with Klimish rating 2 & 4 for target CAS NO 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	Effects	Remarks
1	NOAEL (Maternal)   LOAEL	30 mg/Kg bw /d   100 mg/Kg bw /d	Rat	labored breathing and decreased body weight	Data from publication for target chemical
2	ERBA	0.00042	rat uterine cytosol.	binding affinity is less to cause any damage in uterine tissue	Data from publication for target chemical
3	NOAEL (Maternal)	428 mg/Kg bw /d	Rat	No reproductive parameters were affected in either of the two generations.	Predicted data for target chemical

 

Based on the studies summarized in the above table it can be observed that NOAEL values was found to be in the range of 30 -428 mg/Kg bw/ d and LOAEL was found to be 100 mg/kg bw/day and the ERBA value was found to be 0.00042 based on the data from prediction for target as well as publication. The effects observed on these doses was listed as follows

 

·        labored breathing and decreased body weight.

·        binding affinity is less to cause any damage in uterine tissue

·        No reproductive parameters were affected in either of the two generations

Thus based on above values it can be concluded that substance CAS NO 59-50-7 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the no effective dose value (NOAEL) is 30 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 reproduction below this dose level .Also CAS NO 59-50-7 does not indicates any mechanistic trigger towards the toxicity to reproduction based on absence of noncyclic structure that would raise concern of CAS NO 59-50-7 on toxicity to human reproduction. Thus CAS NO 59-50-7 is considered to be not toxic to reproductive effects for the above mentioned dose levels.

Justification for selection of Effect on fertility via oral route:

Groups of 25 pregnant Wistar rats were given 0, 30, 100, or 300 mg/kg of Preventol CMK (p-chloro-m-cresol) by gavage in 0.5% aqueous methyl cellulose, once per day on Days 6–15 of gestation. Clinical examinations were performed daily, food and water intake were noted and body weights were recorded .Gross pathological examinations were performed on GD 20, at which time uteri were removed and examined for numbers of corpora lutea, implantations, live fetuses, and live fetuses per sex. Uterine and fetal weights were recorded and fetuses were examined for signs of external malformations. Half of the fetuses were examined for gross and skeletal malformations; the other half were prepared for visceral examination. Clinical signs of toxicity, including prostration, convulsions and labored breathing, were observed in high-dose dams. Decrease in body weight, food intake and water consumption was observed in high dose dams. No significant treatment-related effects were found for number of corpora lutea, implantations, live fetuses, and live fetuses per sex in any of the dose groups. Pathological findings in these dams included gas-filled intestines and vaginal bleeding. Hence, the maternal NOAEL and LOAEL was considered to be 30 and 100 mg/kg-day, respectively.

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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 chlorocresol was assessed in pregnant female in 10 days study

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Route of administration:

oral: gavage

Vehicle:

other: aqueous methyl cellulose

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0, 30, 100, or 300 mg/kg
- Amount of vehicle (if gavage): 0.5%
- Lot/batch no. (if required): no data
- Purity: no data

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Pregnant females were used

Duration of treatment / exposure:

Days 6–15 of gestation

Frequency of treatment:

Once daily

Duration of test:

10 days

Remarks:

Doses / Concentrations:
0, 30, 100, or 300 mg/kg
Basis:
nominal conc.

No. of animals per sex per dose:

25 female rats

Control animals:

yes

Maternal examinations:

Clinical examinations were performed daily, food and water intake were noted and body weights were recorded on gestation days (GD) 0, 6–15, and 20.

Ovaries and uterine content:

Gross pathological examinations were performed on GD 20, at which time uteri were removed and examined for numbers of corpora lutea, implantations, live fetuses, and live fetuses per sex.

Fetal examinations:

Uterine and fetal weights were recorded.
Fetuses were examined for signs of external malformations. Half of the fetuses were examined for gross and skeletal malformations; the other half were prepared for visceral examination

Statistics:

no data

Indices:

no data

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Clinical signs of toxicity, including prostration and convulsions, were observed in high-dose dams on Day 6 of gestation. From GD 8 onward, clinical signs of toxicity became increasingly apparent and included labored breathing and bloody nasal exudate.
Between GD 12 and 18, five of the high-dose dams died and another was sacrificed after being found in a moribund state.
Decrease in body weight, food intake and water consumption was observed in high dose dams. No significant treatment-related effects were found for number of corpora lutea, implantations, live fetuses, and live fetuses per sex in any of the dose groups. Pathological findings in these dams included gas-filled intestines and vaginal bleeding.

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Significantly decreased mean fetal weight was observed. Signs of fetotoxicity were observed only in the high-dose group and included significantly increased early resorptions (a mean of 1.8/dam in the high-dose group compared with 0.6/dam in controls). There was a significant skewing of the normal sex ratio from 55.6% males to 45.6% males at the Mid-dose. There were no treatment-related fetal malformations at any dose level

Remarks on result:

not measured/tested

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

The developmental NOAEL and LOAEL (changes in sex ratio) for the study are 30 and 100 mg/kg-day, respectively

Executive summary:

Groups of 25 pregnant Wistar rats were given 0, 30, 100, or 300 mg/kg of Preventol CMK (p-chloro-m-cresol) by gavage in 0.5% aqueous methyl cellulose, once per day on Days 6–15 of gestation. Uterine and fetal weights were recorded and fetuses were examined for signs of external malformations. Half of the fetuses were examined for gross and skeletal malformations; the other half were prepared for visceral examination. Significantly decreased mean fetal weight was observed. Signs of fetotoxicity were observed only in the high-dose group and included significantly increased early resorptions (a mean of 1.8/dam in the high-dose group compared with 0.6/dam in controls). There was a significant skewing of the normal sex ratio from 55.6% males to 45.6% males at the mid-dose. There were no treatment-related fetal malformations at any dose level. Hence, the Developmental NOAEL and LOAEL was considered to be 30 and 100 mg/kg-day, respectively.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Based on the various studies available with Klimish rating 2 and 4 for the target substances CAS NO 59-50-7based 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 (developmental)     LOAEL (developmental)	30 mg/ kg bw/ d   100 mg/ kg bw/ d	Rat	Oral	changes in sex ratio   changes in sex ratio	Data from Study report for target chemical
2	NOAEL (Embryotoxicity)   LOAEL (Embryotoxicity)	40 mg/l     80 mg/l	Xenopus laevis.	N/A	No Mortality observed   Mortality and malformed embryos observed	Data from publication for target chemical
3	LC50   LC10	13 mg/l   6 mg/l	Xenopus laevis.	N/A	Mortality and malformation	Data from publication for target chemical
4	NOAEL (developmental)	47.66 mg/ kg bw/ d	Rat	Oral	clinical signs of toxicity including hypoactivity, ataxia, tremors, twitches, prone positioning, audible respiration and perioral wetness, statistically signifcant reduction in periodic maternal body weights and weight gain during the dosing period	Predicted data of target chemical

 

Based on the studies summarized in the above table with oral routes it can be observed that a NOAEL value varies from 30 mg/Kg bw/ d – 47.66 mg/l and the LOAEL values varies from 80 mg/l to 100 mg/Kg bw/ d. the LC50 and LC10 values was found to bee 16 mg/l and 6 mg/l respectively. The effects observed on these doses was listed as follows

 

·        changes in sex ratio.

·        Mortality and malformed embryos observed

·        Mortality and malformation

 

Thus based on above discussion it can be concluded that substance CAS NO 59-50-7 is expected to show the similar toxicological effect. Since the no effective dose value (NOAEL) is 30 mg/Kg bw/d thus based on this value it can be concluded that substance CAS NO 59-50-7 is considered to be non toxic to developmental effects for the above mentioned dose. Also CAS NO 59-50-7 does not indicates any mechanistic trigger towards the toxicity based on absence of noncyclic structure that would raise concern of CAS NO 59-50-7 on toxicity to human reproduction & developmental effects. Thus CAS NO 59-50-7 is considered to be not toxic to reproductive & developmental effects for the above mentioned dose levels.

Justification for selection of Effect on developmental toxicity: via oral route:

Groups of 25 pregnant Wistar rats were given 0, 30, 100, or 300 mg/kg of Preventol CMK (p-chloro-m-cresol) by gavage in 0.5% aqueous methyl cellulose, once per day on Days 6–15 of gestation. Uterine and fetal weights were recorded and fetuses were examined for signs of external malformations. Half of the fetuses were examined for gross and skeletal malformations; the other half were prepared for visceral examination. Significantly decreased mean fetal weight was observed. Signs of fetotoxicity were observed only in the high-dose group and included significantly increased early resorptions (a mean of 1.8/dam in the high-dose group compared with 0.6/dam in controls). There was a significant skewing of the normal sex ratio from 55.6% males to 45.6% males at the mid-dose. There were no treatment-related fetal malformations at any dose level. Hence, the Developmental NOAEL and LOAEL was considered to be 30 and 100 mg/kg-day, respectively.

Justification for classification or non-classification

The substance, chlorocresol do not show any hazard effect in develpmental or reproductive stage and so cannot be considered for calssification.