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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
0.21 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
0.42 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.25 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):
24
Modified dose descriptor starting point:
NOAEL
Value:
150 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:
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, default assessment factor of 2 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 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. 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. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the rat versus humans is 4.
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
AF for intraspecies differences:
3
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, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.
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.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

DNEL derivation (inhalation)

Referring to long-term exposure, the most relevant NOAEC was obtained from a 2 year chronic inhalation study conducted with mice; the NOAEC was reported to be 0.0625 ppm, corresponding to about 0.25 mg/m3. In fact, at the 2 year NTP inhalation study in rats and mice, considerable non-neoplastic lesions in the noses of both species (resembling those in the short-term studies) were demonstrated. At 0.5 mg/m3 a statistically significant increased incidence in squamous metaplasia in the respiratory epithelium of the nose in female mice was observed. At 0.25 mg/m3, the lowest dose level tested, also a slight, but non-significant increase was observed. The severity of the effect was however minimal. Furthermore, at 0.25 mg/m3 a statistically significant, increased incidence of hyaline degeneration of the respiratory epithelium of the nose in female mice was observed. This finding was however not dose-related. The biological relevance of hyaline degeneration for humans is, however, unknown, whereas hyaline degeneration also occurs spontaneously during ageing in mice. Based on this information, squamous metaplasia of the respiratory epithelium which was statistically significantly increased in incidence at 0.5 mg/m3 was considered as the critical effect for long-term exposure. Nonetheless as a worst-case approach, 0.25 mg/mg3 has been used for the derivation of the DNEL.

 

Assessment of olfactory and chemesthetic sensitivity (feel, sensory irritation) to vapour of glutaraldehyde in young adult females volunteers revealed 50% detection of feel in the eye and nose after 15 minutes of exposure at 0.39 and 0.47 ppm, respectively. Psychometric functions for feel showed much sharper dependence on concentration than those for odor (Cain, 2007). In a study conducted in order to investigate work practices and glutaraldehyde exposure in relation to symptoms and lung function, a questionnaire was given to 76 nurses, and exposed nurses (n = 38) also completed lung function tests and visual analogue scales before and after a work session in which glutaraldehyde exposure occurred. Exposure values above the exposure limit (0.10 ppm) were found for all exposure control methods except for the enclosed washing machine. Skin symptoms were 3.6 times more likely to be reported by exposed workers. No evidence of a dose-response relationship for respiratory symptoms or lung function was found (Waters 2003).

 

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.

 

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, local effects on the respiratory tract are related to the deposited dose per unit of surface area, i.e. concentration rather than the total dose. In addition, 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 a chronic toxicity study is available, default assessment factor of 1 is to be applied, as a standard procedure.

 

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, since local effects are independent of the basal metabolic rate, allometric scaling should not be applied (allometric scaling factor of 1). 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. 

 

According to ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, if no substance-specific data are available, a chemical-specific remaining uncertainties factor or the default factor of 2.5 should be applied. Since data is available for two species (rat and mice) and as a result the most sensitive species can be selected, the AF for other interspecies differences has been already implicitly taken into account.

 

According to ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used. However, the predominant effect after inhalation is due to the corrosive properties of the substance and human epidemiology studies (Waters 2003) indicate that these effects are only to be expected at concentrations exceeding 0.1 ppm (ca. 0.42 mg/m3). As this value exceeds the NOAEC in mice no additional AF for intraspecies differences is needed.

 

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.

 

The resulting DNEL (0.25 mg/m3) is comparable with the MAK-value of 0.21 mg/m3 derived by the working group establishment of MAK values of the Deutsche Forschungsgemeinschaft.

Glutaraldehyde is considered to be a respiratory sensitizer. However, for inhalation exposure of workers respiratory irritation has been identified as the key toxicological concern for GA: in sub-chronic inhalation studies with GA vapour, concentration dependent mucosal irritation was found in the anterior regions of the nose in rats and mice exposed to concentrations down to 0.125 mL/m3. At 0.0625 mL/m3 those effects were not observed. Therefore, the threshold value (MAK, AGW) was set to 0.05 mL/m3, which is the basis for risk assessment via the inhalation route of exposure. Since the MAK-value represents the most conservative approach this value will be used for risk assessment.

General Population - Hazard via inhalation route

Systemic effects

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

Local effects

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

General Population - Hazard via dermal route

Systemic effects

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

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidace and ECETOC TR No.86 (2003)
Overall assessment factor (AF):
20
Dose descriptor starting point:
NOAEL
Value:
3.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The DNEL long-term for oral route - systemic for thegeneral population is derived from the NOAEL of 3.5 mg/kg bw/d, obtained in the chronic oral carcinogenicity study in rats (OECD 451, GLP-compliant) in which the test substance was administered via the drinking water.

The NOAELcorr is calculated as follows:

NOAELcorr = 3.5 mg/kg bw/d * (40% / 100%) * (7 d/wk / 7 d/wk) = 1 .4 mg/kg bw/d, with:

- NOEAL = 3.5 mg/kg bw/d

- absorption (oral, rat) = 40 % (toxicokinetic data)

- absorption (oral, human) = 100 % (default)

- experimental exposure time = 7 days/week

- default exposure time of the general population = 7 days/week.

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:
1
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 general population 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’. As the calculation is based on a chronic toxicity study, no further factor has to be considered.
AF for interspecies differences (allometric scaling):
4
Justification:
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 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. 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. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the rat versus humans is 4.
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.
AF for intraspecies differences:
5
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, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.
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:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

As no use of/contact with glutaraldehyde is expected for the general population, there is no need in determining DNELs for exposure risk assessment.

However, the systemic long-term oral DNEL for the general population is necessary for the assessment of indirect exposure of humans via the environment (ECHA GD R.16, v 3.0, Feb 2016).