2-hexyldecanoic acid [4-(6-tert-butyl-7-chloro-1H-pyrazolo[1,5-b][1,2,4]triazol-2-yl)phenylcarbamoyl]methylester

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.75 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

Modified dose descriptor starting point:

NOAEC

Value:

1 763.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

No study on long-term inhalation toxicity available

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

sub-acute (28-day repeated dose) to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

2

Justification:

Remaining uncertainties due to data waiving for toxicity to reproduction

AF for remaining uncertainties:

1

Justification:

No further remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No study on long-term dermal toxicity available

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

sub-acute (28-day repeated dose) to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The study was conducted with rats.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value according to ECHA REACH Guidance.

AF for the quality of the whole database:

2

Justification:

Remaining uncertainties due to data waiving for toxicity to reproduction.

Justification:

No further remaining unceratainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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

No DNELs have been derived for systemic effects after short-term exposure of 2-hexyldecanoic acid [4-(6-tert-butyl-7-chloro-1H-pyrazolo[1,5-b][1,2,4]triazol-2-yl)phenylcarbamoyl]methylester (UM-235) for workers, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure. In addition, no DNEL has been derived for short-term dermal exposure, since no hazard was identified. Moreover, UM-235 was not skin or eye irritating neither skin sensitising (Teunissen, 2003b; Teunissen, 2003c; Teunissen, 2003d). 

The long-term worker DNEL for dermal systemic effects is based on a 28-day oral repeated dose toxicity study performed according to OECD 407 in rats (Hooiveld, 2004) with test substance concentrations of 50, 150 and 1000 mg/kg bw/day. In this study no adverse effects were observed up to and including the highest dose level. Therefore, the NOAEL of ≥ 1000 mg/kg bw/day was chosen as the starting point for deriving the DNEL as there is no dermal repeated dose study available.

To convert the oral NOAEL [mg/kg bw/day] into a dermal NOAEL [mg/kg bw/day], the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, European Chemicals Agency, November 2012). For UM-235, the dermal bioavailability is expected to be in the same order of magnitude as oral absorption (refert to Toxicokinetics, metabolism and distribution). The NOAEL for the oral and dermal exposure route is therefore identical.

 

The long-term worker DNEL for inhalation systemic effects is based on the 28-day oral repeated dose toxicity study performed according to OECD 407 in rats (Hooiveld, 2004). This study was chosen as the starting point for deriving the DNEL as there is no inhalation repeated dose study available. According to the 'Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health' (European Chemicals Agency, November 2012), the oral NOAEL should be converted into an inhalatory NAEC: the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38m³/kg for 8 h exposure). Additionally, it should be taken into account that during 8 hours light activity at work the respiratory rate becomes higher (10 m³/person) than standard (6.7 m³/person). Based on the water insolubility and the high log Pow, absorption of UM-235 is not likely to occur (refer to Toxicokinetics, metabolism and distribution). Therefore, absorption via the inhalation route is considered to be comparable to absorption via the oral route. Taken together, the corrected starting point is a NAEC of 1763.2 mg/m³.

In general, assessment factors recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. European Chemicals Agency, November 2012) were used when applicable to derive the DNELs.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.9 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):

300

Modified dose descriptor starting point:

NOAEC

Value:

869.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

No study on long-term inhalation toxicity available

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

sub-acute (28-day repeated dose) to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

2

Justification:

Remaining uncertainties due to data waiving for toxicity to reproduction

AF for remaining uncertainties:

1

Justification:

No further remaining unceratainties.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.83 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):

1 200

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No study on long-term dermal toxicity available.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

sub-acute (28-day repeated dose) to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

2

Justification:

Remaining uncertainties due to data waiving for toxicity to reproduction

AF for remaining uncertainties:

1

Justification:

No further remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

0.83 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):

1 200

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation required.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

sub-acute (28-day repeated dose) to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

2

Justification:

Remaining uncertainties due to data waiving for toxicity to reproduction

AF for remaining uncertainties:

1

Justification:

No further remaining uncertainties.

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

The general population is not exposed to 2-hexyldecanoic acid [4-(6-tert-butyl-7-chloro-1H-pyrazolo[1,5-b][1,2,4]triazol-2-yl)phenylcarbamoyl]methylester (UM-235), based on its identified uses. However, the long-term consumer DNEL for oral, dermal and inhalation systemic effects has been derived.

No DNELs have been derived for systemic effects after short-term exposure UM-235 for the general population, as it is assumed that the assessment of hazard is sufficiently covered by deriving the respective DNELs for long-term exposure or since no hazard was identified based on experimental data, respectively. Moreover, UM-235 was not skin or eye irritating neither skin sensitising (Teunissen, 2003b; Teunissen, 2003c; Teunissen, 2003d). 

 

The long-term DNEL for the general population, dermal systemic effects is based on the 28-day oral repeated dose toxicity study performed according to OECD 407 in rats with test substance concentrations fo 50, 150 and 1000 mg/kg bw/day (Hooiveld, 2004). In this study no adverse effects were observed up to and including the highest dose level. Therefore, the NOAEL of ≥ 1000 mg/kg bw/day was chosen as the starting point for deriving the DNEL as there is no dermal repeated dose study available.

 

This NOAEL was chosen as the starting point for deriving the DNEL as there is no dermal repeated dose study available. To convert the oral NOAEL [mg/kg bw/day] into a dermal NOAEL [mg/kg bw/day], the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. European Chemicals Agency, November 2012). For UM-235, the dermal bioavailability is expected to be in the same order of magnitude as oral absorption (refer to Toxicokinetics, metabolism and distribution). The NOAEL for the oral and dermal exposure route is therefore identical.

 

The long-term DNEL for the general population, inhalation systemic effects is also based on the 28-day repeated dose toxicity study performed according to OECD 407 in rats (Hooiveld, 2004). The NOAEL determined in this study was chosen as the starting point for deriving the DNEL as there is no inhalation repeated dose study available. According to the Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health' (European Chemicals Agency, November 2012), the oral NOAEL should be converted into an inhalatory NAEC: the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 h exposure). Therefore, the corrected starting point is a NAEC of 869.6 mg/m³. For UM-235, it is assumed, that the inhalation absorption rate is in the same order of magnitude as the oral absorption.

 

The long-term DNEL for the general population, oral systemic effects is based on the 28-day repeated dose toxicity study (Hooiveld, 2004) performed according to OECD 407 in rats. As no effects were observed up to and including the highest dose level, the NOAEL is ≥ 1000 mg/kg bw/day. The study was performed via the oral route. Therefore, the value can be used directly to derive the oral DNEL.

In general, assessment factors recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. European Chemicals Agency, November 2012) were used when applicable to derive the DNELs.