Diisopentyl ether

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 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

Modified dose descriptor starting point:

NOAEC

Value:

88.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

8 h exposure time, extrapolation from 50% bioavailability oral to 100% bioavailability inhalation, no inhalation study available

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

not for concentrations

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

5

Justification:

for worker

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

270 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

3 377 mg/m³

AF for dose response relationship:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

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:

0.33 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

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

8 h exposure time, no dermal study available

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

5

Justification:

for worker

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

Additional information - workers

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. The substance is classified for acute inhalation toxicity. For short term exposure to diisopentyl ether, a DNEL has been derived based on the results of an acute inhalation study according to the REACH guidance.

Assessment of short term exposure is not considered relevant, when 8 hour exposure levels remain under the chronic-DNEL. The short term DNEL for diisopentyl ether is high (270 mg/m3, about 225 times higher) relative to the chronic DNEL for diisopentyl ether.

The relationship between determinants of acute and full shift exposure distributions have been calculated (Kumagai and Matsunaga, 1994). In general, the 95th percentile of 15 minute exposure data is about twice the 90th percentile and 4 times the 75th percentile of full shift data collected for the same situation. Even in a worst case situation when:

- the full shift measurement data reflects the 75th percentile,

- there is a high variability within the short term data,

- the 99th percentile of the short term value is required,

the factor by which to multiply the 8 hour value to get to the short term value is 40. This is still much lower than 225. This means that when 8 hour exposures remain under the chronic DNEL for diisopentyl ether, the 15 minute exposure levels will always be safe.

The substance is not classified as irritating to the skin or eyes. Based on the results of a LLNA assay, diisopentyl ether is proposed to be classified as skin sensitizing substance. However, it is not possible to derive a DNEL based on the available data. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent dermal exposure that will cause skin sensitisation. No data is available whether the test substance could cause irritation to the respiratory tract and therefore no DNEL could be derived.

 

Long-term toxicity

The key study for DNEL derivation was identified as a recent repeated dose oral study.according to OECD 422 (De Raaf-Beekhuijzen, 2012) where a NOAEL of 100 mg/kg bw/day was derived. The reason for selecting this study is that the design includes both the OECD 407 and OECD 421 guidelines requirements and the exposure duration included an additional 2 weeks exposure duration when compared to a standard 4 weeks toxicity study. The DNELs for chronic systemic toxicity for the inhalation and dermal route are derived via route-to-route extrapolation based on the repeated dose oral toxicity study.

In the absence of substance specific quantitative data on absorption, 100% absorption is assumed for the inhalation and 50% for the oral route. Based on the absence of dermal absorption data, it is assumed that the dermal bioavailability is equal to oral bioavailability (worst case scenario).

Worker DNELs

Long-term inhalation, systemic effects

As inhalation repeated dose toxicity studies with diisopentyl ether are not available, route to route extrapolation was applied to derive a DNEL for the inhalation route, based on the results of a recent oral OECD 422 study in rat (De Raaf-Beekhuijzen, 2012) where an NOAEL of 100 mg/kg bw/day was derived.

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day	Exposure of rats at concentrations up to 1000 mg/kg bw/day did not induce clinical abnormalities, differences in food consumption and body weight, and changes in haematology or clinical chemistry parameters.Based on the increased liver weights (mid and high dose females and high dose males) and treatment-related microscopic findings in thyroid (males), thymus (males) and liver (both sexes), a dose of 100 mg/kg bw/day was considered as NOAEL
Step 2) Modification of starting point	2      0.38 m^3/kg bw           6.7 m^3/10 m^3	The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation.   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2).   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.
Modified dose-descriptor	100 / 2 / 0.38 x (6.7/10) = 88.2 mg/m^3
Step 3) Assessment factors
Interspecies	2.5	No factor for allometric scaling is needed in case of inhalation exposure.A default factor of 2.5 for remaining uncertainties is used.
Intraspecies	5	Default AF for workers
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study
Dose response	1
Quality of database	1
DNEL	Value
	88.2 / (2.5 x 5 x 6 x 1 x 1) = 1.18 mg/m^3

Short-term – inhalation, systemic effects

Approach according to REACH guidance

Based on the available acute inhalation toxicity study in rats (Van Huygevoort, 2012).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 2000 mg/m^3	No deaths occurred and no abnormalities were found at macroscopic examination. Therefore, 2000 mg/m^3is interpreted as a NOAEC.
Step 2) Modification of starting point	3√(2000^3x 16)                       6.7/10	In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. The most appropriate approach is the modified Haber’s law (C^n* t = k). For extrapolation from longer to shorter durations a default value of n=3 should be used.   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m^3/10 m^3).
Step 3) Assessment factors
Interspecies	2.5	For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
Intraspecies	5	Default AF for workers
Exposure duration	1
Dose response	1
Quality of database	1
Step 4) Calculate DNEL	^3√(2000^3x 16) x (6.7/10)/ (2.5 x 5 x 1 x 1 x 1) = 270 mg/m^3

 

Long-term dermal, systemic effects

As dermal repeated dose toxicity studies with diisopentyl ether are not available, route to route extrapolation was applied to derive a DNEL for the dermal route, based on the resuls of a recent oral OECD 422 study in rat (De Raaf-Beekhuijzen, 2012) where an NOAEL of 100 mg/kg bw/day was derived.

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day	Exposure of rats at concentrations up to 1000 mg/kg bw/day did not induceclinical abnormalities, differences in food consumption and body weight, and changes in haematology or clinical chemistry parameters.Based on the increased liver weights (mid and high dose females and high dose males) and treatment-related microscopic findings in thyroid (males), thymus (males) and liver (both sexes), a dose of 100 mg/kg bw/day was considered as NOAEL
Step 2) Modification of starting point	1	Based on the absence of skin absorption data, it is assumed that the dermal bioavailability is equal to the oral bioavailability
Modified dose-descriptor	100 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling and remaining uncertainties.
Intraspecies	5	Default AF for workers
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study
Dose response	1
Quality of database	1
DNEL	Value
	100 / (4 x 2.5 x 5 x 6 x 1 x 1) = 0.33 mg/kg bw/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.29 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

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

24 h exposure time, extrapolation from 50% bioavailability oral to 100% bioavailability inhalation, no inhalation study available

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

not required for concentration

AF for other interspecies differences:

2.5

Justification:

default factor for remaining differences

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

202 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

5 040 mg/m³

AF for dose response relationship:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.17 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

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

24 h exposure time, no dermal study available

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

extrapolation rat to human

AF for other interspecies differences:

2.5

Justification:

remaining differences

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not required

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.17 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

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route to route extrapolation performed

AF for dose response relationship:

1

Justification:

not required, starting point is NOAEL

AF for differences in duration of exposure:

6

Justification:

extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

extrapolation rat to human

AF for other interspecies differences:

2.5

Justification:

remaining differences

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

not required

AF for remaining uncertainties:

1

Justification:

not 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

According to the REACH Guidance on information requirements and chemical safety assessment, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Short-term toxicity

According to the REACH guideline (R8, Appendix R 8-8), a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified and there is a potential risk for high peak exposures. The substance is classified for acute inhalation toxicity. For short term exposure to diisopentyl ether, a DNEL has been derived based on the results of an acute inhalation study according to the REACH guidance.

The substance is not classified as irritating to the skin or eyes. Based on the results of a LLNA assay, diisopentyl ether is proposed to be classified as skin sensitizing substance. However, it is not possible to derive a DNEL based on the available data. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent dermal exposure that will cause skin sensitisation. No data is available whether the test substance could cause irritation to the respiratory tract and therefore no DNEL could be derived.

 

Long-term toxicity

The key study for DNEL derivation was identified as a recent repeated dose oral study.according to OECD 422 (De Raaf-Beekhuijzen, 2012) where a NOAEL of 100 mg/kg bw/day was derived. The reason for selecting this study is that the design includes both the OECD 407 and OECD 421 guidelines requirements and the exposure duration included an additional 2 weeks exposure duration when compared to a standard 4 weeks toxicity study. The DNELs for chronic systemic toxicity for the inhalation and dermal route are derived via route-to-route extrapolation based on the repeated dose oral toxicity study.

In the absence of substance specific quantitative data on absorption, 100% absorption is assumed for the inhalation and 50% for the oral route.

Based on the absence of dermal absorption data, it is assumed that the dermal bioavailability is equal to oral bioavailability (worst case scenario).

General population DNELs

Long-term inhalation, systemic effects

As inhalation repeated dose toxicity studies with diisopentyl ether are not available, route to route extrapolation was applied to derive a DNEL for the inhalation route, based on the results of a recent oral OECD 422 study in rat (De Raaf-Beekhuijzen, 2012) where an NOAEL of 100 mg/kg bw/day was derived

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day	Exposure of rats at concentrations up to 1000 mg/kg bw/day did not induceclinical abnormalities, differences in food consumption and body weight, and changes in haematology or clinical chemistry parameters.Based on the increased liver weights (mid and high dose females and high dose males) and treatment-related microscopic findings in thyroid (males), thymus (males) and liver (both sexes), a dose of 100 mg/kg bw/day was considered as NOAEL
Step 2) Modification of starting point	2     1.15 m^3/kg bw	The REACH Guidance on information requirements and chemical safety assessment (R.8.4.2) prescribes a default factor of 2 in case of oral to inhalation extrapolation.   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance on information requirements and chemical safety assessment (R.8.4.2).
Modified dose-descriptor	100 / 2 / 1.15 = 43.5 mg/m^3
Step 3) Assessment factors
Interspecies	2.5	No factor for allometric scaling is needed in case of inhalation exposure.A default factor of 2.5 for remaining uncertainties is used.
Intraspecies	10	Default AF for general population
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study
Dose response	1
Quality of database	1
DNEL	Value
	43.5 / (2.5 x 10 x 6 x 1 x 1) = 0.29 mg/m^3

Short-term – inhalation, systemic effects

Approach according to REACH guidance

Based on the available acute inhalation toxicity study in rats (Van Huygevoort, 2012).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 2000 mg/m^3	No deaths occurred and no abnormalities were found at macroscopic examination. Therefore, 2000 mg/m^3is interpreted as a NOAEC.
Step 2) Modification of starting point	3√(2000^3x 16)	In the REACH guidance (R.8, Appendix R. 8-8), it is mentioned: ‘If a DNEL for acute toxicity needs to be established, this should be derived only for a specified fraction of the daily exposure duration (usually 15 minutes)’. The most appropriate approach is the modified Haber’s law (C^n* t = k). For extrapolation from longer to shorter durations a default value of n=3 should be used.
Step 3) Assessment factors
Interspecies	2.5	For inhalation studies only a factor 2.5 is used, and no correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans; animals and humans breathe at a rate depending on their caloric requirements.
Intraspecies	10	Default AF for general population
Exposure duration	1
Dose response	1
Quality of database	1
Step 4) Calculate DNEL	^3√(2000^3x 16) / (2.5 x 10 x 1 x 1 x 1) = 202 mg/m^3

Long-term dermal, systemic effects

 

As dermal repeated dose toxicity studies with diisopentyl ether are not available, route to route extrapolation was applied to derive a DNEL for the dermal route, based on the results of a recent oral OECD 422 study in rat (De Raaf-Beekhuijzen, 2012) where an NOAEL of 100 mg/kg bw/day was derived.

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day	Exposure of rats at concentrations up to 1000 mg/kg bw/day did not induceclinical abnormalities, differences in food consumption and body weight, and changes in haematology or clinical chemistry parameters.Based on the increased liver weights (mid and high dose females and high dose males) and treatment-related microscopic findings in thyroid (males), thymus (males) and liver (both sexes), a dose of 100 mg/kg bw/day was considered as NOAEL
Step 2) Modification of starting point	1	Based on the absence of skin absorption data, it is assumed that the dermal bioavailability is equal to the oral bioavailability
Modified dose-descriptor	100 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling and remaining uncertainties.
Intraspecies	10	Default AF for workers
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study
Dose response	1
Quality of database	1
DNEL	Value
	100 / (4 x 2.5 x 10 x 6 x 1 x 1) = 0.17 mg/kg bw/day

 

Long-term – oral, systemic effects

The key study for DNEL derivation was identified as the recent oral OECD 422 study in rat (De Raaf-Beekhuijzen, 2012) where an NOAEL of 100 mg/kg bw/day was derived.

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day	Exposure of rats at concentrations up to 1000 mg/kg bw/day did not induceclinical abnormalities, differences in food consumption and body weight, and changes in haematology or clinical chemistry parameters.Based on the increased liver weights (mid and high dose females and high dose males) and treatment-related microscopic findings in thyroid (males), thymus (males) and liver (both sexes), a dose of 100 mg/kg bw/day was considered as NOAEL
Step 2) Modification of starting point	1	No route to route extrapolation performed.
Modified dose-descriptor	100 mg/kg bw/day
Step 3) Assessment factors
Interspecies	4 x 2.5	Assessment factor for allometric scaling and remaining uncertainties.
Intraspecies	10	Default AF for workers
Exposure duration	6	Extrapolation to chronic exposure based on a sub-acute toxicity study
Dose response	1
Quality of database	1
DNEL	Value
	100 / (4 x 2.5 x 10 x 6 x 1 x 1) = 0.17 mg/kg bw/day