Registration Dossier

Administrative data

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
DNEL 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
DNEL 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 m3/kg bw



75/75


6.7 m3/10 m3

7/5

- Conversion into inhalation NAEC (in mg/m3) 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 m3/10 m3).

- 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/m3

= 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
DNEL 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
DNEL 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
DNEL 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 m3/kg bw



75/75 (adults)

75/100 (children)

- Conversion into inhalation NAEC (in mg/m3) 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/m3(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/m3(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)