1,1'-[oxybis(ethyleneoxy)]diethylene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 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):

75

Dose descriptor starting point:

NOAEL

Value:

80 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

98.7 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term inhalation DNEL by route-to-route extrapolation. Please refer to “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:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

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:

Default 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

0.4 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):

300

Dose descriptor starting point:

NOAEL

Value:

80 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

112 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No repeated dose dermal toxicity study with the substance is available. Therefore, it was necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. Please refer to “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:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

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:

Default 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

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).

Inhalation

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

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. 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 repeated dose inhalation toxicity study with the substance is available. Therefore, it was necessary to obtain a long-term inhalation DNEL by route-to-route extrapolation.

An OECD TG 422 study performed with the substance is available. The test item was administered at 80, 250 or 800 mg/kg bw/day to Hannover Wistar rats for 28 days in males and 50-55 days in females. Based on the results of this study, the following NOAELs were considered: The NOAEL for systemic toxicity of the parental generation was 80 mg/kg bw/day for males based on clinical signs, body weight gain and food consumption effects on the high dose group and on kidney findings in male rats at the mid and high dose group. The NOAEL for systemic toxicity was 250 mg/kg bw/day for females based on clinical signs, body weight gain and food consumption effects. The NOAEL for reproductive effects of the parental generation was 800 mg/kg bw/day based on no findings. The NOAEL for pups’ development and survival was 800 mg/kg bw/day based on no specific findings that were not attributed to maternal toxicity.

The NOAEL of 80 mg/kg bw/day is used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 80 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume, human (sRVhuman) for 8 hours: 6.7 m3

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

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

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)

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

Corrected NOAEC (inhalation) for workers:

= 80 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 98.7 mg/m3

Step 3: Overall AF= 75

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 6 (subacute to chonic)

Whole database AF: 1

The OECD TG 422 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 = 1.3 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

Due to the low vapour pressure (0.17 hPa) of the substance inhalation exposure is not considered as relevant. Inhalation of a saturated test substance atmosphere generated at room temperature did not result in deaths of albino rats (Smyth, 1962). Furthermore, The substance is not classified as acutely toxic with respect to the oral and dermal routes of exposure and the available data set does not show any indication for irritation. Furthermore, as the substance is marketed in a non-solid form no formation of dust is expected. Based on these data no hazard is identified regarding acute/short term inhalation exposure. Therefore, no DNEL was derived.

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

The substance is not classified for skin/ eye irritation or skin sensitization. Due to the low vapour pressure of the substance, inhalation exposure is not considered a relevant route of exposure. Furthermore, as the substance is marketed in a non-solid form no dust formation is expected. In an acute inhalation toxicity study with a saturated test substance atmosphere no irritating effects were described in rats (Smyth, 1962). Based on these data no hazard is expected regarding local effects - long term exposure. Therefore, no DNEL was derived.

Dermal

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

No repeated dose dermal toxicity study with the substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOAEL of 80 mg/kg bw/day derived from an OECD TG 422 study performed with the substance was used as the PoD.

Step 1: PoD: NOAEL = 80 mg/kg bw/day

Step 2: Modification into a correct starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 100%/100 % (default)

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

Corrected NOAEL (dermal) for workers:

= 80 mg/kg bw/day x 1.4

= 112 mg/kg bw/day

Step 3: Overall AF= 300

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: 6

In conclusion, long term systemic dermal DNEL, workers = 0.4 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)

The test substance is not classified for skin irritation/corrosion or skin sensitization. Therefore, no hazard was identified and no DNEL was derived.  

Hazard to the eye-local effects (worker)

The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). No hazard is identified regarding local effects to the eye.

 

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:

0.23 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):

150

Dose descriptor starting point:

NOAEL

Value:

80 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

34.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study with the substance is available. Therefore, it was necessary to obtain a long-term inhalation DNEL by route-to-route extrapolation. Please refer to "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:

4

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

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:

Default for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

0.1 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):

600

Dose descriptor starting point:

NOAEL

Value:

80

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:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

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:

Default for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

0.1 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):

600

Dose descriptor starting point:

NOAEL

Value:

80 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:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

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:

Default for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous 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:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

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).

Inhalation

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

Using a conservative approach, a DNEL (long-term inhalation exposure) is calculated. This 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 repeated dose inhalation toxicity study with the substance is available. Therefore, it was necessary to obtain a long-term inhalation DNEL by route-to-route extrapolation.

An OECD TG 422 study performed with the substance is available. The test item was administered at 80, 250 or 800 mg/kg bw/day to Hannover Wistar rats for 28 days in males and 50-55 days in females. Based on the results of this study, the following NOAELs were considered: The NOAEL for systemic toxicity of the parental generation was 80 mg/kg bw/day for males based on clinical signs, body weight gain and food consumption effects on the high dose group and on kidney findings in male rats at the mid and high dose group. The NOAEL for systemic toxicity was 250 mg/kg bw/day for females based on clinical signs, body weight gain and food consumption effects. The NOAEL for reproductive effects of the parental generation was 800 mg/kg bw/day based on no findings. The NOAEL for pups’ development and survival was 800 mg/kg bw/day based on no specific findings that were not attributed to maternal toxicity.

 

Step 1: PoD: NOAEL = 80 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m3/kg bw

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)

Corrected NOAEC (inhalation) for general population:

= 80 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 34.8 mg/m3

Step 3: Overall AF= 150

Intraspecies AF (General population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 6

Whole database AF: 1

The OECD TG 422 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, general population = 0.23 mg/m3

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

Due to the low vapour pressure (0.17 hPa) of the substance inhalation exposure is not considered as relevant. Inhalation of a saturated test substance atmosphere generated at room temperature did not result in deaths of albino rats (Smyth, 1962). The substance is not classified as acutely toxic with respect to the oral and dermal routes of exposure and the available data set does not show any indication for irritation. Furthermore, as the substance is marketed in a non-solid form no formation of dust is expected. Based on these data no hazard is identified regarding acute/short term inhalation exposure. Therefore, no DNEL was derived.

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

The substance is not classified for skin/ eye irritation or skin sensitization. Due to the low vapour pressure of the substance, inhalation exposure is not considered a relevant route of exposure. Furthermore, as the substance is marketed in a non-solid form no dust formation is expected. In an acute inhalation toxicity study with a saturated test substance atmosphere no irritating effects were described in rats (Smyth, 1962). Based on these data no hazard is expected regarding local effects - long term exposure. Therefore, no DNEL was derived.

Dermal

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

No repeated dose dermal toxicity study with the substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOAEL of 80 mg/kg bw/day derived from an OECD TG 422 study performed with the substance was used as the PoD.

Step 1: PoD: NOAEL= 80 mg/kg bw/day

Oral absorption of the rat/dermal absorption of humans (ABS oral-rat / ABS derm-human): 100%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d, 24 h rat/7 d, 24 h general population

Step 2: Overall AF= 600

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 6

In conclusion, long term systemic dermal DNEL, general population = 0.1 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, the DNEL is not required.

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

The test substance is not classified for skin irritation/corrosion or skin sensitization. Therefore, no hazard was identified and no DNEL was derived. 

Oral

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

A study according OECD TG 422 is available and the NOAEL of 80 mg/kg bw/day was used as PoD.

Step 1: PoD: NOAEL = 80 mg/kg bw/day

Step 2: Overall AF= 600

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: 6

In conclusion, long term systemic oral DNEL, general population= 0.1 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 of >2000 mg/kg. Therefore, the DNEL is not required.

Hazard to the eye-local effects (general population)

The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). No hazard is identified regarding local effects to the eye.

 

 

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