Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
979.53 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
138.89 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA Guidance document “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health”, May 2008.

 

The oral NOAEL of 100000 ppm in feed, corresponding to 10000 mg/kg bw/day, derived from a 4-week feeding study with the structurally related substance erucamide (CAS 112-84-5; WARF, 1960) in rats, served as basis for the extrapolations. Starting point for the DNEL derivation is a corrected NOAEL for oral exposure of 1666.67 mg/kg bw/d. This value is based on the conversion of the subacute oral NOAEL from the 4-week study to a chronic one by an assessment factor of 6.

 

Within the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, it was demonstrated by the VCI Working group “Toxicology” in 2008 by evaluation of the published EU Risk Assessments (by April 2008) that in most cases a factor of 2 is disproportionate because availability after oral intake is comparable to that after inhalation intake.

 

The Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameteres include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure, etc.

 

Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption. Considering the log Kow of 5.8 reflecting the lipophilic nature of oleamide a better oral absorption than inhalation absorption is very likely. Unless valid data suggests that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. Route-to-route extrapolation within the rat was based on the respiratory volume of 0.8 L/min/kg bw, leading to an inhalation volume of 1.15 m³/kg bw for a time period of 24 hours (0.38 m³/kg bw for 8 hours), reflecting continuous exposure via the environment.

 

In order to convert an oral NOAEL derived from rats into a dermal NAEL, the differences in absorption between routes as well as differences in dermal absorption between species have to be accounted for. Actual dermal absorption in man is to be expected much lower, as human skin is much thicker and less penetrable than rat skin (ECETOC, 1993. Percutaneous absorption. Monograph No. 20). Therefore, the corrected oral NOAEL was adapted to dermal absorption by inclusion of a very conservative factor of 1, assuming a dermal absorption of 100% via the intact skin represents a sufficient conservative approach.

 

Since short-term exposure scenarios will not be assessed due to a lack of acute toxicity, only long-term DNELs for workers and the general population are derived. The oral route is not relevant for workers, therefore it will only be assessed for the general population.

It is assumed that use of default AFs recommended by ECHA will in most cases lead to DNELs that are not scientifically justified and consequently lead to unrealistically low exposure levels for establishing safe use. Moreover, ECHA provides limited scientific justification for the default AFs; it is supposed they have relied on ‘standard approaches’ used by other organisations. In contrast, ECETOC based its AFs on a critical review of the literature, in consequence they should be used preferentially.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
289.86 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
83.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
83.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA Guidance document “Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health”, May 2008.

 

The oral NOAEL of 100000 ppm in feed, corresponding to 10000 mg/kg bw/day, derived from a 4-week feeding study with the structurally related substance erucamide (CAS 112-84-5; WARF, 1960) in rats, served as basis for the extrapolations. Starting point for the DNEL derivation is a corrected NOAEL for oral exposure of 1666.67 mg/kg bw/d. This value is based on the conversion of the subacute oral NOAEL from the 4-week study to a chronic one by an assessment factor of 6.

 

Within the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, it was demonstrated by the VCI Working group “Toxicology” in 2008 by evaluation of the published EU Risk Assessments (by April 2008) that in most cases a factor of 2 is disproportionate because availability after oral intake is comparable to that after inhalation intake.

 

The Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameteres include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure, etc.

 

Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption. Considering the log Kow of 5.8 reflecting the lipophilic nature of oleamide a better oral absorption than inhalation absorption is very likely. Unless valid data suggests that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. Route-to-route extrapolation within the rat was based on the respiratory volume of 0.8 L/min/kg bw, leading to an inhalation volume of 1.15 m³/kg bw for a time period of 24 hours (0.38 m³/kg bw for 8 hours), reflecting continuous exposure via the environment.

 

In order to convert an oral NOAEL derived from rats into a dermal NAEL, the differences in absorption between routes as well as differences in dermal absorption between species have to be accounted for. Actual dermal absorption in man is to be expected much lower, as human skin is much thicker and less penetrable than rat skin (ECETOC, 1993. Percutaneous absorption. Monograph No. 20). Therefore, the corrected oral NOAEL was adapted to dermal absorption by inclusion of a very conservative factor of 1, assuming a dermal absorption of 100% via the intact skin represents a sufficient conservative approach.

 

Since short-term exposure scenarios will not be assessed due to a lack of acute toxicity, only long-term DNELs for workers and the general population are derived. The oral route is not relevant for workers, therefore it will only be assessed for the general population.

It is assumed that use of default AFs recommended by ECHA will in most cases lead to DNELs that are not scientifically justified and consequently lead to unrealistically low exposure levels for establishing safe use. Moreover, ECHA provides limited scientific justification for the default AFs; it is supposed they have relied on ‘standard approaches’ used by other organisations. In contrast, ECETOC based its AFs on a critical review of the literature, in consequence they should be used preferentially.