Bis(2-(2-butoxyethoxy)ethyl) adipate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.937 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:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

123.42 mg/m³

Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a sub-chronic toxicity study in rats (OECD 408). To convert the rat oral NOAEL into a corrected inhalatory NOAEC to assess human

inhalatory exposure, the NOAEL has to be corrected as follows:

Corrected inhal NOAEC = NOAEL(oral) × (1 ÷ sRVrat) × (ABSoral-rat ÷ ABSinh-human) × (sRVhuman ÷ wRV) × (Fstudy ÷ Fworker) = 100 mg/kg bw/day × (1 ÷ 0.38 m³/kg bw) × (1 ÷ 2) × (6.7 m³ ÷ 10 m³) × (7d ÷ 5d) = 123.42 mg/m³

sRV = standard respiratory volume; wRV = respiratory volume light activity for worker (8 h); ABS = absorption; Fstudy = frequency of exposure in study; Fworker = frequency of exposure worker

Route-to-route extrapolation within the rat was based on the respiratory volume of 0.8 L/min/kg bw, leading to an inhalation volume of 0.38 m³/kg bw for a time period of 8 hours, reflecting the normal duration of an 8-hour work shift. The resulting air concentration has been corrected by a factor of 0.67 considering the ratio of the normal inhalation volume of 6.7 m³/person over 8 hours and the increased inhalation volume of 10 m³/person of workers during light activity at work. Moreover, the NOAEL was corrected for the differences in the experimental and human exposure conditions. The animals (rats) were exposed to the test substance 7 days/week, whereas workers are in general exposed 5 days/week

(factor 7 days/5 days). As worst case as recommended in the ECHA Guidance R.8 (2012), it is assumed that oral absorption rate is 50% of that of inhalation absorption. Thus, the corrected starting point for workers is 123.42 mg/m³ for inhalation.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

2

Justification:

The DNEL is based on a sub-chronic study peformed in rats over a time period of 90 days.

AF for interspecies differences (allometric scaling):

1

Justification:

Interspecies differences were taken into account for the conversion of the rat oral NOAEL into a cor rected inhalatory NOAEC considering allometric scaling for the respiratory volumes (modification of the dose descriptor starting point). Thus, no additional AF is applicable.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.4 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):

100

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

140 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAELcorr = NOAELoral*(ABSoral-rat/ABSdermal-human) = (100 mg/kg bw/day)*(1/1) * (7 days exposure rat/5 days exposure worker) = 140 mg/kg bw/day. Although dermal absorption is considered relatively low, a default value of 100% skin absorption is used according to ECHA guidance R7 C, since exact dermal absorption data are not available and the test substance has a molecular weight of 434.45 g/mol and a log P of 3.24. According to ECHA guidance R 7C, 10% skin absorption is only considered in case the molecular mass is above 500 and log P is outside the range [-1, 4] (de Heer et al., 1999), otherwise a default value of 100% skin absorption has to be applied. It is assumed that oral and dermal absorption rates are equal.

AF for dose response relationship:

1

Justification:

DNEL is based on a NOAEL

AF for differences in duration of exposure:

2

Justification:

DNEL is based on a 90-day study

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for rats

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

The selected study is the most adequate and reliable study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.869 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):

50

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

43.47 mg/m³

Explanation for the modification of the dose descriptor starting point:

Corrected inhal NOAEC = NOAEL(oral) × (1 ÷ sRVrat) × (ABSoral-rat ÷ ABSinh-human) = 100 mg/kg bw/day × (1 ÷ 1.15 m³/kg bw) × (1 ÷ 2) = 43.47 mg/m³

 

sRV = standard respiratory volume,sRVrat = 1.15,ABS(oral/rat) = oral absorption rate in rats, ABS(inh./human) = inhalation absorption rate in humans

Starting point for the DNEL derivation is the human NAEC for inhalation exposure over 24 hours of43.47 mg/m³. This value is based on the conversion of the sub-chronic oral NOAEL of 100 mg/kg bw/dayfor rats from a 90 day repeated dose toxicity study to the corresponding air concentration over a period of 24 hours. Route to-route extrapolation within the rat was based on the respiratory volume of 0.8 L/min/kg bw,leading to an inhalation volume of 1.15 m³/kg bw for a time period of 24 hours, reflecting continuousexposure via the environment. As worst case as recommended in the ECHA Guidance R.8 (2012), it isassumed that oral absorption rate is 50% of that of inhalation absorption.Thus, the corrected starting point for general population is 43.4 mg/m³ for inhalation.An assessment factor 10 was included to take care of possible intraspecies differences within the general population and an assessment factor of 2.5 for other interspecies differences was considered.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

2

Justification:

The DNEL is based on a sub-chronic study performed in rats over a time period of 90 days.

AF for interspecies differences (allometric scaling):

1

Justification:

Interspecies differences were taken into account for the conversion of the rat oral NOAEL into a corrected inhalatory NOAEC considering allometric scaling for the respiratory volumes (modification of the dose descriptor starting point). Thus, no additional AF is applicable.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default value for general population according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high-quality study.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

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:

0.5 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):

200

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAELcorr = NOAELoral*(ABSoral-rat/ABSdermal-human) = (100 mg/kg bw/day)*(1/1) = 100 mg/kg bw/day.

Although dermal absorption is considered relatively low, a default value of 100% skin absorption is used according to ECHA guidance R7 C, since exact dermal absorption data are not available and the test substance has a molecular weight of 434.45 g/mol and a log P of 3.24.

According to ECHA guidance R 7C, 10% skin absorption is only considered in case the molecular mass is above 500 and log P is outside the range [-1, 4] (de Heer et al., 1999), otherwise a default value of 100% skin absorption has to be applied.

 

AF for dose response relationship:

1

Justification:

DNEL is based on a NOAEL

AF for differences in duration of exposure:

2

Justification:

DNEL is based on a 90-day study

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for rats

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

AF for the quality of the whole database:

1

Justification:

The selected study is the most adequate and reliable study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 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):

200

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 is required.

AF for dose response relationship:

1

Justification:

DNEL is based on a NOAEL

AF for differences in duration of exposure:

2

Justification:

DNEL is based on a 90-day study

AF for interspecies differences (allometric scaling):

4

Justification:

Default AF for rats

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

AF for the quality of the whole database:

1

Justification:

The selected study is the most adequate and reliable study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified