Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
13.5
Dose descriptor starting point:
NOAEC
Value:
400 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
201 mg/m³
Explanation for the modification of the dose descriptor starting point:

correction factor for respiratory volume for light activity at work: 0.67 (6.7 m³ / 10 m³), default value

correction factor for differences between human and experimental exposure conditions: 0.75 (6 h/d vs. 8 h/d), default value

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
subcronic to chronic
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
0.54
Justification:
40 years working life / 75 years expected lifetime vs. chronic lifetime exposure: 0.54
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:
7.8 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):
54
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

correction for differences between human and experimental exposure conditions: 1.4 (7 d vs. 5 d), default value

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
subcronic to chronic
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
0.54
Justification:
40 years working life / 75 years expected lifetime vs. chronic lifetime exposure: 0.54
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

Isononylbenzoate was extensively tested to detect and evaluate potential toxicological properties. The test item showed no acute toxicity after oral, dermal, and inhalative exposure of rats up to the maximum dose /concentration required by the respective guideline or achievable under test conditions. In irritation/corrosion studies according to the relevant guidelines, the test item displayed no corrosive properties and was only mildly irritating to skin and eyes. Furthermore, isononylbenzoate showd no sensitising properties in a guinea pig maximisation study according to OECD 406.

In repeated dose studies, treatment-related changes were observed in a subacute 28 day study above 150 mg/kg/day in female rats and at 150 mg/kg/day in male rats (hydorcarbon nephropathy, peculiar to male rats with no relevance to human health). In a subchronic 90 day repeated dose study in the rat, the NOAEL for both gender was 300 mg/kg/day.

The fact that the NOAEL of the 28 day study is lower than the NOAEL of the 90 day study is certainly a result of the corresponding dose selections. Therefore, the 90 day repeated dose toxicity NOAEL of 300 mg/kg/day was used as starting point for calculation of the corresponding DNEL.

In a 90 day repeated dose inhalation study treatment related changes were observed only in the highest dose group tested. Based on the irritant effects in the highest dose group, the No-Observed-Adverse-Effect-Level (NOAEL) was considered to be 0.400 mg/L air (= 400 mg/m3).

The test item was not mutagnic/genotoxic, neither in vitro in Ames test and chromosomal aberration test or in vivo in a micronucleus test in the rat.

In a study with reproductive screening parameters according to OECD 421, exposure to isononylbenzoate revealed no treatment-related changes of reproductive parameters. Unspecific developmental effects were recorded in an OECD 414 study with rats, but were regarded as secondary effects due to associated maternal toxicity. In rabbits (OECD 414), statistically significant reduction in gravid uterus weight and increase in the intrauterine death at the early stage of gestation was noted in the high-dose group when compared to the controls. On the basis of these results, the mid-dose level of 150 mg/kg/day of the test item was considered as the NOAEL. The Extended One-Generation Reproductive Toxicity study (OECD 433) however showed developmental effects in F1 pups. The NOAEL for general toxicity for Parental females, F1 (Cohort 1A and Cohort 1B males and females) and for reproductive and developmental toxicity of F2 pups was considered to be 300 mg/kg/day.

The calculation of the worker DNEL for inhalation, systemic effects long-term based on the OECD 433 by using the NOAEL of 300 mg/kg, results in a DNEL of 29.6 mg/m³.

The DNEL derivation method is as followed:

Dose descriptor starting point: NOAEL

Modified dose descriptor starting point: NOAEC

Overall Assessment Factor: 12.5

AF for dose response relationship: 1 (Default (DNEL calculator))

AF for difference in duration of exposure: 1 (susceptible window fully covered, no time extrapolation required)

AF for interspecies differences (allometric scaling): 1 (Default (DNEL calculator))

AF for other interspecies differences: 2.5 (Default (DNEL calculator))

AF for intraspecies differences: 5 (Default (DNEL calculator))

AF for the quality of the whole database: 1 (Default (DNEL calculator))

correction for differences in respiratory volume: 2.63 (default)

correction for differences in bioavailability: 0.5 (default)

correction for light activity at work: 0.67

correction for differences between human and experimental exposure conditions: 1.4 (5 d vs. 7 d)

Because the existing DNEL of 14.9 mg/m³ based on the 90-day inhalation study (NOAEL = 400 mg/m³) is lower, it will be further used as a worst case consideration.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.43 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEC
Value:
400 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
71.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

correction for differences between human and experimental exposure conditions: (5 d / 7 d) and (6 h/d / 24 h/d)

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
1.5 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:
300 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
1.5 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:
300 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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