Reaction products of 1H-Imidazole-1-ethanol, 4,5-dihydro-, 2-(C11-17 and C17 unsatd. alkyl) derivs. and sodium hydroxide and 2-propenoic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.4 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 230 mg/m³

Explanation for the modification of the dose descriptor starting point:

Default (DNEL generation plugin)

AF for dose response relationship:

1

Justification:

Default (DNEL generation plugin)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL generation plugin)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL generation plugin)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL generation plugin)

AF for intraspecies differences:

5

Justification:

Default (DNEL generation plugin)

AF for the quality of the whole database:

1

Justification:

Default (DNEL generation plugin)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

4.67 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):

300

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default (DNEL generation plugin)

AF for dose response relationship:

1

Justification:

Default (DNEL generation plugin)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL generation plugin)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL generation plugin)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL generation plugin)

AF for intraspecies differences:

5

Justification:

Default (DNEL generation plugin)

AF for the quality of the whole database:

1

Justification:

Default (DNEL generation plugin)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

153 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

other: generally accepted sensitisation assessment factors

Overall assessment factor (AF):

50

Dose descriptor:

other: NESIL [µg/cm²] =7650

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Local DNEL

Based on the No Expected Sensitization Induction Level (NESIL) of 7650 µg/cm² obtained from the LLNA, a local DNEL of 153 µg/cm² has been derived for workers.

Type of assessment factor	Explanation	SAF for worker
Inter-individual variability	The uncertainty factor (SAF: sensitisation assessment factor) for inter-individual variability allows for possible variations in the sensitivity of individuals within the human population. Default AF for workers (ECHA)	5
Inter-species variability	Inter-species variability is not taken into account in this approach for quantitative risk assessment of contact allergens when extrapolating from the experimental situation to the real life exposure scenarios. This is on the basis that the LLNA data have been correlated with the human data, which is typically not the case in general systemic toxicology.	1
Matrix Effects	Differences between the matrix used under experimental conditions and real life Exposure, especially the possible presence of irritating substances and penetration enhancers. The substance itself is not irritating to skin, but might be used in formulations, where irritants are present, which could increase dermal penetration. DMF, which is a penetration enhancer, was used as vehicle.	3.16 (=sqrt(10))
Use considerations	Site of contact (regional differences in absorption) Barrier integrity (e.g. dermatitis) Occlusion (increased dermal penetration)	3.16 (=sqrt(10))

 

 

DNELs based on NOAEL of 1000 mg/kg bw/d obtained in the subacute toxicity study with rats

 

Hazard conclusions for workers

Route	Type of effect	Hazard conclusion
Inhalation	Systemic effects - Long-term	DNEL (Derived No Effect Level) 16.4 mg/m³
Dermal	Systemic effects - Long-term	DNEL (Derived No Effect Level) 4.67 mg/kg bw/day

​

​Correction factors:

Correction for differences in respiratory volume (workers): 2.63

Correction for differences in bioavailability (oral -> inhalation): 0.5

Correction for light activity at work: 0.67

Correction for differences between human and experimental exposure conditions (workers): 1.4

 

Inhalation Systemic effects - Long-term

DNEL derivation method: ECHA REACH Guidance

Dose descriptor starting point:NOAEL

Overall Assessment Factor:75

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:6 (Default (DNEL calculator))

AF for interspecies differences (allometric scaling):1 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​

​​

Dermal Systemic effects - Long-term

DNEL derivation method: ECHA REACH Guidance

Dose descriptor starting point:NOAEL

Overall Assessment Factor:300

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:6 (Default (DNEL calculator))

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

 

 

DNELs based on NOAEL of 300 mg/kg bw/d obtained in the prenatal developmental toxicity study in rat

 

Hazard conclusions for workers

Route	Type of effect	Hazard conclusion
Inhalation	Systemic effects - Long-term	DNEL (Derived No Effect Level) 29.6 mg/m³
Dermal	Systemic effects - Long-term	DNEL (Derived No Effect Level) 8.4 mg/kg bw/day

​

​Correction factors:

Correction for differences in respiratory volume (workers): 2.63

Correction for differences in bioavailability (oral -> inhalation): 0.5

Correction for light activity at work: 0.67

Correction for differences between human and experimental exposure conditions (workers): 1.4

 

Inhalation Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEC

Overall Assessment Factor:12.5

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required, since the susceptible window is fully covered)

AF for interspecies differences (allometric scaling):1 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​

​​

Dermal Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEL

Overall Assessment Factor:50

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required, since the susceptible window is fully covered)

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​

​

The DNELs obtained with the NOAEL from the prenatal developmental toxicity study are higher than the DNELs obtained with the NOAEL from the subacute repeated dose toxicity study.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.47 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

370 mg/m³

Explanation for the modification of the dose descriptor starting point:

Default (DNEL generation plugin)

AF for dose response relationship:

1

Justification:

Default (DNEL generation plugin)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL generation plugin)

AF for interspecies differences (allometric scaling):

1

Justification:

Default (DNEL generation plugin)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL generation plugin)

AF for intraspecies differences:

10

Justification:

Default (DNEL generation plugin)

AF for the quality of the whole database:

1

Justification:

Default (DNEL generation plugin)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

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

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default (DNEL generation plugin)

AF for dose response relationship:

1

Justification:

Default (DNEL generation plugin)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL generation plugin)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL generation plugin)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL generation plugin)

AF for intraspecies differences:

10

Justification:

Default (DNEL generation plugin)

AF for the quality of the whole database:

1

Justification:

Default (DNEL generation plugin)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral 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

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Default (DNEL generation plugin)

AF for dose response relationship:

1

Justification:

Default (DNEL generation plugin)

AF for differences in duration of exposure:

6

Justification:

Default (DNEL generation plugin)

AF for interspecies differences (allometric scaling):

4

Justification:

Default (DNEL generation plugin)

AF for other interspecies differences:

2.5

Justification:

Default (DNEL generation plugin)

AF for intraspecies differences:

10

Justification:

Default (DNEL generation plugin)

AF for the quality of the whole database:

1

Justification:

Default (DNEL generation plugin)

AF for remaining uncertainties:

1

Justification:

no 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:

medium hazard (no threshold derived)

Additional information - General Population

DNELs based on NOAEL of 1000 mg/kg bw/d obtained in the subacute toxicity study with rats

 

Hazard conclusions for the general population

Route	Type of effect	Hazard conclusion
Inhalation	Systemic effects - Long-term	DNEL (Derived No Effect Level) 2.47 mg/m³
Dermal	Systemic effects - Long-term	DNEL (Derived No Effect Level) 1.67 mg/kg bw/day
Oral	Systemic effects - Long-term	DNEL (Derived No Effect Level) 1.67 mg/kg bw/day

​

Correction factors:

Correction for differences in respiratory volume (general population): 0.78

Correction for differences in bioavailability (oral -> inhalation): 0.5

Correction for differences between human and experimental exposure conditions (general population): 1

 

​Inhalation Systemic effects - Long-term

DNEL derivation method: ECHA REACH Guidance

Dose descriptor starting point:NOAEL

Overall Assessment Factor:150

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:6 (Default (DNEL calculator))

AF for interspecies differences (allometric scaling):1 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:10 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​

​Dermal Systemic effects - Long-term

DNEL derivation method: ECHA REACH Guidance

Dose descriptor starting point:NOAEL

Overall Assessment Factor:600

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:6 (Default (DNEL calculator))

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:10 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​

​Oral Systemic effects - Long-term

DNEL derivation method: ECHA REACH Guidance

Dose descriptor starting point:NOAEL

Overall Assessment Factor:600

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:6 (Default (DNEL calculator))

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:10 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​

 

 

DNELs based on NOAEL of 300 mg/kg bw/d obtained in the subchronic study with beagle dogs

Hazard conclusions for the general population

Route	Type of effect	Hazard conclusion
Inhalation	Systemic effects - Long-term	DNEL (Derived No Effect Level) 5.22 mg/m³
Dermal	Systemic effects - Long-term	DNEL (Derived No Effect Level) 3 mg/kg bw/day
Oral	Systemic effects - Long-term	DNEL (Derived No Effect Level) 3 mg/kg bw/day

​

Correction factors:

Correction for differences in respiratory volume (general population): 2.5

Correction for differences in bioavailability (oral -> inhalation): 0.5

Correction for differences between human and experimental exposure conditions (general population): 1

 

​Inhalation Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEC

Overall Assessment Factor:25

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required, since the susceptible window is fully covered)

AF for interspecies differences (allometric scaling):1 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:10 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​​​

Dermal Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEL

Overall Assessment Factor:100

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required, since the susceptible window is fully covered)

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:10 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​​

Oral Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEL

Overall Assessment Factor:100

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required, since the susceptible window is fully covered)

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:10 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

​

The DNELs obtained with the NOAEL from the prenatal developmental toxicity study are higher than the DNELs obtained with the NOAEL from the subacute repeated dose toxicity study.