Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Value:
24 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):
12.5
Dose descriptor starting point:
NOAEL
DNEL value:
170 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
300 mg/m³
Explanation for the modification of the dose descriptor starting point:
There is no reliable repeated dose inhalation data. For this substance it is unlikely that the toxicological profile is route dependent. Therefore the repeated dose oral data has been used. Diisotridecyl adipate is expeted to be rapidly absorbed from the gastro-intestinal tract, whereas dermal absorption is expected to be slow. There are no exact absorption factors available, therefore in conclusion it is expected that the absoption factors for all routes are 100 %, in this case this means an overestimation of the dermal DNELs. That means also an additional AF for route-to-route is not required.
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Some reliable chronic and subchronic studies on the read-across substance exist. However, the lowest NOAEL was found in a developmental study. Because of the good data base where cannot be observed lower NOAEL in correlation to duration of exposure an AF of more than 1 is not required.
AF for interspecies differences (allometric scaling):
1
Justification:
Not typically applied in the derivation of an inhalation DNEL.
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
workers
AF for the quality of the whole database:
1
Justification:
good quality
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
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:
no hazard identified
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):
50
Dose descriptor starting point:
NOAEL
DNEL value:
170 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
170 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal NOAEL is based on the oral NOAEL of 170 mg/kg bw/d and takes account of relative oral and dermal absorption of 100 %. Therefore the dermal NOAEL is equivalent to the oral NOAEL.
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Some reliable chronic and subchronic studies on the read-across substance exist. However, the lowest NOAEL was found in a developmental study. Because of the good data base where cannot be observed lower NOAEL in correlation to duration of exposure a AF of more than 1 is not required.
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
workers
AF for the quality of the whole database:
1
Justification:
good quality
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
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

Acute / short-term exposure - systemic effects

 

In acute toxicity studies, diisotridecyl adipate has been shown to be of low systemic toxicity.

 

LD50 oral: > 15000 mg/kg bw in rats (Moreno/Mobil, 1978a)

LD50 dermal: > 5000 mg/kg bw in rabbits (Moreno/Mobil, 1978b).

 

From present studies, reliable short-term dose response relations cannot be deduced. Available data do not provide sufficient information on sublethal toxic effects to gather NOAELs as starting points. DNELs cannot be derived.

In accordance with ECHA Guidance on information requirements and chemical safety assessment - Chapter R.8, DN(M)EL need not be derived in case of low acute toxicity.

 

Acute /short-term exposure - local effects

 

Diisotridecyl adipate is not irritating to skin or to eyes. Data on inhalation exposure could not be located.

From the data available, reliable dose descriptors cannot be obtained. DNELs cannot be derived as there are no suitable starting points.

 

Long term exposure systemic effects

 

Data for diisotridecyl adipate on long term-exposure could not be identified. To assess the risk of long-term exposure - systemic effects for diisotridecyl adipate, data for bis(-2 -ethylhexyl) adipate as supporting substance will be used based on the close structural relationship of both substances (Justification in more detail is presented in endpoint summary to section 7.1.1 - basic toxicokinetics).

 

For bis-(2 -ethylhexyl) adipate, several valid studies concerning repeated dose toxicity are available. Besides a 28 day oral study (Miyata, 2006), the substance was investigated by NTP in subchronic and chronic studies in two species (rat and mouse) (NTP, 1982). In addition, there is an oral one-generation reproduction toxicity study with an exposure period of 10 weeks for parental animals (Cefic, 1989).

Other administration routes have been examined for diisotridecyl adipate itself (Mobil, 1989, aerosol inhalation for 14 days) and for ditridecyl adipate (HPV TP, 2003, dermal,13 weeks). This data are of low reliability and are not used for the derivation of DNELs.

The most critical NOAEL was observed in the one-generation study (170 mg/kg bw/day - effects on the offspring: reduced total litter weight and reduced mean litter size). At the same time, this is the lowest NOAEL determined in repeated dose toxicity studies. This value will be taken for derivation of a DNEL for diisotridecyl adipate.

 

DNELs for diisotridecyl adipate

The NOAEL of 170 mg/kg bw/day determined for di-2-ethylhexyl adipate is used for the DNEL-derivation.

Worker long term exposure - systemic effects (oral, dermal and inhalation) DNELs were calculated form the NOAEL, assuming a 100 % dermal

(worst case) and inhalation rate.

 

DNEL dermal - systemic effects

According to ECHA TGD Guidance on information requirements and chemical safety assessment -Chapter R.8: Characterisation of dose[concentration]-response for human health, the NOAEL oral can be used for the deduction of a DNEL dermal without further adjustment. As default, absorption for oral and dermal route is considered equal as long as more definite experimental information is not available.

Assessment factors used are a) allometric scaling factor of 4, b) factor for remaining interspecies differences of 2.5, c) intraspecies factor (worker) of 5. The factor for sub-chronic to chronic exposure extrapolation is set to 1 as for developmental effects chronic exposure is not relevant. With a starting point NOAEL dermal of 170 mg/kg bw/day and an overall assessment factor of 50, a DNEL of 3.4 mg/kg bw/day for diisotridecyl adipate is calculated.

 

DNEL inhalation -systemic effects

The corrected worker inhalation starting point was the corrected NOAEC of 300 mg/m3 and was derived form the oral NOAEL of 170 mg/kg bw/day multiplying by the inverse of the standard respiratory volume of the rat during an 8 hour period (2.63) and multiplied by the ratio of standard respiratory volume for humans to the 8 hour worker standard respiratory volume (0.67). The corrected starting point was adjusted by a factor of 12.5

(factor for remaining interspecies differences 2.5, intraspecies factor (worker) 5, factor for sub-chronic to chronic exposure extrapolation 1, factor for route-to-route expected to be 1 (because the oral absorption is expected for this substance 100 % like the inhalative absorpion rate), resulting in an calculated DNEL of 24 mg/m3.

Long-term exposure - local effects

 

The irritation potential of diisotridecyl adipate is low as demonstrated in acute skin and eye irritation tests. Dose descriptors for long term exposure local effects are not available. DNELs for long-term-exposure local effects are not derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Value:
5.92 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
DNEL value:
170 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
148 mg/m³
Explanation for the modification of the dose descriptor starting point:
There is no repeated dose inhalation data. For this substance it is unlikely that the toxicological profile is route dependent. Therefore the repeated dose oral data has been used. Diisotridecyl adipate is expeted to be rapidly absorbed from the gastro-intestinal tract, whereas dermal absorption is expected to be slow. Therefore in conclusion It is expected that the absoption factors for all routes are 100 %, in this case this means an overestimation of the dermal DNELs. That means also an additional AF for route-to-route is not required.
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Some reliable chronic and subchronic studies on the read-across substance exist. However, the lowest NOAEL was found in a developmental study. Because of the good data base where cannot be observed lower NOAEL in correlation to duration of exposure a AF of more than 1 is not required.
AF for interspecies differences (allometric scaling):
1
Justification:
Not typically applied in the derivation of an inhalation DNEL.
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
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:
no hazard identified
Value:
1.7 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
Dose descriptor starting point:
NOAEL
DNEL value:
170 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
170 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal NOAEL is based on the oral NOAEL of 170 mg/kg bw/d and takes account of relative oral and dermal absorption of 100 %. Therefore the dermal NOAEL is equivalent to the oral NOAEL.
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Some reliable chronic and subchronic studies on the read-across substance exist. However, the lowest NOAEL was found in a developmental study. Because of the good data base where cannot be observed lower NOAEL in correlation to duration of exposure a AF of more than 1 is not required.
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default value
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
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:
no hazard identified
Value:
1.7 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
Dose descriptor starting point:
NOAEL
DNEL value:
170 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
170 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Some reliable chronic and subchronic studies on the read-across substance exist. However, the lowest NOAEL was found in a developmental study. Because of the good data base where cannot be observed lower NOAEL in correlation to duration of exposure a AF of more than 1 is not required.
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default value
AF for intraspecies differences:
10
Justification:
general population
AF for the quality of the whole database:
1
Justification:
good quality
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties identified
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

Acute / short-term exposure - systemic effects

 

In acute toxicity studies, diisotridecyl adipate has been shown to be of low systemic toxicity.

 

LD50 oral: > 15000 mg/kg bw in rats (Moreno/Mobil, 1978a)

LD50 dermal: > 5000 mg/kg bw in rabbits (Moreno/Mobil, 1978b).

 

From present studies, reliable short-term dose response relations cannot be deduced. Available data do not provide sufficient information on sublethal toxic effects to gather NOAELs as starting points. DNELs cannot be derived.

In accordance with ECHA Guidance on information requirements and chemical safety assessment - Chapter R.8, DN(M)EL need not be derived in case of low acute toxicity.

 

Acute /short-term exposure - local effects

 

Diisotridecyl adipate is not irritating to skin or to eyes. Data on inhalation exposure could not be located.

From the data available, reliable dose descriptors cannot be obtained. DNELs cannot be derived as there are no suitable starting points.

 

Long term exposure systemic effects

 

Data for diisotridecyl adipate on long term-exposure could not be identified. To assess the risk of long-term exposure - systemic effects for diisotridecyl adipate, data for di-2-ethylhexyl adipate as supporting substance will be used based on the close structural relationship of both substances (Justification in more detail is presented in endpoint summary to section 7.1.1 - basic toxicokinetics).

 

For di-2-ethylhexyl adipate, several valid studies concerning repeated dose toxicity are available. Besides a 28 day oral study (Miyata, 2006), the substance was investigated by NTP in subchronic and chronic studies in two species (rat and mouse) (NTP, 1982). In addition, there is an oral one-generation reproduction toxicity study with an exposure period of 10 weeks for parental animals (Cefic, 1989).

Other administration routes have been examined for diisotridecyl adipate itself (Mobil, 1989, aerosol inhalation for 14 days) and for ditridecyl adipate (HPV TP, 2003, dermal,13 weeks). This data are of low reliability and are not used for the derivation of DNELs.

The most critical NOAEL was observed in the one-generation study (170 mg/kg bw/day - effects on the offspring: reduced total litter weight and reduced mean litter size). At the same time, this is the lowest NOAEL determined in repeated dose toxicity studies. This value will be taken for derivation of a DNEL for diisotridecyl adipate.

 

DNELs for diisotridecyl adipate

The NOAEL of 170 mg/kg bw/day determined for di-2-ethylhexyl adipate is used for the DNEL-derivation.

General population long-term exposure - systemic effects (oral, dermal and inhalation) DNELs were calculated from the NOAEL, assuming a 100 % dermal (worst case) and inhalation absorption rate.

DNEL dermal and oral- systemic effects

According to ECHA TGD Guidance on information requirements and chemical safety assessment -Chapter R.8: Characterisation of dose[concentration]-response for human health, the NOAEL oral can be used for the deduction of a DNEL dermal without further adjustment. As default, absorption for oral and dermal route is considered equal as long as more definite experimental information is not available.

Assessment factors used are a) allometric scaling factor of 4, b) factor for remaining interspecies differences of 2.5, c) intraspecies factor (general population) of 10. The factor for sub-chronic to chronic exposure extrapolation is set to 1 as for developmental effects chronic exposure is not relevant. With a starting point NOAEL dermal of 170 mg/kg bw/day and an overall assessment factor of 100, a DNEL of 1.7 mg/kg bw/day for diisotridecyl adipate is calculated.

 

DNEL inhalation -systemic effects

The corrected general population inhalation starting point was the corrected NOAEC of 148 mg/m3 and was derived form the oral NOAEL of 170 mg/kg bw/day multiplying by the inverse of the standard respiratory volume of the rat during an 24 hour period (0.87). The corrected starting point was adjusted by a factor of 25 (factor for remaining interspecies differences 2.5, intraspecies factor (general population) 10, factor for sub-chronic to chronic exposure extrapolation 1, factor for route-to-route expected to be 1 (because the oral absorption is expected for this substance 100 % like the inhalative absorpion rate) resulting in a calculated DNEL of 5.92 mg/m3.

 

Long-term exposure - local effects

 

The irritation potential of diisotridecyl adipate is low as demonstrated in acute skin and eye irritation tests. Dose descriptors for long term exposure local effects are not available. DNELs for long-term-exposure local effects are not derived.