4-chloro-α,α,α-trifluorotoluene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.029 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25 000

Dose descriptor starting point:

T25

Modified dose descriptor starting point:

other: corrected T25

Value:

741.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

A two year carcinogenicity study via inhalation route on rats and mice was selected as most sensitive end-point. 

For non-threshold carcinogencity studies, the dose descriptor to be calculated is the T25.

T25 values were calculated for both benign and malignant tumours at the lowest tumorogenic response, according to ECHA guidance R.8 and Dybing E. et all (1997)¹

The lowest T25 calculated for inhalation exposure was 738.45 mg/m3 obtained from the % of incidence of neoplastic lesions on thyroid gland of female rats.

The corrected T25 and the DMEL for inhalation workers were calculated using a default sequence of extrapolation and a “linearised” approach:

T25_corrected = 738.45 mg/m3 x 6.7/10 x 1.5 * = 741.7 mg/m3

DMEL (based on T25) = T25_corrected/factor for high to low dose extrapolation = 741.7 mg/m3 / 25.000 = 0.029 mg/m³

* this factor is calculated considering the hours of exposure during inhalation study (6), the hours of exposure of workers (8), the day per week of exposure (5 in the study for rats and 5 per workers), the week of workers exposure per years (48 vs 52) and the years in the lifetime (40 vs 75), following the formula: 6/8 x 5/5 x 52/48 x 75/40 

1. Dybing E, Sanner, Roelfzema H., Kroese D. and Tennant R.; “Simplified Carcinogenic Potency Index: Description of the System and Study of Correlations between Carcinogenic Potency and Specied Site Specificity and Mutagenicity”, Pharmacology & Toxicology 1997, 80, 272-279.

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

carcinogenicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.017 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25 000

Dose descriptor starting point:

T25

Modified dose descriptor starting point:

other: corrected T25

Value:

417.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A two year carcinogenicity study via inhalation route on rats and mice was selected as most sensitive end-point. 

For non-threshold carcinogencity studies, the dose descriptor to be calculated is the T25.

T25 values were calculated for all benignant and malignant tumours at the lowest tumorogenic response, according to ECHA guidance R.8 and Dybing E. et all (1997)¹

The lowest T25 calculated was 738.5 mg/m3, obtained from data on the incidence % of neoplastic lesions on thyroid gland of female rats.

To correct this value in mg/kg bw the following formula is applied:

T25 (mg/kg bw) = (hours of exposure x inhalation volume for female rats x 738.5 mg/m3) x 1000 g / mean bw rats in g = (6h x 15.7 l/h x 0.001 x 738.5 mg/m3) x 1000 / 250 = 278.25 mg/kg bw

The corrected T25 for workers dermal, is calculated using a default sequence of extrapolation and a “linearised” approach:

T25_corrected = 278.25 mg/kg bw x 1.5*= 417.4 mg/kg bw

DMEL (based on T25) = T25_corrected/factor for high to low dose extrapolation = 417.4 mg/kg bw / 25.000 = 0.017 mg/kg/bw

* this factor is calculated considering the hours of exposure during inhalation study (6), the hours of exposure of workers (8), the day per week of exposure (5 in the study for rats and 5 per workers), the week of workers exposure per years (48 vs 52) and the years in the lifetime (40 vs 75), following the formula: 6/8 x 5/5 x 52/48 x 75/40 

1. Dybing E, Sanner, Roelfzema H., Kroese D. and Tennant R.; “Simplified Carcinogenic Potency Index: Description of the System and Study of Correlations between Carcinogenic Potency and Specied Site Specificity and Mutagenicity”, Pharmacology & Toxicology 1997, 80, 272-279.

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

carcinogenicity

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.6 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

450

Dose descriptor starting point:

other: LOAEL

AF for dose response relationship:

3

Justification:

LOAEL as the starting dose

AF for interspecies differences (allometric scaling):

1

Justification:

included in the AF for other interspecies differences

AF for other interspecies differences:

10

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

3

Justification:

skin sensitization specific AF ( 3 for differences in vehicle, 1 for differences in exposure conditions)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.001 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100 000

Dose descriptor starting point:

T25

Modified dose descriptor starting point:

other: corrected T25

Value:

131.9 mg/m³

Explanation for the modification of the dose descriptor starting point:

A two year carcinogenicity study via inhalation route on rats and mice was selected as most sensitive end-point. 

For non-threshold carcinogencity studies, the dose descriptor to be calculated is the T25.

T25 values were calculated for both benign and malignant tumours at the lowest tumorogenic response, according to ECHA guidance R.8 and Dybing E. et all (1997)¹

The lowest T25 calculated for inhalation exposure was 738.45 mg/m3 obtained from the % of incidence of neoplastic lesions on thyroid gland of female rats.

The corrected T25 and the DMEL for inhalation general population were calculated using a default sequence of extrapolation and a “linearised” approach:

T25_corrected = 738.45 mg/m3 x 0.18 * = 131.9 mg/m3

DMEL (based on T25) = T25_corrected/(interspecies extrapolation factor x factor for high to low dose extrapolation) = 131.9 mg/m3 /(4 x 25.000) = 0.0013 mg/m³

* this factor is calculated considering the hours of exposure during inhalation study (6), the hours of exposure for general population (24), the day per week of exposure (5 in the study for rats and 7 for general population): 6/24 x 5/7 

1. Dybing E, Sanner, Roelfzema H., Kroese D. and Tennant R.; “Simplified Carcinogenic Potency Index: Description of the System and Study of Correlations between Carcinogenic Potency and Specied Site Specificity and Mutagenicity”, Pharmacology & Toxicology 1997, 80, 272-279.

AF for dose response relationship:

1

AF for interspecies differences (allometric scaling):

4

Justification:

From rat to human

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

carcinogenicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.001 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100 000

Dose descriptor starting point:

T25

Modified dose descriptor starting point:

other: corrected T25

Value:

50.1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A two year carcinogenicity study via inhalation route on rats and mice was selected as most sensitive end-point. 

For non-threshold carcinogencity studies, the dose descriptor to be calculated is the T25.

T25 values were calculated for both benign and malignant tumours at the lowest tumorogenic response, according to ECHA guidance R.8 and Dybing E. et all (1997)¹

The lowest T25 calculated for inhalation exposure was 738.45 mg/m3 obtained from the % of incidence of neoplastic lesions on thyroid gland of female rats.

To correct this value in mg/kg bw the following formula is applied:

T25 (mg/kg bw) = (hours of exposure x inhalation volume for female rats x 738.5 mg/m3) x 1000 g / mean bw rats in g = (6h x 15.7 l/h x 0.001 x 738.5 mg/m3) x 1000 / 250 = 278.24 mg/kg bw

The corrected T25 for general population dermal, is calculated using a default sequence of extrapolation and a “linearised” approach:

T25_corrected = 278.24 mg/kg bw x 0.18*= 50.1 mg/kg bw

DMEL (based on T25) = T25_corrected/(interspecies extrapolation factor x factor for high to low dose extrapolation) = 50.1 mg/kg bw /(4 x 25.000) = 0.0005 mg/kg bw

* this factor is calculated considering the hours of exposure during inhalation study (6), the hours of exposure for general population (24), the day per week of exposure (5 in the study for rats and 7 for general population): 6/24 x 5/7 

1. Dybing E, Sanner, Roelfzema H., Kroese D. and Tennant R.; “Simplified Carcinogenic Potency Index: Description of the System and Study of Correlations between Carcinogenic Potency and Specied Site Specificity and Mutagenicity”, Pharmacology & Toxicology 1997, 80, 272-279.

AF for dose response relationship:

1

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

carcinogenicity

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.8 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

900

Dose descriptor starting point:

other: LOAEL

AF for dose response relationship:

3

Justification:

LOAEL as the starting dose

AF for interspecies differences (allometric scaling):

1

Justification:

included in the AF for other interspecies differences

AF for other interspecies differences:

10

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

3

Justification:

skin sensitization specific AF ( 3 for differences in vehicle, 1 for differences in exposure conditions)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.001 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100 000

Dose descriptor starting point:

T25

Modified dose descriptor starting point:

other: corrected T25

Value:

50.1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A two year carcinogenicity study via inhalation route on rats and mice was selected as most sensitive end-point. 

For non-threshold carcinogencity studies, the dose descriptor to be calculated is the T25.

T25 values were calculated for both benign and malignant tumours at the lowest tumorogenic response, according to ECHA guidance R.8 and Dybing E. et all (1997)¹

The lowest T25 calculated for inhalation exposure was 738.45 mg/m3 obtained from the % of incidence of neoplastic lesions on thyroid gland of female rats.

To correct this value in mg/kg bw the following formula is applied:

T25 (mg/kg bw) = (hours of exposure x inhalation volume for female rats x 738.5 mg/m3) x 1000 g / mean bw rats in g = (6h x 15.7 l/h x 0.001 x 738.5 mg/m3) x 1000 / 250 = 278.24 mg/kg bw

The corrected T25 for general population dermal, is calculated using a default sequence of extrapolation and a “linearised” approach:

T25_corrected = 278.24 mg/kg bw x 0.18*= 50.1 mg/kg bw

DMEL (based on T25) = T25_corrected/(interspecies extrapolation factor x factor for high to low dose extrapolation) = 50.1 mg/kg bw /(4 x 25.000) = 0.0005 mg/kg bw

* this factor is calculated considering the hours of exposure during inhalation study (6), the hours of exposure for general population (24), the day per week of exposure (5 in the study for rats and 7 for general population): 6/24 x 5/7 

1. Dybing E, Sanner, Roelfzema H., Kroese D. and Tennant R.; “Simplified Carcinogenic Potency Index: Description of the System and Study of Correlations between Carcinogenic Potency and Specied Site Specificity and Mutagenicity”, Pharmacology & Toxicology 1997, 80, 272-279.

AF for dose response relationship:

1

Justification:

NOAEL as starting point

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified