Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
59.9 mg/m³
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC (2003; 2010)
Overall assessment factor (AF):
6
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.2 mg/kg bw/day
DNEL related information
DNEL derivation method:
other: ECETOC (2003; 2010)
Overall assessment factor (AF):
24
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:
medium hazard (no threshold derived)

Additional information - workers

Hazard Overview and DNEL Derivation - Workers

Acute toxicity:

Phenyl ethyl alcohol is acutely hazardous after ingestion (oral LD50 = 1603 mg/kg bw) but not following contact with skin (dermal LD50=2535 mg/kg bw).

Irritation:

The skin and eye irritation potential of Phenyl ethyl alcohol have been evaluated in the rabbit. There was no evidence of skin irritation, however it was irritating to eye. The available information is insufficient to characterise the dose-response relationship for this finding, hence no DNEL will be derived and qualitative risk characterisation will be applied to this endpoint.

Sensitisation:

Phenyl ethyl alcohol was not a skin sensitiser when tested using the local lymph node assay, hence no DNEL is required for this endpoint.

Repeated dose toxicity:

The sub-chronic dermal NOAEL for Phenyl ethyl alcohol in the rat is 0.5 ml/kg bw/day, equivalent to 510 mg/kg bw/d. This value will be used directly for derivation of a dermal DNEL, with route-to-route extrapolation used for the development of DNELs covering inhalation and oral routes of exposure.

Genetic toxicity:

Phenyl ethyl alcohol was not mutagenic or clastogenic when tested in vitro, hence no DNEL is required.

Reproductive / developmental toxicity:

No fetal effects were apparent in litters from pregnant rats exposed on days 7-20 of pregnancy and followed to post-natal day 21, with a NOAEL of 439 mg/kg bw/d (the highest dose tested).

DNEL for acute toxicity – oral

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute hazard leading to classification has been identified, with the long-term DNEL considered normally sufficient when an acute hazard is present. Based on a corrected repeated dose oral NOAEL of 204 mg/kg bw/d (see section dealing with General Population) and an assessment factor of 24 (reflecting principles detailed for the dermal route (Workers), below), a long-term oral DNEL of 8.5 mg/kg bw/d results for Phenylethyl alcohol. This value will also be used for the characterisation of acute oral hazards.

DNEL for repeated dose toxicity – systemic effects

Mode of Action Considerations:

For studies relevant to the setting of DNELs, a threshold mode of action is assumed.

Modification of Relevant Dose Descriptors to the Correct Starting Point :

Relevant dose descriptors have been developed for the different endpoints and routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). The values are provided below. For potential dermal and inhalation exposures, route-to-route extrapolation from the oral NOAEL value was performed. Dermal uptake has been assumed to be 40%, and oral and inhalation absorption assumed to be 100%, for both rats and humans for the purpose of these calculations.

Dermal route:

No modification required, NOAEL = 510 mg/kg bw/d.

Inhalation route:

Corrected inhalatory NOAEC = [1/sRV-rat] x [ ABSdermal-rat/ABSinh-human] x [sRV-human/wRV]

Corrected inhalatory NOAEC = 510 mg/kg/day x [1/0.38] x [40/100] x [6.7/10]

Corrected inhalatory NOAEC = 359.7 mg/m3

Oral route:

Not relevant for this population.

Application of Assessment Factors to the Corrected Dose Descriptors and Calculation of DNELs

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC 2003; 2010). In this case, the NOAEL is based on a BWG effect that was caused by a palatability issue and not by oral toxicity. Therefore, the inter/intra species difference is expected to be very low, which justifies the use of the ECETOC AF values.

ECETOC (2003). Derivation of Assessment Factors for Human Health Risk Assessment, Technical Report 86, Brussels, February 2003.

ECETOC (2010). Guidance on assessment factors to derive a DNEL. Technical report No. 110, ECETOC, Brussels, October 2010.

Dermal route:

Assessment factors relevant to the dermal route are as follows:

 

Interspecies

4

Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2003; 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2003; 2010).

Intraspecies

3

An informed assessment factor of 3 is proposed (ECETOC, 2003; 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered acceptable since the population exposed in the workplace is highly homogeneous and the health of the work force is typically good (healthy worker effect) while metabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since alternative pathways of elimination are often present (ECETOC, 2003, 2010). The analysis of assessment factors conducted by ECETOC also showed thatestimates of the upper 95thpercentile of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states supports use of an assessment factor of 3 to account for intraspecies variability within workers.

Exposure duration

2

A factor of 2 is appropriate since the results were obtained from a sub-chronic study.

 

Worker dermal DNEL calculation:

510 / 24 = 21.2 mg/kg bw/d

Inhalation route:

Assessment factors relevant to the dermal route are as follows:

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements (ECETOC, 2003; 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already in the intraspecies assessment factor (ECETOC, 2003; 2010).

Intraspecies

3

An informed assessment factor of 3 is proposed (ECETOC, 2003; 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered acceptable since the population exposed in the workplace is highly homogeneous and the health of the work force is typically good (healthy worker effect) while metabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since alternative pathways of elimination are often present (ECETOC, 2003, 2010). The analysis of assessment factors conducted by ECETOC also showed thatestimates of the upper 95thpercentile of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states supports use of an assessment factor of 3 to account for intraspecies variability within workers.

Exposure duration

2

A factor of 2 is appropriate since the results were obtained from a sub-chronic study.

 

Worker inhalation DNEL calculation:

359.7 / 6 = 59.9 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.7 mg/m³
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC (2003; 2010)
Overall assessment factor (AF):
10
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.7 mg/kg bw/day
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC (2003; 2010)
Overall assessment factor (AF):
40
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:
5.1 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC (2003; 2010)
Overall assessment factor (AF):
40
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.1 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: REACH guidance and ECETOC (2003; 2010)
Justification:
ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute hazard leading to classification has been identified, with the long-term DNEL considered normally sufficient when an acute hazard is present. A long-term oral DNEL of 5.1 mg/kg bw/d has been derived for Phenylethyl alcohol (see below). This value will also be used for the characterisation of acute oral hazards.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Hazard Overview and DNEL Derivation - General Population

Acute toxicity:

Phenyl ethyl alcohol is acutely hazardous after ingestion (oral LD50 = 1603 mg/kg bw) but not following contact with skin (dermal LD50 =2535 mg/kg bw). ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute hazard leading to classification has been identified. Hence an acute DNEL will be considered only for the oral route of exposure.

Irritation:

The skin and eye irritation potential of Phenyl ethyl alcohol have been evaluated in the rabbit. There was no evidence of skin irritation, however it was irritating to eye. The available information is insufficient to characterise the dose-response relationship for this finding, hence no DNEL will be derived and qualitative risk characterisation will be applied to this endpoint.

Sensitisation:

Phenyl ethyl alcohol was not a skin sensitiser when tested using the local lymph node assay, hence no DNEL is required for this endpoint.

Repeated dose toxicity:

The sub-chronic dermal NOAEL for Phenyl ethyl alcohol in the rat is 0.5 ml/kg bw/day, equivalent to 510 mg/kg bw/d. This value will be used directly for derivation of a dermal DNEL, with route-to-route extrapolation used for the development of DNELs covering inhalation and oral routes of exposure.

Genetic toxicity:

Phenyl ethyl alcohol was not mutagenic or clastogenic when tested in vitro, hence no DNEL is required.

Reproductive / developmental toxicity:

No fetal effects were apparent in litters from pregnant rats exposed on days 7-20 of pregnancy and followed to post-natal day 21, with a NOAEL of 439 mg/kg bw/d (the highest dose tested).

DNEL for acute toxicity – oral

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not required if no acute hazard leading to classification has been identified, with the long-term DNEL considered normally sufficient when an acute hazard is present. A long-term oral DNEL of 5.1 mg/kg bw/d has been derived for Phenyl ethyl alcohol (see below). This value will also be used for the characterisation of acute oral hazards.

DNEL for repeated dose toxicity – systemic effects

Mode of Action Considerations:

For studies relevant to the setting of DNELs, a threshold mode of action is assumed.

Modification of Relevant Dose Descriptors to the Correct Starting Point:

Relevant dose descriptors have been developed for the different endpoints and routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). The values are provided below. For potential dermal and inhalation exposures, route-to-route extrapolation from the oral NOAEL value was performed. Dermal uptake has been assumed to be 40%, and oral and inhalation absorption assumed to be 100%, for both rats and humans for the purpose of these calculations.

Dermal route:

No modification required, NOAEL = 510 mg/kg bw/d.

Inhalation route:

Corrected inhalatory NOAEC = [1/sRV-rat] x [ ABSdermal-rat/ABSinh-human]

Corrected inhalatory NOAEC = 510 mg/kg/day x [1/1.15] x [40/100]

Corrected inhalatory NOAEC = 177.4 mg/m3

Oral route:

Corrected oral NOAEL = NOAEL-dermal x [ ABSdermal-rat/ABSoral-human]

Corrected oral NOAEL = 510 mg/kg/day x [40/100]

Corrected oral NOAEL = 204 mg/kg bw/d

Application of Assessment Factors to the Corrected Dose Descriptors and Calculation of DNELs

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC 2003; 2010). In this case, the NOAEL is based on a BWG effect that was caused by a palatability issue and not by oral toxicity. Therefore, the inter/intra species difference is expected to be very low, which justifies the use of the ECETOC AF values.

ECETOC (2003). Derivation of Assessment Factors for Human Health Risk Assessment, Technical Report 86, Brussels, February 2003.

ECETOC (2010). Guidance on assessment factors to derive a DNEL. Technical report No. 110, ECETOC, Brussels, October 2010.

Dermal route:

Assessment factors relevant to the dermal route are as follows:

 

Interspecies

4

Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2003; 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010).

Intraspecies

5

An informed assessment factor of 3 is proposed (ECETOC, 2003; 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered acceptable sincemetabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since alternative pathways of elimination are often present (ECETOC, 2003, 2010). The analysis of assessment factors conducted by ECETOC also showed thatestimates of the upper 95thpercentile of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states supports use of an assessment factor of 3 to account for intraspecies variability.

Exposure duration

2

A factor of 2 is appropriate since the results were obtained from a sub-chronic study.

 

General population dermal DNEL calculation:

510 / 40 = 12.7 mg/kg bw/d

Oral route:

Assessment factors relevant to the oral route are as follows:

 

Interspecies

4

Assessment factor for allometric scaling from rats to humans as proposed by ECETOC (2003; 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already through the use of allometric scaling (where appropriate) and in the intraspecies assessment factor (ECETOC, 2010).

Intraspecies

5

An informed assessment factor of 3 is proposed (ECETOC, 2003; 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered acceptable sincemetabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since alternative pathways of elimination are often present (ECETOC, 2003, 2010). The analysis of assessment factors conducted by ECETOC also showed thatestimates of the upper 95thpercentile of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states supports use of an assessment factor of 3 to account for intraspecies variability.

Exposure duration

2

A factor of 2 is appropriate since the results were obtained from a sub-chronic study.

 

General population oral DNEL calculation:

204 / 40 = 5.1 mg/kg bw/d

Inhalation route:

Assessment factors relevant to the dermal route are as follows:

 

Interspecies

1

No allometric scaling is needed in case of inhalation exposure because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animal and humans breathe at a rate depending on their caloric requirements (ECETOC, 2003; 2010). No additional assessment factor is required for “remaining differences” since inter- and intraspecies variability are not independent variables, with any remaining uncertainty accounted for already in the intraspecies assessment factor (ECETOC, 2003; 2010).

Intraspecies

5

An informed assessment factor of 3 is proposed (ECETOC, 2003; 2010) based on an analysis of the available scientific literature rather than the adoption of standard defaults. This is considered acceptable sincemetabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since alternative pathways of elimination are often present (ECETOC, 2003, 2010). The analysis of assessment factors conducted by ECETOC also showed thatestimates of the upper 95thpercentile of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states supports use of an assessment factor of 3 to account for intraspecies variability.

Exposure duration

2

A factor of 2 is appropriate since the results were obtained from a sub-chronic study.

 

General population inhalation DNEL calculation:

177.4 / 10 = 17.7 mg/m3