Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
42.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Dose descriptor starting point:
BMDL10
Value:
369 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
858.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
Starting BMDL10 = 369 mg/kg bw/day. Converted to Dose descriptor starting point according to ECHA guidance (route to route). 369/0.38 x 0.67 = 651 mg/m3. This value is further converted for the molecular weight difference between the target (Di-EPh) and source (EPh) chemicals: 182.2/138.2 x 651 = 858.3 mg/m3
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:
5
Justification:
ECHA default
AF for the quality of the whole database:
1
Justification:
ECHA Default
AF for remaining uncertainties:
1
Justification:
Read across is used to address the 90-day and developmental toxicity endpoints. However the data on both the registered substance and the analogue are consistent and the trends across the database indicate that Di-EPh is less toxic than EPh. Therefore there is minimal remaining uncertainty and no additional assessment is proposed.
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:
10.6 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
3
Dose descriptor:
NOAEC
Value:
31.9 mg/m³
AF for dose response relationship:
1
Justification:
Single study with a clear dose response for the effect. Default value
AF for differences in duration of exposure:
1
Justification:
the critical effect is a local irritation effect. No correction for study duration is required due to the effect being more closely associated with concentration in the respiratory tract. For additional justification refer to section 3.3.2 of ECETOC TR 110
AF for interspecies differences (allometric scaling):
1
Justification:
Inhalation data are the basis for the DNEL therefore no interspecies factor is required and the mechanism of the local effect in different species is supposed to be the same
AF for other interspecies differences:
1
Justification:
The key effect is local irritation. This is a local effect and the physiology of the rat upper respiratory tract and the fact that they are obligate nose breathers makes rats more sensitive to this type of effect compared to humans. As such no additional factor of 2.5 is considered appropriate.
AF for intraspecies differences:
3
Justification:
ECETOC factor is used - refer to ECETOC TR 110. See discussion below.
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
The key study is on the read across substance EPh. There appear to be minimal differences between the irritation potential of Di-EPh and EPh as such it is predicted that they will have similar irritation potential in the upper respiratory tract following an aerosol exposure.
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:
27.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
24
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
659.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Starting NOAEL = 500 mg/kg bw/day. This dose descriptor value was converted for the molecular weight difference between the target (Di-EPh) and source (EPh) chemicals: 182.2/138.2 x  500 = 659.2 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
ECHA default, sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
2.4
Justification:
rabbit data used as the starting point
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:
ECHA default
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
Read across is used to address the 90-day and developmental toxicity endpoints. However the data on both the registered substance and the analogue are consistent and the trends across the database indicate that Di-EPh is less toxic than EPh. Therefore there is minimal remaining uncertainty and no additional assessment is proposed.
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

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.

Long-term inhalation 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 with EPh (JBRC, 2003 and JBRC, 2007). An oral study is being used for long-term systemic inhalation since exposure will be to vapor and the only repeat dose inhalation study was performed using aerosol. The 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. Based on this, a dose of 369 mg/kg/day has been used as the basis of the point of departure in the derivation of the DNEL. This was converted from oral to inhalation according to ECHA guidance (369/0.38 x 0.67 = 651 mg/m3) and then molecular weight corrected (182.2/138.2 x 651 = 858.3).  Therefore, the point of departure for the derivation of the DNEL for Di-EPh long-term systemic inhalation exposure will be 858.3 mg/m3.

The overall assessment factor for derivation of the long-term inhalation DNEL from the converted BMDL10 is 20 (allometric scaling: 4; intraspecies differences: 5). An assessment factor of 1 (instead of 2.5) for remaining uncertainties was used in risk assessment of systemic effects induced by Di-EPh, because the mechanism of detoxification of EPh (which the studies are read across from) is well investigated and the capacity to detoxify phenoxyethanol (EPh) to phenoxyacetic acid is highest in humans compared to animal species (humans>rat>mouse>rabbit). Di-EPh undergoes the same detoxification mechanism to the acetic acid metabolite. Also, based on the toxicity of the E-series glycol ethers, Di-EPh has a lower order of toxicity than EPh.

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, therefore resulting in a value of 24.2 mg/m3. This value was then corrected for molecular weight due to read across from EPh to Di-EPh (182.2/138.2 x 24.2) resulting in a PoD of 31.9 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)."). 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. There appears to be minimal differences between the irritation potential of Di-EPh and EPh as such it is predicted that they will have similar irritation potential in the upper respiratory tract, hence, the DNEL of 10.6 mg/m3 Di-EPh is considered to be valid to protect from local effects at the respiratory tract.

The long term inhalation local effects DNEL is protective of short term effect so no additional DNEL for acute effects is necessary.

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). The NOAEL was then corrected for molecular weight due to read across from EPh to Di-EPh (182.2/138.2 x 500) resulting in a PoD of 659.2 mg/kg bw/day. 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 EPh are of adaptive character (see IUCLID chapter7.5), 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 by EPh 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 EPh is well investigated. The capacity to detoxify EPh to phenoxyacetic acid is highest in humans compared to other animal species (humans>rat>mouse>rabbit) and sinceDi-EPh undergoes the same detoxification mechanism to the acetic acid metabolite, humans are considered less sensitive. Also, based on the toxicity of the E-series glycol ethers, Di-EPh has a lower order of toxicity than EPh. Hence, an assessment factor of 1 (instead of 2.5) for remaining uncertainties was used in risk assessment of systemic effects induced by Di-EPh.

Also, based on the toxicity of the E-series glycol ethers, Di-EPh has a lower order of toxicity than EPh.

The overall assessment factor for derivation of the long-term dermal DNEL from the converted NOAEL is 24 (duration of exposure: 2; allometric scaling: 2.4; intraspecies differences: 5).

Default assumptions for bioavailability:

100% oral

100% inhalation

100% dermal

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Dose descriptor starting point:
BMDL10
Value:
369 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
858.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
Starting BMDL10 = 369 mg/kg bw/day. Converted to Dose descriptor starting point according to ECHA guidance (route to route). 369/0.38 x 0.67 = 651 mg/m3.  This value is further converted for the molecular weight difference between the target (Di-EPh) and source (EPh) chemicals: 182.2/138.2 x  651 = 858.3 mg/m3
AF for dose response relationship:
1
Justification:
ECHA default
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 was derived in rat.
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:
ECHA default
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
Read across is used to address the 90-day and developmental toxicity endpoints. However the data on both the registered substance and the analogue are consistent and the trends across the database indicate that Di-EPh is less toxic than EPh. Therefore there is minimal remaining uncertainty and no additional assessment is proposed.
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:
3.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Value:
15.9 mg/m³
AF for dose response relationship:
1
Justification:
Single study with a clear dose response for the effect. Default value
AF for differences in duration of exposure:
1
Justification:
the critical effect is a local irritation effect. No correction for study duration is required due to the effect being more closely associated with concentration in the respiratory tract. For additional justification refer to section 3.3.2 of ECETOC TR 110
AF for interspecies differences (allometric scaling):
1
Justification:
Inhalation data are the basis for the DNEL therefore no interspecies factor is required and the mechanism of the local effect in different species is supposed to be the same
AF for other interspecies differences:
1
Justification:
The key effect is local irritation. This is a local effect and the physiology of the rat upper respiratory tract and the fact that they are obligate nose breathers makes rats more sensitive to this type of effect compared to humans. As such no additional factor of 2.5 is considered appropriate.
AF for intraspecies differences:
5
Justification:
ECETOC factor is used - refer to ECETOC TR 110. See discussion below.
AF for the quality of the whole database:
1
Justification:
ECHA Default
AF for remaining uncertainties:
1
Justification:
The key study is on the read across substance EPh. There appear to be minimal differences between the irritation potential of Di-EPh and EPh as such it is predicted that they will have similar irritation potential in the upper respiratory tract following an aerosol exposure.
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:
13.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
48
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
659.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Starting NOAEL = 500 mg/kg bw/day. This dose descriptor value was converted for the molecular weight difference between the target (Di-EPh) and source (EPh) chemicals: 182.2/138.2 x 500 = 659.2 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA default
AF for differences in duration of exposure:
2
Justification:
ECHA default, sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
2.4
Justification:
rabbit data used as the starting point
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:
ECHA default
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
Read across is used to address the 90-day and developmental toxicity endpoints. However the data on both the registered substance and the analogue are consistent and the trends across the database indicate that Di-EPh is less toxic than EPh. Therefore there is minimal remaining uncertainty and no additional assessment is proposed.
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:
12.2 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):
40
Dose descriptor starting point:
BMDL10
Value:
369 mg/kg bw/day
Modified dose descriptor starting point:
BMDL10
Value:
486.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Starting BMDL10 = 369 mg/kg bw/day. This value was converted for the molecular weight difference between the target (Di-EPh) and source (EPh) chemicals: 182.2/138.2 x 369 = 486.5 mg/m3
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:
rat data used as the starting point
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:
ECHA default
AF for the quality of the whole database:
1
Justification:
ECHA default
AF for remaining uncertainties:
1
Justification:
Read across is used to address the 90-day and developmental toxicity endpoints. However the data on both the registered substance and the analogue are consistent and the trends across the database indicate that Di-EPh is less toxic than EPh. Therefore there is minimal remaining uncertainty and no additional assessment is proposed.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Long-term inhalation 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 with EPh (JBRC, 2003 and JBRC, 2007). An oral study is being used for long-term systemic inhalation since exposure will be to vapor and the only repeat dose inhalation study was performed using aerosol. The 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. Based on this, a dose of 369 mg/kg/day has been used as the basis of the point of departure in the derivation of the DNEL. This was converted from oral to inhalation according to ECHA guidance (369/0.38 x 0.67 = 651 mg/m3) and then molecular weight corrected (182.2/138.2 x 651 = 858.3).  Therefore, the point of departure for the derivation of the DNEL for Di-EPh long-term systemic inhalation exposure will be 858.3 mg/m3.

The overall assessment factor for derivation of the long-term inhalation DNEL from the converted 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 Di-EPh, because the mechanism of detoxification of EPh (which the studies are read across from) is well investigated and the capacity to detoxify phenoxyethanol (EPh) to phenoxyacetic acid is highest in humans compared to animal species (humans>rat>mouse>rabbit). Di-EPh undergoes the same detoxification mechanism to the acetic acid metabolite. Also, based on the toxicity of the E-series glycol ethers, Di-EPh has a lower order of toxicity than EPh.

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 (24h/d) and assuming light activity, therefore resulting in a value of 12.1 mg/m3. This value was then corrected for molecular weight due to read across from EPh to Di-EPh (182.2/138.2 x 12.1) resulting in a PoD of 15.9 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)."). 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. There appears to be minimal differences between the irritation potential of Di-EPh and EPh as such it is predicted that they will have similar irritation potential in the upper respiratory tract, hence, the DNEL of 3.2 mg/m3 Di-EPh is considered to be valid to protect from local effects at the respiratory tract.

The long term inhalation local effects DNEL is protective of short term effect so no additional DNEL for acute effects is necessary.

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). The NOAELwas then corrected for molecular weight due to read across from EPh to Di-EPh (182.2/138.2 x 500) resulting in a PoD of 659.2 mg/kg bw/day. 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 EPh are of adaptive character (see IUCLID chapter7.5), 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 by EPh 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 EPh is well investigated. The capacity to detoxify EPh to phenoxyacetic acid is highest in humans compared to other animal species (humans>rat>mouse>rabbit) and since Di-EPh undergoes the same detoxification mechanism to the acetic acid metabolite, humans are considered less sensitive. Also, based on the toxicity of the E-series glycol ethers, Di-EPh has a lower order of toxicity than EPh. Hence, an assessment factor of 1 (instead of 2.5) for remaining uncertainties was used in risk assessment of systemic effects induced by Di-EPh.

The overall assessment factor for derivation of the long-term dermal DNEL from the converted NOAEL is 48 (duration of exposure: 2; allometric scaling: 2.4; intraspecies differences: 10).

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 was molecular weight corrected (182.2/138.2 x 369 = 486.5).  Therefore, the point of departure for the derivation of the DNEL for Di-EPh long-term systemic inhalation exposure will be 486.5 mg/kg bw/day.

The overall assessment factor for derivation of the long-term oral 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 Di-EPh, because the mechanism of detoxification of EPh (which the studies are read across from) is well investigated and the capacity to detoxify phenoxyethanol (EPh) to phenoxyacetic acid is highest in humans compared to animal species (humans>rat>mouse>rabbit). Di-EPh undergoes the same detoxification mechanism to the acetic acid metabolite. Also, based on the toxicity of the E-series glycol ethers, Di-EPh has a lower order of toxicity than EPh.

Default assumptions for bioavailability:

100% oral

100% inhalation

100% dermal