glyoxal … %; ethandial … %

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.96 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):

12.5

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

37 mg/m³

Explanation for the modification of the dose descriptor starting point:

The DNEL is derived on basis of a chronic repeated oral toxicity study in the rat. This oral NOAEL for rats was converted to the corresponding air concentration using a standard breathing volume for the rat of 0.38 m³/kg (for 8 hours exposure of workers). The resulting air concentration was additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor derives from the inhalative volumes in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity). A correction factor for the difference between human and experimental exposure conditions was included (see "Additional Information-worker").

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

included in route to route extrapolation

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

Further toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.9 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):

0.33

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

40 µg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor:

NOAEC

Value:

0.4 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

Local effects are considered time independent.

AF for interspecies differences (allometric scaling):

1

Justification:

Local effects are independent of the basal metabolic rate, allometric scaling should not be applied.

AF for other interspecies differences:

1

Justification:

Local effects are considered species independent.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

Further toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

328 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The carcinogenic potential of Glyoxal in mice after dermal application was determined, but no NOAEL is available from this study for using as POD (Unione Carbide, 1982). In addition, data from a preliminary test conducted for the purpose of dosage estimation for a main dermal carcinogenicity study are available, which also cannot be used as POD (BRRC 45-508, 1979). Therefore, it was necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. See "Additional information-worker".

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

Further toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

1.    Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No chronic studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects. Therefore, it will be necessary to obtain a long-term inhalatory DNEL by route-to route extrapolation.

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (oral)

The NOAEL of 25 mg/kg bw/day derived from an OECD TG 453 study was used as the PoD.

Step 2: Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 25 mg/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABS oral-rat / ABS inh-human): 60/100

A 60 % oral absorption is assumed for Glyoxal from in vivo toxicokinetic studies and used for the purpose of route-to-route extrapolation. As a worst-case assumption 100 % absorption after inhalatory exposure is assumed in absence of any experimental data as recommended in TGD R8.

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 25 mg/kg bw/day× 0.6 × (1 / 0.38 m³/kg bw/day) × (6.7 m³/10 m³) × 1.4

= 37 mg/m³

Step 3: Overall AF= 12.5

Interspecies: According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF is needed when route (oral)-to route (inhalation) is applied.

Interspecies AF, remaining differences: no evidence for species differences in the general mode of action

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 1 (chronic study)

Whole database AF: 1

The repeated dose oral toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term systemic inhalation DNEL, workers = 2.96 mg/m³

Acute, systemic DNEL- exposure via inhalation (workers)

Due to the inhalative toxicity of the aerosol observed for this test item (rat 4 h; LC50=2.44 mg/L), the substance is considered to be classified for acute inhalative toxicity under Regulation (EC) No. 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776. The DNEL for acute systemic inhalation, worker was extrapolated according to the ECHA Guidance by applying the AF of 0.33.

 

DNEL, long-term systemic inhalation (2.96 mg/m3) x AF (0.33)

 

DNEL, short-term systemic inhalation = 8.9 mg/m3

 

Long term, local DNEL- exposure via inhalation (workers)

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (inhalation)

The NOAEC (local) of 0.4 mg/m³derived from an OECD TG 412 study.

Step 2: Modification into a correct starting point:  

Relevant dose descriptor (NOAEC): 0.4 mg/m³

A DNEL for local effects due to inhalatory long term exposure of Glyoxal aerosol was derived from the NOAEC of an inhalatory subacute repeated dose study (according to OECD 412; Hoechst 1995). Male and female Wistar rats were subjected to test concentrations of 0.4, 2.0 and 10 mg/m³. A systemic toxicity of Glyoxal aerosol after repeated inhalation exposure could not be evidenced. Local effects were observed in the larynx, that consisted of minimal squamous metaplasia of the epiglottal epithelium with minimal submucosal lymphoid cell infiltration; the NO(A)EC was 0.4 mg/m³air. The

NOAEC (local) has to be adapted considering different respiratory volumes of humans at rest (6.7 m³) and with physical light activity (10 m³) for 8 hours. Moreover, an adaptation was done for difference in duration of exposure: 6 h in the in vivo study and 8 h during a normal working day. Thus, the modified NOAEC is 0.20 mg/m³.

Corrected NOAEC (inhalation) for workers:

= 0.4 mg/m³× (6.7 m³/10 m³)

= 0.268 mg/m³

Step 3: Overall AF= 5

Interspecies: Local effects are independent of the basal metabolic rate, allometric scaling should not be applied.

Interspecies AF, remaining differences: 1

Intraspecies AF (worker): 5

Dose response relationship AF: 1

Exposure duration AF: 1

Whole database AF: 1

The repeated dose inhalation toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor. In conclusion,long term local inhalation DNEL, workers = 40 µg/m3.

Short term, local DNEL- exposure via inhalation (workers)

Covered by long-term DNEL. Glyoxal is in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 classified as skin irritant (Cat. 2), eye irritant (Cat. 2) and skin sensitising (Cat. 1). According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent skin, eye and mucous membrane exposure.

2.    Dermal

The carcinogenic potential of Glyoxal in mice after dermal application was determined, but no NOAEL is available from this study for using as POD (Unione Carbide, 1982). In addition, data from a preliminary test conducted for the purpose of dosage estimation for the main dermal carcinogenicity study are available, which also cannot be used as POD (BRRC 45-508, 1979). 

Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

 

Long term, systemic DNEL- exposure via dermal route (workers)

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (oral)

The NOAEL of 25 mg/kg bw/day derived from an OECD TG 453 study was used as the PoD.

Step 2: Modification into a correct starting point:

Relevant dose descriptor (NOAEL): 25 mg/kg bw/day

In ECHA guidance R.8 it is stated that “substance specific data on absorption via the different routes are to be preferred.” Therefore, in the present situation experimental data from a dermal toxicokinetic study was used showing up to 6.4 % absorption by rat skin and 60 % absorption after oral exposure.

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

= 25 mg/kg bw/day x 60 / 6.4 × 1.4

= 328 mg/kg bw/day

Step 3: Overall AF= 50

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 1 (chronic)

In conclusion, long term systemic dermal DNEL, workers = 6.6 mg/kg bw/day.

Acute, systemic DNEL- dermal exposure (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

Long term & acute, local DNEL- dermal exposure (workers)

A qualitative approach has to be implemented to deal with the eye as well as skin irritating and skin sensitizing properties of Glyoxal. As a result, a medium hazard is derived. All skin and mucous membranes with potential exposure should be protected.

Hazard to the eye-local effects (worker)

The test item is classified for eye irritation/corrosion (cat. 2, H 315) according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (low hazard).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.44 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):

25

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

11.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

An oral-to-inhalation extrapolation with respect to the chronic cancerogenicity study is done (see "Additional Information-General population").

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

Further toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.32 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

0.33

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 µg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

NOAEC

Value:

0.4 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

Local effects are considered time independent.

AF for interspecies differences (allometric scaling):

1

Justification:

not applicable (inhalative exposure)

AF for other interspecies differences:

1

Justification:

Local effects are considered species independent.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

Further toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

234 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The carcinogenic potential of Glyoxal in mice after dermal application was determined, but no NOAEL is available from this study for using as POD (Unione Carbide, 1982). In addition, data from a preliminary test conducted for the purpose of dosage estimation for a main dermal carcinogenicity study are available, which also cannot be used as POD (BRRC 45-508, 1979). Therefore, it was necessary to obtain a long-term dermal DNEL by route-to-route extrapolation (see "Additional Information-General population").

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

Further toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

Further toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

1.    Inhalation

Long term, systemic DNEL – exposure by inhalation (general population)

Using a conservative approach, a DNEL (long-term inhalation exposure) is derived. This long-term DNEL for the general population is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No chronic studies have been undertaken by the inhalatory route to characterize the dose-response relationship for systemic effects. Therefore, it will be necessary to obtain a long-term inhalatory DNEL by route-to route extrapolation.

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (oral)

The NOAEL of 25 mg/kg bw/day derived from an OECD TG 453 study was used as the PoD.

Step 2: Modification into a correct starting point:  

Relevant dose descriptor (NOAEL): 25 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.35 m³/kg bw

Oral absorption of the rat / inhalation absorption of humans (ABS oral-rat / ABS inh-human): 60/100

A 60 % oral absorption is assumed for Glyoxal from in vivo toxicokinetic studies and used for the purpose of route-to-route extrapolation. As a worst-case assumption 100 % absorption after inhalatory exposure is assumed in absence of any experimental data as recommended in TGD R8.

Differences experimental/human exposure conditions: 7d/24h rat vs.7d/24h (general population)

Corrected NOAEC (inhalation) for general population:

= 25 mg/kg bw/day× 0.6 × (1 / 1.35 m³/kg bw/24h)

= 11.1 mg/m³

Step 3: Overall AF= 25

Interspecies: According to Table R.8.4 in chapter R.8 of the ECHA Guidance Document no AF for allometric scaling is needed when route (oral)-to route (inhalation) extrapolation is applied.

Intraspecies AF (general population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 1 (chronic)

In conclusion, long term systemic inhalation DNEL, general population= 0.44 mg/m3.

Acute, systemic DNEL- exposure via inhalation (general population)

Due to the inhalative toxicity of the aerosol observed for this test item (rat 4 h; LC50=2.44 mg/L), the substance is considered to be classified for acute inhalative toxicity under Regulation (EC) No. 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776. The DNEL for acute systemic inhalation, worker was extrapolated according to the ECHA Guidance by applying the AF of 0.33.

DNEL, long-term systemic inhalation (0.44 mg/m3) x AF (0.33)

 

DNEL, short-term systemic inhalation = 1.32 mg/m3.

 

Long term, local DNEL- exposure via inhalation (general population)

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (inhalation)

The NOAEC (local) of 0.4 mg/m³derived from an OECD TG 412 study.

A DNEL for local effects due to inhalatory long term exposure of Glyoxal aerosol was derived from the NOAEC of an inhalatory subacute repeated dose study (according to OECD 412; Hoechst 1995). Male and female Wistar rats were subjected to test concentrations of 0.4, 2.0 and 10 mg/m³. A systemic toxicity of Glyoxal aerosol after repeated inhalation exposure could not be evidenced. Local effects were observed in the larynx, that consisted of minimal squamous metaplasia of the epiglottal epithelium with minimal submucosal lymphoid cell infiltration. An adaptation was done for difference in duration of exposure: 6 h in the in vivo study and 24 h during a normal day. Thus, the modified NOAEC is 0.10 mg/m³.

Step 2: Overall AF= 10

Interspecies: Local effects are independent of the basal metabolic rate, allometric scaling should not be applied.

Interspecies AF, remaining differences: 1

Intraspecies AF (general population): 10

Dose response relationship AF: 1

Exposure duration AF: 1

Whole database AF: 1

The repeated dose inhalation toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term local inhalation DNEL, general population = 10 µg/m3.

Acute, local

Covered by long-term DNEL. Glyoxal is in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 classified as skin irritant (Cat. 2), eye irritant (Cat. 2) and skin sensitising (Cat. 1). According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint.

2.    Dermal

The carcinogenic potential of Glyoxal in mice after dermal application was determined, but no NOAEL is available from this study for using as POD (Unione Carbide, 1982). In addition, data from a preliminary test conducted for the purpose of dosage estimation for a main dermal carcinogenicity study are available, which also cannot be used as POD (BRRC 45-508, 1979). 

Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

Long term, systemic DNEL- exposure via dermal route (general population)

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (oral)

The NOAEL of 25 mg/kg bw/day derived from an OECD TG 453 study was used as the PoD.

Relevant dose descriptor (NOAEL): 25 mg/kg bw/day

In ECHA guidance R.8 it is stated that “substance specific data on absorption via the different routes are to be preferred.” Therefore, in the present situation experimental data from a dermal toxicokinetic study was used showing up to 6.4 % absorption by rat skin and 60% absorption after oral exposure.

Correction for difference between human and experimental exposure conditions: 7d animal/7d general population

Corrected NOAEL (dermal) for general population:

= 25 mg/kg bw/day × 60 / 6.4 × 1

= 234 mg/kg bw/day

Step 2: Overall AF= 100

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 10

Dose-response relationship AF: 1

Exposure duration AF: 1 (chronic)

In conclusion, long term systemic dermal DNEL, general population = 2.3 mg/kg bw/day.

Acute, systemic DNEL- dermal exposure (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, a DNEL is not required.

Long term & acute, local DNEL- dermal exposure (general population)

A qualitative approach has to be implemented to deal with the eye as well as skin irritating and skin sensitizing properties of Glyoxal. As a result, a high hazard is derived.

3.    Oral

Long term, systemic DNEL – exposure by oral route (general population)

Step 1: PoD and most sensitive endpoint: repeated dose toxicity (oral)

Step 2: Relevant dose descriptor (NOAEL): 25 mg/kg bw/day

Oral absorption of the rat / oral absorption of humans (ABS oral-rat / ABS oral-human): 60/100

A 60 % oral absorption is assumed for Glyoxal from in vivo toxicokinetic studies and used for the purpose of route-to-route extrapolation. As a worst-case assumption 100 % absorption after oral exposure is assumed in absence of any experimental data as recommended in TGD R8.

Corrected NOAEL (oral) for general population:

= 25 mg/kg bw/day × 60 / 100

= 15 mg/kg bw/day

Step 3: Overall AF= 100

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric scaling

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 1 (chronic)

In conclusion, long term systemic oral DNEL, general population= 0.15 mg/kg bw/day

Acute, systemic DNEL- exposure by oral route (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, "a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute oral toxicity with the LD50 >2000 mg/kg bw. Therefore, a DNEL is not required.

Hazard to the eye-local effects (general population)

The test item is classified for eye irritation/corrosion (cat. 2, H 315) according to Regulation (EC) No1272/2008 (CLP). Thus, a qualitative risk assessment is conducted and a low hazard is derived.

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterization of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterization, Version 3.0, May 2016