3-(2,2-dimethyl-3-hydroxypropyl)toluene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

310 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

382 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard respiratory volume, human (sRVhuman) for 8 h per person (70 kg): 6.7 m³

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity per person: 10 m³

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

NOEC_corr = NOAEL_oral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABS_oral/ABS_inh

NOEC_corr = 310 mg/kg bw/day x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x 1/2

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 407 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.45 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

310 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

434 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 1/1

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

NOAEL_corr = NOAEL_oral x 7d/5d x ABS_oral/ABS_inh

NOAEL_corr = 310 mg/kg bw/day x 7d/5d x 1/1

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute to chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 407 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Systemic long-term DNEL for inhalation exposure

The respective NOAEC is based on a NOAEL of 310 mg/kg bw/day from a subacute oral rat study, considering an oral bioavailability of 100%. It was modified  using a human standard respiratory volume (sRVhuman) of 6.7 m³ for 8 hours per person (70 kg), a rat standard respiratory volume (sRVrat) of 0.38 m³/kg bw for 8 hours, a worker respiratory volume (wRV) of 10 m³ for 8 hours with light physical activity, the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) and a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 382 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOEC_corr = NOAEL_oral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABS_oral/ABS_inh

Using assessment factors of (i) 6 for duration of exposure, (ii) 2.5 for remaining species differences and (iii) 5 for intraspecies extrapolation, a DNEL of 5.1 mg/m³ for long-term, systemic inhalative exposure was calculated.

 

Systemic acute DNEL for inhalation exposure

In accordance with column 2 of REACH Annex VIII, an acute inhalation toxicity study (required in section 8.5.3) does not need to be conducted as the oral and dermal routes are more relevant for exposure and no adverse systemic effects were observed in the acute oral and dermal toxicity study and in in vivo skin irritation/sensitisation studies. Due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure =2.8 Pa), high peak-inhalation exposure is not considered relevant. Moreover, the LD50 of the test item in rats by the oral and dermal route was more than 2000 mg/kg bw and therefore acute toxicity is of a low concern. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for inhalation exposure

No study on respiratory irritation is available, but, due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure = 2.8 Pa), inhalation exposure is considered unlikely. Furthermore, the test item was not classified for skin irritation or sensitisation. Thus, long-term and acute local effects in the respiratory tract are not expected.

 

Systemic long-term DNEL for dermal exposure

The NOAEL of 310 mg/kg bw/day from a subacute oral toxicity study according to OECD guideline 407 was used as POD. It was modified using a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 434 mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAEL_corr = NOAEL_dermal x 7d/5d

Using assessment factors of (i) 6 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 5 for intraspecies extrapolation, a DNEL of 1.45 mg/kg bw/day for long-term, systemic dermal exposure was calculated.

 

Systemic acute DNEL for dermal exposure

In an acute dermal toxicity study, the NOAEL was >2000 mg/kg bw/day. Thus, no hazard is identified and it is considered that long-term DNELs are sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for dermal exposure

No hazards were identified in skin irritation and sensitisation studies. Thus, long-term and acute local dermal effects are unlikely. 

 

Hazard for the eyes

No hazards were identified in an eye irritation study. Thus, local effects on the eyes are unlikely. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.899 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Dose descriptor starting point:

NOAEL

Value:

310 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

135 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw/day

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2 (default)

Corrected NOAEC (inhalation) for general population:

NOEC_corr = NOAEL_oral x 1/1.15 m³/kg bw/day x ABS_oral/ABS_inh

NOEC_corr = 310 mg/kg bw/day x 0.87 m³/kg bw/day x 1/2

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 407 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.517 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

310 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

310 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No corrections are needed as a similar absorption through the oral and dermal route is assumed.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute to chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 407 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.517 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

310 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

310 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification is needed as the same route of exposure is assessed and the same exposure period is assumed.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute to chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 407 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Systemic long-term DNEL for inhalation exposure

The respective NOAEC is based on a NOAEL of 310 mg/kg bw/day from a subacute oral rat study, considering an oral bioavailability of 100%. It was modified  using a rat standard respiratory volume (sRVrat) of 1.15 m³/kg bw/day for 24 hours and the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) to 135 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8.

NOEC_corr = NOAEL_oral x 1/1.15 m³/kg bw/day x ABS_oral/ABS_inh

Using assessment factors of (i) 6 for duration of exposure, (ii) 2.5 for remaining species differences and (iii) 10 for intraspecies extrapolation, a DNEL of 0.889 mg/m³ for long-term, systemic inhalative exposure was calculated.

 

Systemic acute DNEL for inhalation exposure

In accordance with column 2 of REACH Annex VIII, an acute inhalation toxicity study (required in section 8.5.3) does not need to be conducted as the oral and dermal routes are more relevant for exposure and no adverse systemic effects were observed in the acute oral and dermal toxicity study and in in vivo skin irritation/sensitisation studies. Due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure =2.8 Pa), high peak-inhalation exposure is not considered relevant. Moreover, the LD50 of the test item in rats by the oral and dermal route was more than 2000 mg/kg bw and therefore acute toxicity is of a low concern. Long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for inhalation exposure

No study on respiratory irritation is available, but, due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure = 2.8 Pa), inhalation exposure is considered unlikely. Furthermore, the test item was not classified for skin irritation or sensitisation. Thus, long-term and acute local effects in the respiratory tract are not expected.

 

Systemic long-term DNEL for dermal exposure

The NOAEL of 310 mg/kg bw/day from a subacute oral toxicity study according to OECD guideline 407 was used as POD. It does not have to be modified according to Guidance Document on Information Requirement, Chapter R8 as a similar absorption through the oral and dermal route is assumed.

Using assessment factors of (i) 6 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 10 for intraspecies extrapolation, a DNEL of 0.517 mg/kg bw/day for long-term, systemic dermal exposure of the general population was calculated.

 

Systemic acute DNEL for dermal exposure

In an acute dermal toxicity study, the NOAEL was >2000 mg/kg bw/day. Thus, no hazard is identified and it is considered that long-term DNELs are sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for dermal exposure

No hazards were identified in skin irritation and sensitisation studies. Thus, long-term and acute local dermal effects are unlikely. 

 

Systemic long-term DNEL for oral exposure

The NOAEL of 310 mg/kg bw/day from a subacute oral toxicity study is used as POD considering a 100% oral absorption. It does not have to be modified according to Guidance Document on Information Requirement, Chapter R8.

Using assessment factors of (i) 6 for duration of exposure, (ii) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 10 for intraspecies extrapolation, a DNEL of 0.517 mg/kg bw/day for long-term, systemic oral exposure was calculated.

 

Systemic acute DNEL for oral exposure

In an acute oral toxicity study, the NOAEL was >2000 mg/kg bw/day. Thus, no hazard is identified and it is considered that long-term DNELs are sufficient to ensure that acute effects do not occur.

 

Hazard for the eyes

No hazards were identified in an eye irritation study. Thus, local effects on the eyes are unlikely.