Bis(2-ethylhexyl) phthalate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.6 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

7.5

Modified dose descriptor starting point:

NOAEC

Value:

11.85 mg/m³

Explanation for the modification of the dose descriptor starting point:

After oral or inhalative exposure only sytemic but no local effects were observed.

AF for dose response relationship:

1

Justification:

ECHA Guidance - NOAEL

AF for differences in duration of exposure:

1

Justification:

ECHA Guidance - long-term study

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA Guidance - inhalation route

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

3

Justification:

EU Risk Asseessment Report, see REACH Annex 1, 0.5

AF for the quality of the whole database:

1

Justification:

ECHA Guidance

AF for remaining uncertainties:

1

Justification:

ECHA Guidance

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:

3.4 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEL

Value:

100.8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

After oral and dermal exposure especially sytemic toxicity was observed.

AF for dose response relationship:

1

Justification:

ECHA Guidance - NOAEL

AF for differences in duration of exposure:

1

Justification:

ECHA Guidance - long-term study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Guidance

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

3

Justification:

EU Risk Asseessment Report, see REACH Annex 1, 0.5

AF for the quality of the whole database:

1

Justification:

ECHA Guidance

AF for remaining uncertainties:

1

Justification:

ECHA Guidance

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

 Long –term – inhalation, systemic toxicity

NOAEL of 4.8 mg/kg bw/d for reproductive and developmental effects observed in 3-generation oral study in rats (Wolfe and Layton, 2004).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 4.8 mg/kg bw/day	NOAEL from 3-Generation study in rats
Step 2) Modification of starting point	0.38 m^3/kg bw 75/75 6.7 m^3/10 m^3 7/5	- Conversion into inhalation NAEC (in mg/m^3) by using an 8-hour respiratory volume for the rat. - Correction for 75% bioavailability for inhalation in humans and 75% for oral absorption in adult rats - Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m^3/10 m^3). - Correction for use of NOAEL from feeding study with 7d exposure/week compared to worker's exposure 5 d/week
Step 3) Assessment factors
Interspecies	2.5	Only a factor 2.5 is used, and no allometric scaling factors is used
Intraspecies	3	In the EU RA of DEHP anassessment factors of 3 is used for potential intraspecies differences for the worker (see also see REACH Annex 1, 0.5 for justification).
Exposure duration	1	The NOAEL is based on a 3-Generation study
Dose response	1
Quality of database	1
DNEL	Value
based on NOAELrat	1.6 mg/m^3 = 4.8 x 1/0.38 x 75/75 x 6.7/10 x 7/5 x1/(2.5 x 3 x 1 x 1 x 1)

This DNEL of 1.6 mg/m³ corresponds to an oral intake of 230 µg/kg bw/day (assuming equal absorption rates of 75% for oral and inhalation exposure, 70 kg body weight, respiratory volume 10 m³ /work day: 1.6 mg/m³ x 10 m³/day x 1/70 kg bw).

Long –term – dermal, systemic toxicity

NOAEL of 4.8 mg/kg bw/d for reproductive and developmental effects observed in 3-generation oral study in rats (Wolfe and Layton, 2004).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 4.8 mg/kg bw/day	NOAEL from 3-Generation study in rats
Step 2) Modification of starting point	75/5 7/5	- Correction for 5%bioavailability for dermal exposure in human and 75% for oral absorption in adults rats  - Correction for use of NOAEL from feeding study with 7d exposure/week compared to worker's exposure 5 d/week
Step 3) Assessment factors
Interspecies	2.5 x 4
Intraspecies	3	In the EU RA of DEHP anassessment factors of 3 is used for potential intraspecies differences for the worker (see also see REACH Annex 1, 0.5 for justification).
Exposure duration	1	The NOAEL is based on a 2-year study
Dose response	1
Quality of database	1
DNEL	Value
based on NOAELrats	3.4 mg/kg bw/day = 4.8 x 75/5 x 7/5 x 1/(10 x 3 x 1 x 1 x 1)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

4.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

After oral or inhalative exposure only sytemic but no local effects were observed.

AF for dose response relationship:

1

Justification:

ECHA Guidance - NOAEL

AF for differences in duration of exposure:

1

Justification:

ECHA Guidance - long-term study

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA Guidance - inhalation route

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance

AF for the quality of the whole database:

1

Justification:

ECHA Guidance

AF for remaining uncertainties:

1

Justification:

ECHA Guidance

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:

0.72 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

72 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

After oral and dermal exposure especially sytemic toxicity was observed.

AF for dose response relationship:

1

Justification:

ECHA Guidance - NOAEL

AF for differences in duration of exposure:

1

Justification:

ECHA Guidance - long-term study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Guidance

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance

AF for the quality of the whole database:

1

Justification:

ECHA Guidance

AF for remaining uncertainties:

1

Justification:

ECHA Guidance

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:

0.036 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

3.6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route to route extrapolation

AF for dose response relationship:

1

Justification:

ECHA Guidance - NOAEL

AF for differences in duration of exposure:

1

Justification:

ECHA Guidance - long-term study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Guidance

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance

AF for the quality of the whole database:

1

Justification:

ECHA Guidance

AF for remaining uncertainties:

1

Justification:

ECHA Guidance

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

Long –term – inhalation, systemic toxicity

NOAEL of 4.8 mg/kg bw/d for reproductive and developmental effects observed in 3-generation oral study in rats (Wolfe and Layton, 2004).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 4.8 mg/kg bw/day	NOAEL from 3-Generation study in rats
Step 2) Modification of starting point	1.15 m^3/kg bw 75/75 (adults) 75/100 (children)	- Conversion into inhalation NAEC (in mg/m^3) by using a 24-hour respiratory volume for the rat.  - no difference in inhalative bioavailability assumed: 75% bioavailability for inhalative exposure in adult humans and 75% for oral absorption in adult rats - correction factor 75/100 for children
Step 3) Assessment factors
Interspecies	2.5	Only a factor 2.5 is used, and no allometric scaling factors is used
Intraspecies	10
Exposure duration	1	The NOAEL is based on a 3-Generation study
Dose response	1
Quality of database	1
DNEL	Value
based on NOAELrats	0.17 mg/m^3(0.04 ppm) for adults = 4.8 x 1/1.15 x 75/75 x 1/(2.5 x 10 x 1 x 1 x 1)  0.13 mg/m^3(0.04 ppm) for children = 4.8 x 1/1.15 x 75/100 x 1/(2.5 x 10 x 1 x 1 x 1)

Long –term – oral, systemic toxicity

NOAEL of 4.8 mg/kg bw/d for reproductive and developmental effects observed in 3-generation oral study in rats (Wolfe and Layton, 2004).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 4.8 mg/kg bw/day	NOAEL from 3 -Generation study in rats
Step 2) Modification of starting point	75/75 (adults) 75/100 (children)	- no difference in oral bioavailability assumed: 75% bioavailability for oral exposure in adult humans and 75% for oral absorption in adult rats - correction factor 75/100 for children
Step 3) Assessment factors
Interspecies	2.5 x 4
Intraspecies	10
Exposure duration	1	The NOAEL is based on a 3 -Generation study
Dose response	1
Quality of database	1
DNEL	Value
based on NOAELrats	0.048 mg/kg bw/d for adults  = 4.8 x 75/75 x 1/(10 x 10 x 1 x 1 x 1) 0.036 mg/kg bw/d for children = 4.8 x 75/100 x 1/(10 x 10 x 1 x 1 x 1)

 Long –term – dermal, systemic toxicity

NOAEL of 4.8 mg/kg bw/d for reproductive and developmental effects observed in 3-generation oral study in rats (Wolfe and Layton, 2004).

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 4.8 mg/kg bw/day	NOAEL from 3-Generation study in rats
Step 2) Modification of starting point	75/5	Correction for 5%bioavailability for dermal exposure in humans and 75% for oral absorption in adult rats
Step 3) Assessment factors
Interspecies	2.5 x 4
Intraspecies	10
Exposure duration	1	The NOAEL is based on 3-Generation study
Dose response	1
Quality of database	1
DNEL	Value
based on NOAELrats	0.72 mg/kg bw/d = 4.8 x 75/5 x 1/(10 x 10 x 1 x 1 x 1)