Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 072 mg/m³
AF for dose response relationship:
1
Justification:
When the starting point for the DNEL delineation is a NOAEC, the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
2
Justification:
The default assessment factor according to Guidance Document R.8 (ECHA, 2012) for exposure duration from subacute exposure to chronic risk assessment is 6, but justified compound specific deviations are possible. In this case comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar. Consequently, the factor of 2 used in this derivation can be considered conservative. A second argument to deviate from the default values is the starting point used. In this study benzyl alcohol is well-tolerated by male and female rats with no adverse effects at any exposure concentration, consequently, the NOAEC of 1072 mg/m³ used as a starting point is conservative because no LOAEC is identified. A third argument is the conservatism and consistency of the derived DNEL compared with potential DNEL derived by independent calculations using the oral studies or ADI value as starting points. See discussionfor further details.
AF for interspecies differences (allometric scaling):
1
Justification:
Already covered with correction of dose-descriptor; corrected NOAEC for workers 8h/day exposed: 539 mg/m³
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
5
Justification:
Default factor for intraspecies differences for workers.
AF for the quality of the whole database:
1
Justification:
The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
110 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
8 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):
50
Modified dose descriptor starting point:
NOAEL
DNEL value:
400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No studies on repeated dermal exposure are available for

benzyl alcohol. Based on experimental data a high dermal penetration and resorption has to be assumed (DFG, 2006, MAK value documentation on benzyl alcohol, The MAK Collection for Occupational Health and Safety, Wiley Online Library). Since a rapid and almost quantitative resorption of benzyl alcohol after oral exposure has been shown, route to route-extrapolation from repeated oral dose studies (subchronic and chronic) is justified.

AF for dose response relationship:
1
Justification:
When the starting point for the DNEL delineation is a NOAEL, the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
1
Justification:
comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar.
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for differences rat vs. human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
5
Justification:
Default factor for intraspecies differences for workers.
AF for the quality of the whole database:
1
Justification:
The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
low hazard (no threshold derived)

Additional information - workers

General considerations:

Experts of the WHO and FAO have defined and derived an Acceptable Daily Intake (ADI) value which accounts for the amount of a substance which can be ingested daily by consumers over lifetime without appreciable risk. In the case of the benzoate category, including benzyl alcohol, this value is 0-5 mg/kg bw (WHO 1997). This ADI was confirmed by e.g. EFSA in 2012 and the European Commission (SCF) in 2002.

Workers

Definition of starting points for calculation:

With regard to acute inhalation toxicity only slight and transient effects were observed in a study according to OECD TG 403 on rats at the maximum technically achievable concentration (4178 mg/m³, 4 hour-exposure to aerosol; Bayer AG 1990). These effects were concluded to be effects related to sensory irritation (reflex bradypnoea). No indication of a respiratory damaging property was found in the study. A second acute inhalation study on rats revealed no signs of test substance related intoxication at all (Elf Atochem SA 1993).

In a recently performed subacute (4 weeks) aerosol inhalation study concentrations of up to 1072 mg/m³ were well-tolerated by male and female rats with no adverse effects at any exposure concentration (Roper 2010).

Altogether, a NOAEC of 1072 mg/m³ can be set as point of departure DNEL-derivation for repeated inhalation exposure – systemic effects, and no hazard is concluded for local effects after inhalation exposure.

Acute oral exposure revealed an LD50 of 1610 mg/kg (Bayer AG 1978). Only unspecific clinical signs were observed (e.g. sedation, side and prone-position, bloody eyes and reduction of general condition). Repeated oral exposure was studied on rats and mice in studies of the US National Toxicology Programme (NTP TR 343, 1989). Although clinical pathology was not performed in these studies a high degree of certainty is concluded from these studies, as they are reviewed from a peer review panel for NTP. The NOAEL from these studies was for rats 400 mg/kg, based on a chronic (2 year, carcinogenicity study) and a subchronic (13 weeks, dose range-finder) study. At the LOAEL of 800 mg/kg (13-week study) signs of neurotoxicity (staggering, laboured breathing, lethargy), reduced body weight and histopathological effects mainly in the brain were reported. Gross necropsy and histopathology revealed no apparent compound-related non-neoplastic responses in the chronic rat study. Thus, 400 mg/kg can be considered a NOAEL from these studies. The respective mice studies (2 year and 13 weeks) revealed a NOAEL of 200 mg/kg. At the LOAEL of 400 mg/kg (13-week study) a slight decreased body weight gain was reported and at 800 mg/kg additionally staggering after dosing during the first and second weeks of the studies was observed. No compound-related histopathological effects were found in the mice study, indicating adaptive response to the compound and no adverse effect at 400 or 800 mg/kg. Therefore, the rat NOAEL of 400 mg/kg in the rat studies was considered to be relevant as a starting point for DNEL calculation since more pronounced effects occurred, i.e. clinical signs of neurotoxicity and histopathological effects compared to mice. None of the 2 year studies revealed indications of a carcinogenic potential.

Neither of the repeated oral toxicity studies nor any of the studies on skin irritation or skin sensitisation indicate that significant local effects result from exposure to the benzyl alcohol. On the contrary, a moderate potential for eye irritation was observed in the respective studies. In conclusion, a NOAEL of 400 mg/kg can be set as point of departure for DNEL-derivation for repeated dermal exposure – systemic effects, and no hazard is concluded for local effects after dermal exposure, as the toxicological mode of action is not characterized by significant local effects.

No potential for skin sensitisation was concluded for benzyl alcohol based on the available data.

Summarizing, DNELs for systemic toxicity after inhalation and dermal exposure have to be delineated for workers. No hazard for local effects is identified for inhalation or skin contact.

DNEL systemic, long-term for workers for hazard via inhalation route:

For rats exposed to the substance 6 h/d 5 d/w for 4 weeks NOAEC = 1072 mg/m³

Correction of dose-descriptors (Guidance Document R.8, Figure R. 8-2, ECHA, 2012):

In case of workers 8h/day exposed:

exp. cond. rat

corrected NOAEC = inhalatory NOAEC * ————————

exp. cond. human

corrected NOEAC = inhalatory NOAEC * 6h/d * (8h/d)-1 * 6.7 m³ * (10 m³)-1

corrected NOAEC = inhalatory NOAEC * 0.75 * 0.67 = 539 mg/m³

According to Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the corrected NOAEC and are summarized in the table below:

 Assessment  Assessment Factor
For interspecies differences rat vs. human (allometric scaling)  1 (Already covered with correction of dose-descriptor)
For remaining interspecies differences 2.5 
For intraspecies differences (workers)  5
Differences in duration of exposure (subacute to chronic)  2 (The default assessment factor according to Guidance Document R.8 (ECHA, 2012) for exposure duration from subacute exposure to chronic risk assessment is 6, but justified compound specific deviations are possible. In this case comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar. Consequently, the factor of 2 used in this derivation can be considered conservative. A second argument to deviate from the default values is the starting point used. In this study benzyl alcohol is well-tolerated by male and female rats with no adverse effects at any exposure concentration, consequently, the NOAEC of 1072 mg/m³ used as a starting point is conservative because no LOAEC is identified. A third argument is the conservatism and consistency of the derived DNEL compared with potential DNEL derived by independent calculations using the oral studies or ADI value as starting points (see discussion)).
Dose-response relationship  1
Quality of whole Database  1
Overall Assessment Factor  25

DNEL systemic, long-term for workers for hazards via inhalation route = NOAEC corr./ Overall AF

DNEL systemic, long-term for workers for hazards via inhalation route = 22 mg/m³

This DNEL should be considered conservative based on the following considerations:

The derived DNEL is consistent with an alternative derivation based on the oral toxicity studies. Taking into account a starting point of 400 mg/kg/day and an overall assessment factor of 50 (10 for interspecies differences and 5 for intraspecies differences in worker, conservative default absorption oral/inhalation of 0.5, worker body weight of 70 kg and a respiratory volume of 10 m³ per shift, the DNEL derived from oral studies would be 28 mg/kg/day.

(400 mg/kg /50) x 0.5 x (70/10) = 28 mg/m³.

The derived DNEL is also consistent and should be considered conservative when compared with an alternative derivation method using the above mentioned 5 mg/kg/day ADI for the general population as a starting point and taking into account a worker body weight of 70 kg, a respiratory volume of 10 m³ per shift, conservative default absorption oral/inhalation of 0.5 and a factor 10/5 for interspecies variability in worker compared to the general population.

5 x (70/10) x 0.5 x 2 = 35 mg/m³

According to Guidance Document R.8., Appendix R. 8-8, Box 6 (ECHA, 2012) a DNELacute can be set based on the long-term inhalation DNEL by multiplying with a factor of 1-5. Since only effects related to sensory irritation were concluded from acute inhalation studies a factor of 5 was chosen here.

Therefore a DNEL systemic, acute for workers for hazards via inhalation route of 110 mg/m³ is derived.

DNEL systemic, long-term for workers for hazard via dermal route:

For rats exposed to the substance for 13 weeks and 2 years NOAEL = 400 mg/kg bw/d

Correction of dose-descriptors (Guidance Document R.8, Example B. 5, ECHA, 2012):

In case of workers 8h/day exposed:

ABSoral-rat **

corrected dermal NOAEL = oral NOAEL * ——————

ABSderm-human

corrected dermal NOAEL = 400 mg/kg

**According to the Guidance Document R.8. (ECHA, 2012) in general it can be assumed that dermal absorption will not be higher than oral absorption and no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation.

According to Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the corrected NOAEL and are summarized in the table below:

Assessment  Assessment Factor
For interspecies differences rat vs. human(allometric scaling)  4
For remaining interspecies differences  2.5
For intraspecies differences (workers)  5
Differences in duration of exposure (chronic study)  1 (Comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar).
Dose-response relationship  1
Quality of whole Database  1
Overall Assessment Factor  50

DNEL systemic, long-term for workers for hazards via dermal route = NOAEL corr./ Overall AF

DNEL systemic, long-term for workers for hazards via dermal route = 8 mg/kg bw/d

This DNEL is conservative and consistent with the ADI of 5 mg/kg/day for the general population

According to Guidance Document R.8., Appendix R. 8-8, Box 6 (ECHA, 2012) a DNELacute can be set based on the long-term inhalation DNEL by multiplying with a factor of 1-5. A factor of 5 should provide sufficient safety and is applied here since no hazard is concluded for local effects after dermal exposure and acute toxicity is low (LD50 = 1620 mg/kg) after oral exposure.

Therefore, a DNEL systemic, acute for workers for hazards via dermal route of 40 mg/kg is derived.

The DNELs systemic acute/long-term for workers cover also reproductive toxicity/fertility, as no indications for effects on reproductive toxicity/fertility were seen in the dataset for benzyl alcohol or for any other of the group members. Furthermore, the DNELs systemic acute/long-term for workers cover also developmental toxicity, as no indications for teratogenicity were found in any of the developmental toxicity studies available for the group (benzyl alcohol, benzoic acid, sodium benzoate) and effects on development were only observed in gavage studies in the presence of clear maternal toxicity with NOAEL above the starting point used for DNEL calculation (OECD 2004: “In conclusion: The compounds exhibit no developmental toxicity and a NOEL of 500 mg/kg/day can be established for developmental effects for this group of substances”.

A comprehensive document providing discussion and justification for the conclusions drawn also in this chapter is attached to this endpoint summary.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 072 mg/m³
AF for dose response relationship:
1
Justification:
When the starting point for the DNEL delineation is a NOAEC, the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
2
Justification:
The default assessment factor according to Guidance Document R.8 (ECHA, 2012) for exposure duration from subacute exposure to chronic risk assessment is 6, but justified compound specific deviations are possible. In this case comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar. Consequently, the factor of 2 used in this derivation can be considered conservative. A second argument to deviate from the default values is the starting point used. In this study benzyl alcohol is well-tolerated by male and female rats with no adverse effects at any exposure concentration, consequently, the NOAEC of 1072 mg/m³ used as a starting point is conservative because no LOAEC is identified. A third argument is the conservatism and consistency of the derived DNEL compared with potential DNEL derived by independent calculations using the oral studies or ADI value as starting points. See discussionfor further details.
AF for interspecies differences (allometric scaling):
1
Justification:
Already covered with correction of dose-descriptor; corrected NOAEC for the general population : 268 mg/m³
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
Default factor for intraspecies differences for the general population.
AF for the quality of the whole database:
1
Justification:
The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
27 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
4 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):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No studies on repeated dermal exposure are available for benzyl alcohol. Based on experimental data a high dermal penetration and resorption has to be assumed (DFG, 2006, MAK value documentation on benzyl alcohol, The MAK Collection for Occupational Health and Safety, Wiley Online Library). Since a rapid and almost quantitative resorption of benzyl alcohol after oral exposure has been shown, route to route-extrapolation from repeated oral dose studies (subchronic and chronic) is justified.
AF for dose response relationship:
1
Justification:
When the starting point for the DNEL delineation is a NOAEL, the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
1
Justification:
comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar.
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for differences rat vs. human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
Default factor for intraspecies differences for the general population.
AF for the quality of the whole database:
1
Justification:
The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

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:
4 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):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
400 mg/kg bw/day
AF for dose response relationship:
1
Justification:
When the starting point for the DNEL delineation is a NOAEL, the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
1
Justification:
comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar.
AF for interspecies differences (allometric scaling):
4
Justification:
Default factor for differences rat vs. human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
Default factor for intraspecies differences for the general population.
AF for the quality of the whole database:
1
Justification:
The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

General considerations:

Experts of the WHO and FAO have defined and derived an Acceptable Daily Intake (ADI) value which accounts for the amount of a substance which can be ingested daily by consumers over lifetime without appreciable risk. In the case of the benzoate category, including benzyl alcohol, this value is 0-5 mg/kg bw (WHO 1997). This ADI was confirmed by e.g. EFSA in 2012 and the European Commission (SCF) in 2002.

General population

Definition of starting points for calculation:

With regard to acute inhalation toxicity only slight and transient effects were observed in a study according to OECD TG 403 on rats at the maximum technically achievable concentration (4178 mg/m³, 4 hour-exposure to aerosol; Bayer AG 1990). These effects were concluded to be effects related to sensory irritation (reflex bradypnoea). No indication of a respiratory damaging property was found in the study. A second acute inhalation study on rats revealed no signs of test substance related intoxication at all (Elf Atochem SA 1993).

In a recently performed subacute (4 weeks) aerosol inhalation study concentrations of up to 1072 mg/m³ were well-tolerated by male and female rats with no adverse effects at any exposure concentration (Roper 2010).

Altogether, a NOAEC of 1072 mg/m³ can be set as point of departure DNEL-derivation for repeated inhalation exposure – systemic effects, and no hazard is concluded for local effects after inhalation exposure.

Acute oral exposure revealed an LD50 of 1610 mg/kg (Bayer AG 1978). Only unspecific clinical signs were observed (e.g. sedation, side and prone-position, bloody eyes and reduction of general condition). Repeated oral exposure was studied on rats and mice in studies of the US National Toxicology Programme (NTP TR 343, 1989). Although clinical pathology was not performed in these studies a high degree of certainty is concluded from these studies, as they are reviewed from a peer review panel for NTP. The NOAEL from these studies was for rats 400 mg/kg, based on a chronic (2 year, carcinogenicity study) and a subchronic (13 weeks, dose range-finder) study. At the LOAEL of 800 mg/kg (13-week study) signs of neurotoxicity (staggering, laboured breathing, lethargy), reduced body weight and histopathological effects mainly in the brain were reported. Gross necropsy and histopathology revealed no apparent compound-related non-neoplastic responses in the chronic rat study. Thus, 400 mg/kg can be considered a NOAEL from these studies. The respective mice studies (2 year and 13 weeks) revealed a NOAEL of 200 mg/kg. At the LOAEL of 400 mg/kg (13-week study) a slight decreased body weight gain was reported and at 800 mg/kg additionally staggering after dosing during the first and second weeks of the studies was observed. No compound-related histopathological effects were found in the mice study, indicating adaptive response to the compound and no adverse effect at 400 or 800 mg/kg. Therefore, the rat NOAEL of 400 mg/kg in the rat studies was considered to be relevant as a starting point for DNEL calculation since more pronounced effects occurred, i.e. clinical signs of neurotoxicity and histopathological effects compared to mice. None of the 2 year studies revealed indications of a carcinogenic potential.

Neither of the repeated oral toxicity studies nor any of the studies on skin irritation or skin sensitisation indicate that significant local effects result from exposure to the benzyl alcohol. On the contrary, a moderate potential for eye irritation was observed in the respective studies. In conclusion, a NOAEL of 400 mg/kg can be set as point of departure for DNEL-derivation for repeated dermal exposure – systemic effects, and no hazard is concluded for local effects after dermal exposure, as the toxicological mode of action is not characterized by significant local effects.

No potential for skin sensitisation was concluded for benzyl alcohol based on the available data.

Summarizing, DNELs for systemic toxicity after inhalation and dermal exposure have to be delineated for workers. No hazard for local effects is identified for inhalation or skin contact.

DNEL systemic, long-term for general population for hazard via inhalation route:

For rats exposed to the substance 6 h/d 5 d/w for 13 weeks NOAEC = 1072 mg/m³

Correction of dose-descriptors (Guidance Document R.8, Figure R. 8-2, ECHA, 2012):

In case of the general population:

exp. cond. rat

corrected NOAEC = inhalatory NOAEC * ————————

exp. cond. human

corrected NOEAC = inhalatory NOAEC * 6h/d * (24h/d)-1

corrected NOAEC = 268 mg/m³

According to Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the corrected NOAEC and are summarized in the table below:

 Assessment  Assessment Factor
For interspecies differences rat vs. human (allometric scaling)  1 (Already covered with correction of dose-descriptor)
For remaining interspecies differences 2.5 
For intraspecies differences (gen. pop.)  10
Differences in duration of exposure (subacute to chronic)  2 (The default assessment factor according to Guidance Document R.8 (ECHA, 2012) for exposure duration from subacute exposure to chronic risk assessment is 6, but justified compound specific deviations are possible. In this case comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar. Consequently, the factor of 2 used in this derivation can be considered conservative. A second argument to deviate from the default values is the starting point used. In this study benzyl alcohol is well-tolerated by male and female rats with no adverse effects at any exposure concentration, consequently, the NOAEC of 1072 mg/m³ used as a starting point is conservative because no LOAEC is identified. A third argument is the conservatism and consistency of the derived DNEL compared with potential DNEL derived by independent calculations using the oral studies or ADI value as starting points (see discussion)).
Dose-response relationship  1
Quality of whole Database  1
Overall Assessment Factor  50

DNEL systemic, long-term for general population for hazards via inhalation route = NOAEC corr./ Overall AF

DNEL systemic, long-term for general population for hazards via inhalation route = 5.4 mg/m³

According to Guidance Document R.8., Appendix R. 8-8, Box 6 (ECHA, 2012) a DNELacute can be set based on the long-term inhalation DNEL by multiplying with a factor of 1-5. Since only effects related to sensory irritation were concluded from acute inhalation studies a factor of 5 was chosen here.

Therefore a DNEL systemic, acute for general population for hazards via inhalation route of 27 mg/m³ is derived.

DNEL systemic, long-term for the general population for hazard via oral and dermal route:

For rats exposed to the substance for 13 weeks or 2 years NOAEL = 400 mg/kg bw/d

Correction of dose-descriptors (Guidance Document R.8, Example B. 5, ECHA, 2012):

In case of the general population:

ABSoral-rat **

corrected dermal NOAEL = oral NOAEL * ——————

ABSderm-human

corrected dermal NOAEL = 400 mg/kg

**According to the Guidance Document R.8. (ECHA, 2012) in general it can be assumed that dermal absorption will not be higher than oral absorption and no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation.

According to Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the corrected NOAEL and are summarized in the table below:

Assessment  Assessment Factor
For interspecies differences rat vs. human(allometric scaling)  4
For remaining interspecies differences  2.5
For intraspecies differences (ge. pop.)  10
Differences in duration of exposure (chronic study)  1 (Comprehensive data on mice and rats are available from oral sub-chronic and chronic studies demonstrating that toxicity is not depending on time of exposure. The NOAEL in oral sub-chronic and chronic studies are similar).
Dose-response relationship  1
Quality of whole Database  1
Overall Assessment Factor  100

DNEL systemic, long-term for general population for hazards via oral and dermal route = NOAEL corr./ Overall AF

DNEL systemic, long-term for general population for hazards via oral and dermal route = 4 mg/kg bw/d

According to Guidance Document R.8., Appendix R. 8-8, Box 6 (ECHA, 2012) a DNELacute can be set based on the long-term inhalation DNEL by multiplying with a factor of 1-5. A factor of 5 should provide sufficient safety and is applied here, since no hazard is concluded for local effects after dermal exposure and acute toxicity is low (LD50 = 1620 mg/kg) after oral exposure..

Therefore, a DNEL systemic, acute for general population for hazards via oral and dermal route of 20 mg/m³ is derived.

The DNELs systemic acute/long-term for the general population cover also reproductive toxicity/fertility, as no indications for effects on reproductive toxicity/fertility were seen in the dataset for benzyl alcohol or for any other of the group members. Furthermore, the DNELs systemic acute/long-term for the general population cover also developmental toxicity, as no indications for teratogenicity were found in any of the developmental toxicity studies available for the group (benzyl alcohol, benzoic acid, sodium benzoate) and effects on development were only observed in the presence of clear maternal toxicity with NOAEL above the starting point used for DNEL calculation (OECD 2004: “In conclusion: The compounds exhibit no developmental toxicity and a NOEL of 500 mg/kg/day can be established for developmental effects for this group of substances”.

A comprehensive document providing discussion and justification for the conclusions drawn also in this chapter is attached to this endpoint summary.