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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.07 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
other: NAEC
Value:
24.22 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
3
AF for the quality of the whole database:
1
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.07 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
3
Dose descriptor:
other: NAEC: 24.22 mg/m3
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
For local effects, time scaling is not necessary
AF for interspecies differences (allometric scaling):
1
Justification:
The starting point has been derived in rats. However, for local effects, the mechanism in different species is supposed to be the same
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability. See discussion below.
AF for intraspecies differences:
3
Justification:
Default value proposed by ECETOC since there are no substance specific data available. See discussion below.
AF for the quality of the whole database:
1
Justification:
Default value since there is adequate data available for this endpoint.
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:
20.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic exposure
AF for interspecies differences (allometric scaling):
2.4
Justification:
The starting point has been derived in rabbits.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability. See discussion below.
AF for intraspecies differences:
5
Justification:
Default value proposed by ECETOC since there are no substance specific data available. See discussion below.
AF for the quality of the whole database:
1
Justification:
Default value since there is adequate data available for this endpoint.
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

The pattern of identified uses described for phenoxyethanol includes short-term peak exposure by inhalation and the dermal route as well as long-term repeated exposure by inhalation and the dermal route. In the case of short-term exposure, it is not possible to derive a DNEL for systemic effects, since local irritation on mucous membranes, e. g. eye and respiratory tract, are the leading effects. Therefore, appropriate risk management measures will be identified.

Long-term dermal exposure - systemic effects

The starting point is a NOAEL of 500 mg/kg bw/d obtained from a subchronic dermal study with rabbits (The Dow Chemical Company, 1986 and Breslin et al., 1991). In this study, no treatment-related effects were observed on body weights, organ weights, haematologic and clinical chemistry parameters, or gross and histopathologic examinations. Although it is indicated from chronic studies in rat and mouse that the hemolytic effects induced by phenoxyethanol are of adaptive character (see IUCLID chapter 7.5), the 10-day gavage study in rabbits (Breslin et al., 1991) or the dermal developmental toxicity study in rabbits (Scortichini et al., 1987) should not be used to set up values for risk assessment on systemic toxicity as it was shown in an in vitro study that rabbits are highly sensitive for haemolysis when compared to other species: high sensitivity -mice>rabbits>rat>dog>man – low sensitivity (BASF AG, 2007). Humans are even less sensitive than the rat for which data show that at the limit dose no haemolysis occurs (BASF AG, 2002). Additionally, the mechanism of detoxification of 2-phenoxyethanol is well investigated. The capacity to detoxify phenoxyethanol to phenoxyacetic acid is highest in humans compared to animal species (humans>rat>mouse>rabbit). Hence, an assessment factor of 1 (instead of 2.5) for remaining uncertainties was used in risk assessment of systemic effects induced by phenoxyethanol.

The overall assessment factor for derivation of the long-term dermal DNEL from the subchronic dermal study is 24 (allometric scaling: 2.4; intraspecies differences: 5; time-extrapolation (subchronic to chronic): 2). A recently developed physiologically-based pharmacokinetic (PBPK) model of phenoxyethanol and its main metabolite phenoxyacetic acid shows that the overall assessment factor of 25 is sufficient for human risk assessment of systemic effects induced by phenoxyethanol in animal studies (Troutman, JA, Rick, DL, Stuard, SB, Fisher, J, Bartels, MJ, Development of a Physiologically-Based Pharmacokinetic Model of 2-Phenoxyethanol and its Metabolite Phenoxyacetic Acid in Rats and Humans to Address Toxicokinetic Uncertainty in Risk Assessment, Regulatory Toxicology and Pharmacology (2015), doi: 10.1016/j.yrtph.2015.07.012). The overall assessment factor for workers using EChA-recommended default factors is close to the uncertainty factor of 25 recommended by Troutman et al, and in light of the fact that dermal exposure of workers will be further reduced by using appropriate risk management measures, a long-term dermal DNEL for workers of 20.8 mg/kg bw/d is considered to be valid to protect from systemic effects after dermal exposure.

Long-term inhalation exposure - local effects

The starting point is a NOAEC of 48.2 mg/m3 obtained from a subacute inhalation study in rats focusing on effects on the respiratory tract (BASF AG, 2007). Because of differences in exposure conditions between experimental animals and workers, the starting point needs to be modified according to ECHA Guidance R8 (2012), chapter 8.4.2. Thus, the point of departure (PoD) was modified using the NOAEC of 48.2 mg/m3 and the respective factors to extrapolate from experimental exposure (6h/d) to worker exposure (8h/d) and assuming light activity, resulting in a PoD of 24.2 mg/m3. Furthermore, an assessment factor of 3 (according to ECETOC TR110) was used to reflect additional intraspecies differences. Due to the fact that the leading toxic effect was an irritation of the upper respiratory tract, which is a concentration- but not time-dependent effect, further time extrapolation was not performed (REACh TGD (p.28 "Time scaling is not appropriate when the toxic effect is mainly driven by the exposure concentration (as for irritation)."). It is furthermore considered that the respiratory irritation is induced by phenoxyethanol-aerosol interception by the upper respiratory mucosa (which leads to locally high concentrations of phenoxyethanol), but not by phenoxyethanol-vapor. Saturated phenoxyethanol-vapor exists at about 50 mg/m3 (8.7 ppm), this concentration reflects the NOAEC determined in the subacute study. At higher concentrations phenoxyethanol exists mainly as droplet aerosol. Respiratory irritation was observed only at concentrations, where phenoxyethanol was present as aerosol. An increase of the respiratory irritation over time is not expected for vapors, hence, the DNEL of 8.07 mg/m3 (1.4 ppm), at which no phenoxyethanol-aerosol is available, is considered to be valid to protect from local effects at the respiratory tract. This long-term inhalation DNEL for local effects which is deduced from a subacute inhalation study in rats takes into account irritation effects in the upper respiratory tract. Therefore, this value is also considered valid for the acute and long-term DNEL since effects, e. g. acute irritation or systemic, are not expected at this concentration.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.41 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
other: NAEC
Value:
12.05 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.41 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor:
other: NAEC: 12.05 mg/m3
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
For local effects, time scaling is not necessary.
AF for interspecies differences (allometric scaling):
1
Justification:
The starting point has been derived in rats. However, for local effects, the mechanism in different species is supposed to be the same.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability. See discussion below.
AF for intraspecies differences:
5
Justification:
Default value proposed by ECETOC since there are no substance specific data available. See discussion below.
AF for the quality of the whole database:
1
Justification:
Default value since there is adequate data available for this endpoint.
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:
10.42 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic exposure
AF for interspecies differences (allometric scaling):
2.4
Justification:
The starting point has been derived in rabbits.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability. See discussion below
AF for intraspecies differences:
10
Justification:
Default value proposed by ECETOC since there are no substance specific data available. See discussion below
AF for the quality of the whole database:
1
Justification:
Default value since there is adequate data available for this endpoint.
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:
9.23 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
BMDL10
Value:
369 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
BMLD10 derived from a chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
The starting point has been derived in rats.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability. See discussion below
AF for intraspecies differences:
10
Justification:
Default value proposed by ECETOC since there are no substance specific data available. see discussion below
AF for the quality of the whole database:
1
Justification:
Default value since there is adequate data available for this endpoint.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.23 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
BMDL10
Value:
369 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default value
AF for interspecies differences (allometric scaling):
4
Justification:
The starting point has been derived in rats.
AF for other interspecies differences:
1
Justification:
In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability. See discussion below
AF for intraspecies differences:
10
Justification:
Default value proposed by ECETOC since there are no substance specific data available. See discussion below
AF for the quality of the whole database:
1
Justification:
Default value since there is adequate data available for this endpoint

General Population - Hazard for the eyes

Additional information - General Population

Short- and long-term oral exposure - systemic effects

The starting point is a BMDL10 of 369 mg/kg bw/d determined by combining reliable data from a subchronic and chronic oral (drinking water) study in rats (JBRC, 2003 and JBRC, 2007). This BMDL10 of 369 mg/kg bw corresponds to the NOAEL from the subchronic drinking water study and lies between the LOAEL of 510 mg/kg/day and the NOAEL of 248 mg/kg/day of the chronic study. Therefore, a dose of 369 mg/kg/day has been used as point of departure in the derivation of the DNEL. This long-term oral BMDL10 represents at the same time a worst case for short-term oral exposure.

The overall assessment factor for derivation of the long-term dermal DNEL from the BMDL10 is 40 (allometric scaling: 4; intraspecies differences: 10). An assessment factor of 1 (instead of 2.5) for remaining uncertainties was used in risk assessment of systemic effects induced by phenoxyethanol, because the mechanism of detoxification of 2-phenoxyethanol is well investigated and the capacity to detoxify phenoxyethanol to phenoxyacetic acid is highest in humans compared to animal species (humans>rat>mouse>rabbit). A recently developed physiologically-based pharmacokinetic (PBPK) model of phenoxyethanol and its main metabolite phenoxyacetic acid shows that the overall assessment factor of 25 is sufficient for human risk assessment of systemic effects induced by phenoxyethanol in animal studies (Troutman et al 2015; reference see above). The overall assessment factor for the general population using EChA-recommended default factors is clearly above the uncertainty factor of 25 recommended by Troutman et al, thus, a long-term oral DNEL for the general population of 9.2 mg/kg bw/d is considered to be valid to protect from systemic effects after oral exposure.

Long-term dermal exposure - systemic effects

The starting point is a NOAEL of 500 mg/kg bw/d obtained from a subchronic dermal study with rabbits (The Dow Chemical Company, 1986 and Breslin et al., 1991). In this study, no treatment-related effects were observed on body weights, organ weights, haematologic and clinical chemistry parameters, or gross and histopathologic examinations. Although it is indicated from chronic studies in rat and mouse that the hemolytic effects induced by phenoxyethanol are of adaptive character (see IUCLID chapter 7.5), the 10-day gavage study in rabbits (Breslin et al., 1991) or the dermal developmental toxicity study in rabbits (Scortichini et al., 1987) should not be used to set up values for risk assessment on systemic toxicity as it was shown in an in vitro study that rabbits are highly sensitive for haemolysis when compared to other species: high sensitivity -mice>rabbits>rat>dog>man – low sensitivity (BASF AG, 2007). Humans are even less sensitive than the rat for which data show that at the limit dose no haemolysis occurs (BASF AG, 2002). Additionally, the mechanism of detoxification of 2-phenoxyethanol is well investigated. The capacity to detoxify phenoxyethanol to phenoxyacetic acid is highest in humans compared to animal species (humans>rat>mouse>rabbit). Hence, an assessment factor of 1 (instead of 2.5) for remaining uncertainties was used in risk assessment of systemic effects induced by phenoxyethanol.

The overall assessment factor for derivation of the long-term dermal DNEL from the subchronic dermal study is 48 (allometric scaling: 2.4; intraspecies differences: 10; time-extrapolation (subchronic to chronic): 2). A recently developed physiologically-based pharmacokinetic (PBPK) model of phenoxyethanol and its main metabolite phenoxyacetic acid shows that the overall assessment factor of 25 is sufficient for human risk assessment of systemic effects induced by phenoxyethanol in animal studies (Troutman et al 2015; reference see above). The overall assessment factor for the general population using EChA-recommended default factors is clearly above the uncertainty factor of 25 recommended by Troutman et al, thus, a long-term dermal DNEL for the general population of 10.4 mg/kg bw/d is considered to be valid to protect from systemic effects after dermal exposure.

Long-term inhalation exposure - local effects

The starting point is a NOAEC of 48.2 mg/m3 obtained from a subacute inhalation study in rats focussing on effects on the respiratory tract (BASF AG, 2007). Because of differences in exposure conditions between experimental animals and the general population, the starting point needs to be modified according to ECHA Guidance R8 (2012), chapter 8.4.2. Thus, the point of departure (PoD) was calculated using the NOAEC of 48.2 mg/m3 and the respective factors to extrapolate from experimental exposure (6h/d) to consumer exposure (24h/d), resulting in a PoD of 12.1 mg/m3. Furthermore, an assessment factor of 5 (according to ECETOC TR110) was used to reflect additional intraspecies differences. Due to the fact that the leading toxic effect was an irritation of the upper respiratory tract, which is a concentration- but not time-dependent effect, further time extrapolation was not performed (REACh TGD (p.28 "Time scaling is not appropriate when the toxic effect is mainly driven by the exposure concentration (as for irritation)."). It is furthermore considered that the respiratory irritation is induced by phenoxyethanol-aerosol interception on the upper respiratory mucosa (which leads to locally high concentrations of phenoxyethanol), but not by phenoxyethanol-vapor. Saturated phenoxyethanol-vapor exists at about 50 mg/m3 (8.7 ppm), this concentration reflects the NOAEC determined in the subacute study. At higher concentrations phenoxyethanol exists mainly as droplet aerosol. Respiratory irritation was observed only at concentrations, where phenoxyethanol was present as aerosol. An increase of the respiratory irritation over time is not expected for vapors, hence, the DNEL of 2.4 mg/m3 (0.42 ppm), at which no phenoxyethanol-aerosol is available, is considered to be valid to protect from local effects at the respiratory tract. The long-term inhalation DNEL for local effects which is derived from a subacute inhalation study in rats which has shown irritation effects in the upper respiratory tract. The derived DNEL value of 2.4 mg/m3 (0.42 ppm) is considered to be protective for acute and long-term effects, as acute and long-term effects are not expected at this concentration.