Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.4 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):
10
Modified dose descriptor starting point:
NOAEC
Value:
264.47 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by the inhalation route. For further details please refer to the discussion.
AF for dose response relationship:
1
Justification:
NOAEL used as starting point. The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default value for extrapolation from subchronic to chronic exposure is used.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.
AF for other interspecies differences:
1
Justification:
There is evidence to suggest that target organ toxicity (hepatotoxicity) is associated with peroxisome proliferation which is of minor relevance for human risk assessment. Therefore, no additional factor for interspecies differences is used.
AF for intraspecies differences:
5
Justification:
Default factor for workers
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient (GLP guideline studies).
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factor is required.
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:
37.5 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):
40
Modified dose descriptor starting point:
NOAEL
Value:
1 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by the dermal route. Please refer to the discussion.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default value for extrapolation from subchronic to chronic exposure is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is evidence to suggest that target organ toxicity (hepatotoxicity) is associated with peroxisome proliferation which is of minor relevance for human risk assessment. Therefore, no additional factor for interspecies differences is used.
AF for intraspecies differences:
5
Justification:
The default value for "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient (GLP guideline studies).
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factor is required.
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 exposure - systemic effects

In the absence of suitable inhalation or dermal toxicity studies with repeated exposure, the worker-DNEL long-term for inhalation and dermal route - systemic was derived from the lowest NOAEL obtained in repeated dose studies available for the main component Dipropylheptyladipat, i.e. the 90 days oral toxicity study in rats (BASF SE 2015; NOAEL = 209 mg/kg bw/day for males and 244 mg/kg bw/day for females) and the oral prenatal developmental toxicity study in rats (WIL 2015, NOAEL = 200 mg/kg bw/day). The leading health effect was hepatotoxicity observed at higher doses in both studies. The lowest NOAEL obtained from repeated dose studies with the main component Dipropylheptyladipat (= 200 mg/kg bw/day) was used as basis for the calculation of long-term systemic DNELs.

Inhalation exposure

A corrected inhalatory NOAEC (NOAECcorr) was calculated using the default respiratory volume for the rat and a correction for the difference between human respiratory rates under standard conditions and under conditions of light activity. Toxicokinetic studies with Diethylhexyladipat, a structural surrogate of the main component Dipropylheptyladipat, revealed an oral absorption of about 75% in rats. For human absorption after inhalation the worst case of 100% was assumed.

 

Calculation of the NOAECcorr

- Standard dose descriptor (NOAEL): 200 mg/kg bw/d

- Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d

- Oral absorption of the rat/inhalation absorption of humans (ABSoral-rat)/ABSinhal-human): 75/100

- Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

- Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Corrected inhalatory NOAEC for workers:

= NOAEL * (1/sRVrat) * (ABSoral-rat/ABSinhal-human) *(sRVhuman/wRV)

= 200 mg/kg bw/d * (1/0.38 m³/kg bw/d)* (75/100) * (6.7 m³/10 m³)

= 264.47 mg/m³

 

Dermal exposure

The dermal NOAEL was calculated by means of route-to-route extrapolation as follows:

NOAELdermal = NOAELoral*ABSoral-rat/ABSdermal-human = 200 mg/kg bw/day*75/10 = 1500 mg/kg bw/day

An oral absorption rate in rats (ABSoral-rat) of 75% was used with regards to toxicokinetics data of Diethylhexyladipat, a structural surrogate of the main component Dipropylheptyladipat. The dermal absorption rate in humans (ABSdermal-human) was assumed to be 10% because the main component Dipropylheptyladipat is not water soluble and possesses an logP value of 10.08 and a molecular weight of 426.68 g/mol.

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.Version: 2.1, ECHA-2012 -G-19 -EN.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.5 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):
20
Modified dose descriptor starting point:
NOAEC
Value:
130.43 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by the inhalation route.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default value for extrapolation from subchronic to chronic exposure is used.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.
AF for other interspecies differences:
1
Justification:
There is evidence to suggest that target organ toxicity (hepatotoxicity) is associated with peroxisome proliferation which is of minor relevance for human risk assessment. Therefore, no additional factor for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
Default factor for consumers
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient (GLP guideline studies).
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factor is required.
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:
18.75 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):
80
Modified dose descriptor starting point:
NOAEL
Value:
1 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by the dermal route.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default value for extrapolation from subchronic to chronic exposure is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is evidence to suggest that target organ toxicity (hepatotoxicity) is associated with peroxisome proliferation which is of minor relevance for human risk assessment. Therefore, no additional factor for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
Default factor for consumers
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient (GLP guideline studies).
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factor is required.
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:
2.5 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):
80
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default value for extrapolation from subchronic to chronic exposure is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
1
Justification:
There is evidence to suggest that target organ toxicity (hepatotoxicity) is associated with peroxisome proliferation which is of minor relevance for human risk assessment. Therefore, no additional factor for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
Default factor for consumers
AF for the quality of the whole database:
1
Justification:
The quality of the whole database is considered to be sufficient (GLP guideline studies).
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factor is 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

General population

In the absence of a suitable inhalation or dermal toxicity study with repeated exposure, the DNEL long-term for inhalation and dermal route - systemic was derived from the lowest NOAEL obtained in repeated dose studies available for the main component Dipropylheptyladipat, i.e. the 90 days oral toxicity study in rats (BASF SE 2015; NOAEL = 209 mg/kg bw/day for males and 244 mg/kg bw/day for females) and the oral prenatal developmental toxicity study in rats (WIL 2015, NOAEL = 200 mg/kg bw/day). The leading health effect was hepatotoxicity observed at higher doses in both studies. The lowest NOAEL obtained from repeated dose studies with the main component Dipropylheptyladipat (= 200 mg/kg bw/day) was used as basis for the calculation of long-term systemic DNELs.

Inhalation exposure

A corrected inhalatory NOAEC (NOAECcorr) was calculated using the default respiratory volume for the rat. Toxicokinetic studies with Diethylhexyladipat, a structural surrogate of the main component Dipropylheptyladipat, revealed an oral absorption of about 75% in rats. For human absorption after inhalation the worst case of 100% was assumed.

Calculation of the NOAECcorr

- Standard dose descriptor (NOAEL): 200 mg/kg bw/d

- Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw/d

- Oral absorption of the rat/inhalation absorption of humans (ABSoral-rat)/ABSinhal-human): 75/100

Corrected inhalatory NOAEC for general population:

= NOAEL * (1/sRVrat) * (ABSoral-rat/ABSinhal-human)

= 200 mg/kg bw/d * (1/1.15 m³/kg bw/d)* (75/100)

= 130.43 mg/m³

Dermal exposure

The dermal NOAEL was calculated by means of route-to-route extrapolation as follows:

NOAELdermal = NOAELoral*ABSoral-rat/ABSdermal-human = 200 mg/kg bw/day*75/10 = 1500 mg/kg bw/day

An oral absorption rate in rats (ABSoral-rat) of 75% was used with regards to toxicokinetics data of Diethylhexyladipat, a structural surrogate of the main component Dipropylheptyladipat. The dermal absorption rate in humans (ABSdermal-human) was assumed to be 10% because the main component Dipropylheptyladipat is not water soluble and possesses an logP value of 10.08 and a molecular weight of 426.68 g/mol.

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.Version: 2.1, ECHA-2012 -G-19 -EN.