Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
23.3 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10.2
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
See Discussion
AF for differences in duration of exposure:
3.4
Justification:
See Discussion
Justification:
Local effects - allometric scaling not relevant
AF for other interspecies differences:
1
Justification:
See Discussion
AF for intraspecies differences:
3
Justification:
See Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
79.3 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
See Discussion
Justification:
Local effects - allometric scaling not relevant
AF for other interspecies differences:
1
Justification:
See Discussion
AF for intraspecies differences:
3
Justification:
See Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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

The repeated dose toxicological study identified a local effect in the upper respiratory tract as the key effect driving LOEC for propyl-propionate. There were no significant systemic effects in any of the studies available on this substance or the others in the category. Therefore the only DNEL considered appropriate is that for Local effects, via inhalation (short term and long term).

The starting point for the DNEL derivation is the LOEC of 50 ppm (238 mg/m3) for local effects in the 28 -day repeated dose inhalation study on propyl propionate.

For Workers, this is converted to take into consideration exposure differences and differences in respiratory rate.

Adjusted starting point = 238 * 6/8 * 6.7/10 = 120 mg/m3

Assessment factors to be used:

Intra species variation (Worker): 3 (taken from ECETOC report on assessment factors and consistent with the approach taken by SCOEL in setting OELs for irritants)

Allometric scaling - N/A due to local effect

Other differences - according to the guidance either a factor of 1 or of 2.5 is appropriate depending on the nature of the effects. In this case the effect is in the upper respiratory tract and involved the degeneration of the olfactory epithelia. This is an irritant effect.

Irritating effects on the respiratory epithelium, and atrophy/degeneration of the nasal and olfactory epithelium are critical effects consistently observed with various ester derivatives (butyl acrylate, methyl acrylate, methylmethacrylate, methyl acetate, ethyl acrylate, lactate esters). These effects are thought to be related to a mechanism common between esters which involves hydrolysis by unspecific carboxylesterases located in the nasal/olfactory epithelium to release corresponding acids and alcohols. However, there are well-known differences in the anatomy and physiology of the nasal and olfactory epithelia between rats and humans. Although some variability in the experimental results of carboxylesterase activity exists, depending on the methodology and the substrate used, there is a general trend supporting lower nasal esterase activity towards esters from human tissues compared to those from rat tissues. (Ref. Frederick C. B. et al. Use of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry comparisons of ester vapours. Toxicol Appl Pharmacol. 183(1): 23-40, 2002). The respiratory local effects should therefore be of a lower concern in the human situation. These effects are thought to be overpredictive in the rat model as compared to humans, because of the morphological and physiological differences.

Therefore the factor for other differences will be 1

Dose response: 1

Database quality: 1

Duration of exposure:

For acute/short term effects: 1 - the LOEC is from a 28 day study.

For Chronic effects: 3.4 this is taken from the publication of Batke, M., et al., Evaluation of time extrapolation factors based on the database RepDose. Toxicol. Lett. (2011), doi:10.1016/j.toxlet.2011.05.1030.

Total Factor = 10.2 (Chronic) and 3 (Acute)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
15.9 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20.4
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
See Discussion
AF for differences in duration of exposure:
3.4
Justification:
See Discussion
Justification:
Local effects - allometric scaling not relevant
AF for other interspecies differences:
1
Justification:
See Discussion
AF for intraspecies differences:
6
Justification:
See Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
54.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
6
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
Justification:
See Discussion
Justification:
Local effects - allometric scaling not relevant
AF for other interspecies differences:
1
Justification:
See Discussion
AF for intraspecies differences:
6
Justification:
See Discussion
AF for the quality of the whole database:
1
Justification:
See Discussion
AF for remaining uncertainties:
1
Justification:
See Discussion

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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 repeated dose toxicological study identified a local effect in the upper respiratory tract as the key effect driving the LOEC for propyl-propionate. There were no significant systemic effects in any of the studies available on this substance or the others in the category. Therefore the only DNEL considered appropriate is that for Local effects, via inhalation (short term and long term).

The starting point for the DNEL derivation is the LOEC of 50 ppm (238 mg/m3) for local effects in the 28 -day inhalation study on propyl-propionate.

For General Population, this is converted to take into consideration exposure differences and differences in respiratory rate.

Adjusted starting point = 238 * 6/24 = 59.5 mg/m3

Assessment factors to be used:

Intra species variation (General Pop): 6 (taken from ECETOC report on assessment factors and consistent with the approach taken by SCOEL in setting OELs for irritants)

Allometric scaling - N/A due to local effect

Other differences - according to the guidance either a factor of 1 or of 2.5 is appropriate depending on the nature of the effects. In this case the effect is in the upper respiratory tract and involved the degeneration of the olfactory epithelia. This is an irritant effect.

Irritating effects on the respiratory epithelium, and atrophy/degeneration of the nasal and olfactory epithelium are critical effects consistently observed with various ester derivatives (butyl acrylate, methyl acrylate, methylmethacrylate, methyl acetate, ethyl acrylate, lactate esters). These effects are thought to be related to a mechanism common between esters which involves hydrolysis by unspecific carboxylesterases located in the nasal/olfactory epithelium to release corresponding acids and alcohols. However, there are well-known differences in the anatomy and physiology of the nasal and olfactory epithelia between rats and humans. Although some variability in the experimental results of carboxylesterase activity exists, depending on the methodology and the substrate used, there is a general trend supporting lower nasal esterase activity towards esters from human tissues compared to those from rat tissues. (Ref. Frederick C. B. et al. Use of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry comparisons of ester vapours. Toxicol Appl Pharmacol. 183(1): 23-40, 2002). The respiratory local effects should therefore be of a lower concern in the human situation. These effects are thought to be overpredictive in the rat model as compared to humans, because of the morphological and physiological differences.

Therefore the factor for other differences will be 1

Dose response: 1

Database quality: 1

Duration of exposure:

For acute/short term effects: 1 - the NOEL is from a 90-day study.

For Chronic effects: 3.4 this is taken from the publication of Batke, M., et al., Evaluation of time extrapolation factors based on the database RepDose. Toxicol. Lett. (2011), doi:10.1016/j.toxlet.2011.05.1030.

Total Factor = 20.4 (Chronic) and 6 (Acute)