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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:
16.3 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):
10
Dose descriptor starting point:
NOAEC
Value:
245 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
163 mg/m³
Explanation for the modification of the dose descriptor starting point:

The relevant dose-descriptor for long-term exposure via the inhalation route is the NOAEC of 41 ppm (245 mg/m3) from a 13-week vapor inhalation study in rats with EGHE, corresponding to 325 mg/m3 for the test substance. This value has been corrected for exposure duration (6h – 8h), differences between respiratory rates under standard conditions and under conditions of light activity (6.7 vs 10 m3).

NOAEC corrected = NOAEC x 6h/8h x 6.7 m3/10 m3 = 325 mg/m3 x6/8 x 6.7/10 = 163,3 mg/m3.

AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
2
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-chronic toxicity study is available, a default assessment factor of 2 is to be applied, as a standard procedure.
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed.
In 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, a similar approach is followed. The rationale here is that allometric scaling should not be applied because in humans inhalation rate is 4-fold lower compared to rats according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.
AF for other interspecies differences:
1
Justification:
Since the most sensitive effect identified in the 90 d inhalation study was an increase in liver weights which can be regarded as an unspecific effect not significantly differing between species, a remaining difference factor of 2.5 seems to be unreasonable. Therefore a factor of 1 is applied.
AF for intraspecies differences:
5
Justification:
Default factor
AF for the quality of the whole database:
1
Justification:
The physical chemical properties of the two analogues DEGHE and EGHE suggest an absorption rate of 100 % for the inhalation route (EGHE) and oral route (DEGHE). Therefore, the bioavailability and toxicological potency of the two substances can be assumed as similar. This assumption is supported by the findings of the13-week vapor inhalation study in rats with EGHE and the Combined Repeated Dose Toxicity Study oral with the Reproduction/Developmental Toxicity Screening Test (OECD 422) with DEGHE. The most sensitive effects consistently observed in both studies were increases in liver weights and decreased body weights throughout the study period. These findings show that both substances affect the same target organs and show the same spectrum of effects after oral and inhalation exposure. Taking all these facts into account, a DNEL derivation for DEGHE with the dose descriptor for long-term exposure from a 13-week vapor inhalation study in rats with the structural analogue EGHE must be considered as reasonable and valid. Therefore, an assessment factor > 1 for the quality of the whole database (according to the ECHA Guidance Document, Chapter R.8: Completeness and consistency of available data; Reliability of alternative data) is not necessary and was not applied in addition to the used assessment factors for the respective DNEL derivations.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
50 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):
40
Dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
2
Justification:
default factor for subchronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.25. This results in a default allometric scaling factor for the rat when compared with humans, namely 4.
AF for other interspecies differences:
1
Justification:
No adverse effects were observed in the dermal study. After oral and inhalation uptake, the most sensitive effect identified was an increase in liver weights, which can be regarded as an unspecific effect not significantly differing between species. A remaining difference factor of 2.5 seems to be unreasonable.
AF for intraspecies differences:
5
Justification:
Default factor
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainities
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.1 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):
20
Dose descriptor starting point:
NOAEC
Value:
245 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
81.25 mg/m³
Explanation for the modification of the dose descriptor starting point:

As the relevant dose-descriptor for long-term exposure via the inhalation route, the NOAEC of 41 ppm (245 mg/m3) from a 13-week vapor inhalation study in rats with EGHE (read-across) was identified, corresponding to 325 mg/m3 for the test substance.The only test substance-related effect observed in this study was a dose-dependent increase in liver weights which was not reversed after 4 weeks of recovery in animals exposed to 71 ppm. No effects on red blood cells or histologic changes in the liver or kidney were noted up to the highest concentration tested (71 ppm or 425 mg/m3). Therefore, the NOAEC of 41 ppm has been used as the critical dose descriptor to derive the DNEL. This value has been corrected for exposure duration (6h - 24h).

NOAEC corrected = NOAEC x 6h/24h = 325 mg/m3 x 6/24 = 81.25 mg/m3

AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
2
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-chronic toxicity study is available, a default assessment factor of 2 is to be applied, as a standard procedure.
AF for interspecies differences (allometric scaling):
1
Justification:
n accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed.
In 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, a similar approach is followed. The rationale here is that allometric scaling should not be applied because in humans inhalation rate is 4-fold lower compared to rats according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.
AF for other interspecies differences:
1
Justification:
Since the most sensitive effect identified in the 90 d inhalation study was an increase in liver weights which can be regarded as an unspecific effect not significantly differing between species, a remaining difference factor of 2.5 seems to be unreasonable. Therefore a factor of 1 is applied.
AF for intraspecies differences:
10
Justification:
Default factor
AF for the quality of the whole database:
1
Justification:
The physical chemical properties of the two analogues DEGHE and EGHE suggest an absorption rate of 100 % for the inhalation route (EGHE) and oral route (DEGHE). Therefore, the bioavailability and toxicological potency of the two substances can be assumed as similar. This assumption is supported by the findings of the13-week vapor inhalation study in rats with EGHE and the Combined Repeated Dose Toxicity Study oral with the Reproduction/Developmental Toxicity Screening Test (OECD 422) with DEGHE. The most sensitive effects consistently observed in both studies were increases in liver weights and decreased body weights throughout the study period. These findings show that both substances affect the same target organs and show the same spectrum of effects after oral and inhalation exposure. Taking all these facts into account, a DNEL derivation for DEGHE with the dose descriptor for long-term exposure from a 13-week vapor inhalation study in rats with the structural analogue EGHE must be considered as reasonable and valid. Therefore, an assessment factor > 1 for the quality of the whole database (according to the ECHA Guidance Document, Chapter R.8: Completeness and consistency of available data; Reliability of alternative data) is not necessary and was not applied in addition to the used assessment factors for the respective DNEL derivations.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 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):
80
Dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
2
Justification:
default factor for subchronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.25. This results in a default allometric scaling factor for the rat when compared with humans, namely 4.
AF for other interspecies differences:
1
Justification:
No adverse effects were observed in the dermal study. After oral and inhalation uptake, the most sensitive effect identified was an increase in liver weights, which can be regarded as an unspecific effect not significantly differing between species. A remaining difference factor of 2.5 seems to be unreasonable.
AF for intraspecies differences:
10
Justification:
default factor
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
1.25 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):
240
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As the relevant dose-descriptor for long-term exposure via the dermal route, the NOAEL form the Reproductive Screening Study (OECD422) is taken as the starting point. Since liver effects have been observed at the high dose of 1000 mg/kg/d in this study (no effects on reproduction perfomance has been noted), the NOAEL was set at 300 mg/kg/d.

AF for dose response relationship:
1
Justification:
n accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.
AF for differences in duration of exposure:
6
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, a default assessment factor of 6 is to be applied, as a standard procedure.
AF for interspecies differences (allometric scaling):
4
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.25. This results in a default allometric scaling factor for the rat when compared with humans, namely 4.
AF for other interspecies differences:
1
Justification:
Since the most sensitive effect identified in the OECD422 Screening study with the test substance was an increase in liver weights which can be regarded as an unspecific effect not significantly differing between species, a remaining difference factor of 2.5 seems to be unreasonable.
AF for intraspecies differences:
10
Justification:
Default factor
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database).
When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population