1,4-dioxane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

37 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: OEL value as determined by German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission), 2019

Explanation for the modification of the dose descriptor starting point:

According to German MAK Commission (2019). For more details please refer to the discussion below.

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

74 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: German MAK Commission, 2019

DNEL extrapolated from long term DNEL

Explanation for the modification of the dose descriptor starting point:

An excursion factor of 2 from long-term threshold to short-term due to local effects is applied.

Local effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

37 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German MAK Commission, 2019

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

74 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: German MAK Commission, 2019

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

6.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: German MAK Commission, 2019

Explanation for the modification of the dose descriptor starting point:

450 mg per person is considered systemically tolerable amount for workers according to German MAK Commission (2019). This value is based on the following:

NOAEC for systemic inhalation in the rat was 50 mL/m³(=180 mg/m³). Considering human respiratory volume for 8 h (=10 m³), under elevated activity (1:2) and the interspecies correction factor (1:2) an acceptable amount of 450 mg / person / shift is determined.

Further, 450 mg / 70 kg (average body weight worker) = 6.4 mg/kg bw/d

For more details please refer to the discussion below.

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:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

DNEL Derivation approach for 1,4 -Dioxane

According to ECHA Guidance on Information Requirements and chemical safety assessment Chapter R.8 DNEL derivation may take into account community/national occupational exposure limits (OEL). The guidance states that:

“When an EU IOEL exists the registrant may, under conditions as described below, use the IOEL in place of developing a DNEL (…) A registrant is allowed to use an IOEL as a DNEL for the same exposure route and duration, unless new scientific information that he has obtained in fulfilling his obligations under REACH does not support the use of the IOEL for this purpose. This could be because the information obtained is more recent than the information that was used to support setting the IOEL at EU level and because it leads to another value being derived which requires different risk management measures (RMMs) and operational conditions (OCs).”

It is further stated that

“A registrant cannot use a national OEL in place of a DNEL without an evaluation of the scientific background for setting the national OEL. However, in cases where toxicological information and evaluations of health effects used for setting the national OEL are documented and available, this may, as for IOELs, be used and taken into account in deriving the DNEL. In this evaluation, the approach used for setting the national OEL should be compared to the approach for deriving DNELs as described in the in the main body of this chapter, and any differences in approach should be taken into account.”

 

For 1,4-Dioxane an IOEL of 73 mg/m³ was determined in 2004.

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) conducted a re-evaluation of the national OEL (MAK) for 1,4-Dioxane in 2019 (MAK Commission, 2019) and concluded on an OEL value of 37 mg/m³.

The following main arguments were considered:

“The critical effect is nasal toxicity and irritation as well as carcinogenic effects in the nose, liver, and kidneys. New carcinogenicity studies with 1,4-dioxane in drinking water confirm the previous tumour findings in rats and mice. Squamous cell carcinomas in the rat nose, also occurring in a long-term rat inhalation study at 1250 ml/m3, are a result of direct tissue contact with 1,4-dioxane in the drinking water. At 50 ml/m3 (LOAEC, lowest observed adverse effect level), no increase in tumour incidences, but nuclear enlargement, atrophy, and respiratory metaplasia in the nasal cavity were noted. The mechanisms involved in the tumour development in the nose are most likely cytotoxicity, inflammation, regenerative cell proliferation and hyperplasia. As the primary mode of action is non-genotoxic and genotoxic effects play no or at most a minor part at cytotoxic doses, 1,4-dioxane remains in Carcinogen Category 4. A NAEC of 16.67 ml/m3 (LOAEC / 3) for effects in the nose was calculated from the long-term rat inhalation study, which is in the same range as the NOAEC of 20 ml/m3 from studies with 2- to 8-hour inhalation exposure of volunteers. To provide additional protection from tumour induction in the nose, the MAK value is lowered to 10 ml/m3. As the critical effect of 1,4-dioxane is local and no irritation was observed in the study with 2-hour exposure of volunteers to 20 ml/m3, Peak Limitation Category I and the excursion factor of 2 are retained.”

 

This recently re-evaluated OEL by the German MAK commission being lower than the current IOEL (2004) is considered to reflect a valid and also more protective threshold value. It has taken into account all relevant and reliable data in regards to human health hazard assessment. Therefore, for worker DNEL derivation this MAK value is applied.

 

Inhalation

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

1,4-dioxane is not considered a volatile substance based on its moderate vapor pressure. However, at higher temperatures worker exposure via the inhalation route cannot completely ruled out.

The German MAK Commission set an OEL to 37 mg/m³

 

Acute, systemic DNEL- exposure via inhalation (workers)

The German MAK Commission states: “As the critical effect of 1,4-dioxane is local and no irritation was observed in the study with 2-hour exposure of volunteers to 20 mL/m³, Peak Limitation Category I and the excursion factor of 2 are retained.”
Therefore, acute systemic worker DNEL for exposure via inhalation is set to 37 mg/m³ * 2 = 74 mg/m³

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

The German MAK value was set up to be protective against local as well as systemic effects induced by 1,4-dioxane upon inhalation. Thus, for local long term DNEL via inhalation route the OEL of 37 mg/m³ is applied. For peak exposures the excursion factor of 2 is applied according to MAK Commission.

 

Dermal

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

1,4-Dioxane is not irritating to skin. Thus, local effects such as irritation seen in the respiratory tract are not relevant when deriving a long term systemic threshold for the dermal route.

According to German MAK Commission 450 mg per person and day is considered systemically tolerable amount for workers.

This value is derived based on the following assumption:

NOAEC for systemic inhalation in the rat was 50 mL/m³ (=180 mg/m³). Considering human respiratory volume for 8 h (=10 m³), under elevated activity (1:2) and the interspecies correction factor (1:2) an acceptable amount of 450 mg / person / shift is determined.

Further, 450 mg / 70 kg (standard average body weight worker according to ECETOC Guidance, 2010) = 6.4 mg/kg bw/d

 

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

1,4 -Dioxane is not classified as irritating or corrosive to the skin according to Regulation (EC) No 1272/2008 (CLP). However, 1,4-dioxane is labelled with EUH066. Thus, it is required to ensure respective protection of the skin in order to prevent formation of e. g. eczema following repeated dermal exposure. Long term and short term hazard for local effects to the skin is thus indicated as “low hazard” in order to address this property with appropriate RMMs and OCs by qualitative risk assessment.

Hazard to the eye-local effects (worker)

1,4 -Dioxane is classified for eye irritiation according to Regulation (EC) No 1272/2008 (CLP). Therefore, a qualitative risk assessment is performed. 1,4 -dioxane is regarded as low hazard in terms of local effects to the eye according to ECHA Guidance on CSA & IR Part E: Risk Characterisation (Version 3.0, May 2016).

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

ECETOC Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, 2010

 

The MAK Collection for Occupational Health and Safety 2019, Vol4, No2

 

SCOEL/SUM/112 June 2004

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

6.6 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Modified OEL (MAK Commission, 2019)

Overall assessment factor (AF):

0.177

Explanation for the modification of the dose descriptor starting point:

The OEL of 37 mg/m3 for workers is modified in terms of application for general population:

An assessment factor of 10 is used instead of 5 for intraspecies differences --> 1 : 2 (factor x 0.5)
7 instead of 5 days per week are considered --> 1 : 1.4 (factor 0.71)

20 m³  instead of 10 m³ exposed respiratory volume per day are taken into account --> 1 : 2 (factor 0.5)

Overall correction factor for consumers: 0.1775

For more details please refer to the discussion below.

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

13.1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Modified OEL (German MAK Commission, 2019)

DNEL extrapolated from long term DNEL

Explanation for the modification of the dose descriptor starting point:

The same considerations as for long-term systemic inhalation DNEL apply.

In addition, the excursion factor of 2 is applied.

Local effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

6.6 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: Modified OEL (German MAK Commission, 2019)

Overall assessment factor (AF):

0.177

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

13.1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: Modified OEL (German MAK Commission, 2019)

Overall assessment factor (AF):

0.177

DNEL extrapolated from long term DNEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

2.27 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Modified OEL (German MAK Commission, 2019)

Explanation for the modification of the dose descriptor starting point:

Modified OEL (German MAK Commission, 2019). For more details please refer to the discussion below.

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:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

0.096 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:

9.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation is not applicable.

AF for dose response relationship:

1

Justification:

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

AF for differences in duration of exposure:

1

Justification:

Extrapolation from chronic toxicity study to chronic exposure duration does not require an additional AF.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively heterogeneous group "general population" is applied.

AF for the quality of the whole database:

1

Justification:

The quality of the whole database is considered unremarkable.

AF for remaining uncertainties:

1

Justification:

There are 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:

low hazard (no threshold derived)

Additional information - General Population

DNEL Derivation 1,4-Dioxane

General Population

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

Worker to general population:

The OEL of 37 mg/m³ for workers is modified in terms of application for general population:

An assessment factor of 10 is used instead of 5 for intraspecies differences --> 1 : 2 (factor 0.5)

7 instead of 5 days per week are considered --> 1 : 1.4 (factor 0.71)

20 m³ instead of 10 m³ exposed respiratory volume per day are taken into account --> 1 : 2 (factor 0.5)

Overall correction factor for consumers: 0.1775

 

Worker:                       Systemic Long term inhalation OEL = 37 mg/m³
General Population:      Systemic Long term inhalation DNEL = OEL x 0.5 x 0.71 x 0.5 = 6.6 mg/m³

 

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

Worker:                       Systemic short term inhalation OEL = 74 mg/m³
General Population:      Systemic short term inhalation DNEL= OEL x 0.5 x 0.71 x 0.5 = 13.1 mg/m³

 

The same considerations as for long-term systemic inhalation DNEL apply. In addition, the excursion factor of 2 is applied for peak exposure.

 

Long term and short term, local DNEL – exposure by inhalation (general population)

Worker:                       Local long term inhalation OEL = 37 mg/m³
General Population:      Local long term inhalation DNEL = OEL x 0.5 x 0.71 x 0.5 = 6.6 mg/m³

Worker:                       Local short term inhalation OEL = 74 mg/m³
General Population:      Local short term inhalation DNEL = OEL x 0.5 x 0.71 x 0.5 = 13.1 mg/m³

The German MAK value was set up to be protective against local as well as systemic effects induced by 1,4-dioxane upon inhalation. Thus, for local long term DNEL via inhalation route the OEL of 37 mg/m³is applied. For peak exposures the excursion factor of 2 is applied according to MAK Commission.

Modification factor of this value for general population is 0.1775. The same considerations as for systemic exposure via the inhalation route apply.

 

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

Worker to general population:

450 mg per person and day is considered systemically tolerable amount for workers according to the German MAK Commission.

This value is derived based on the following assumption:

1,4-Dioxane is not irritating to skin. Thus, local effects such as irritation seen in the respiratory tract are not relevant when deriving a long term systemic threshold for the dermal route.

NOAEC for systemic inhalation in the rat was 50 mL/m³(=180 mg/m³). Considering human respiratory volume for 8 h (=10 m³), under elevated activity (1:2) and the interspecies correction factor (1:2) an acceptable amount of 450 mg / person / shift is determined.

Further, 450 mg / 70 kg (standard average body weight worker according to ECETOC Guidance, 2010) = 6.4 mg/kg bw/d

This value for workers is modified in terms of application for general population:

An assessment factor of 10 is used instead of 5 for intraspecies differences --> 1 : 2 (factor x 0.5)

7 instead of 5 days per week are considered --> 1 : 1.4 (factor 0.71)

Overall correction factor for consumers: 0.355

Worker:                       Systemic Long term dermal OEL = 6.4 mg/m³
General Population:      Systemic Long term dermal DNEL = OEL x 0.5 x 0.71 = 2.27 mg/m³

 

Long term and short term, local DNEL – exposure by dermal route (general population)

1,4 -Dioxane is not classified as irritating or corrosive to the skin according to Regulation (EC) No 1272/2008 (CLP). However, 1,4-dioxane is labelled with EUH066. Thus, it is required to ensure respective protection of the skin in order to prevent formation of e. g. eczema following repeated dermal exposure. Long term and short term hazard for local effects to the skin is thus indicated as “low hazard” in order to address this property with appropriate RMMs and OCs by qualitative risk assessment.

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

Using a conservative approach, a DNEL for general population (long-term oral exposure) is calculated. This long-term DNEL is considered to ensure an appropriate level of protection.

Based on a Weight of Evidence approach the NOAEL of 9.6 mg/kg bw/d is selected as key value for hazard assessment via the oral route of exposure. In a 2 year drinking water study in rats renal tubular epithelial and hepatocellular degeneration and necrosis accompanied by regenerative activities in the liver and renal tubuli were observed . Male and female rats receiving 0.1% (equivalent to 94 and 148 mg/kg/day respectively) and 0.01 % (equivalent to 9.6 and 19 mg/kg/day respectively) dioxane in drinking water showed no evidence of tumour formation. Only in the highest dose group 1.0% (1055 and 1599 mg/kg/day for males and females respectively) treatment-related tumours found: in the liver (carcinomas were found in 10/66 animals and cholangiomas in 2/66 animals), while squamous cell carcinomas of the nasal cavities were found in 3/66 animals.

Step 1: PoD: NOAEL = 9.6 mg/kg bw/day

Step 2: Overall AF= 100

Interspecies AF, allometric scaling (rat to human): 4
The default allometric scaling factor for the differences between rats and humans is applied.

 

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (general population): 10
The default value for the relatively heterogeneous group "general population" is applied.

 

In conclusion, long term systemic oral DNEL, general population= 0.096 mg/kg bw/day

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

1,4-Dioxane is not classified as acutely toxic via oral route. Thus, there is no hazard identified in this regards. Moreover, no peak exposures to the general population with 1,4-Dioxane via the oral route are expected. Long term systemic oral DNEL is considered as sufficient to serve as protective threshold.

Hazard to the eye-local effects (general population)

1,4 -Dioxane is classified for eye irritiation according to Regulation (EC) No 1272/2008 (CLP). Therefore, a qualitative risk assessment is performed. 1,4 -dioxane is regarded as low hazard in terms of local effects to the eye according to ECHA Guidance on CSA & IR Part E: Risk Characterisation (Version 3.0, May 2016).

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

ECETOC Guidance on Assessment Factors to Derive a DNEL, Technical Report No. 110, 2010

 

The MAK Collection for Occupational Health and Safety 2019, Vol4, No2

 

SCOEL/SUM/112 June 2004