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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.29 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
132.24 mg/m³
AF for differences in duration of exposure:
2
Justification:
subchronic study factor of 2
AF for interspecies differences (allometric scaling):
2.5
AF for other interspecies differences:
2.5
Justification:
interspecies factor of 2.5
AF for intraspecies differences:
5
Justification:
worker factor of 5
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:
41.67 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
60
Dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
2
Justification:
subchronic study factor of 2
AF for other interspecies differences:
2.5
Justification:
interspecies factor of 2.5
AF for intraspecies differences:
2.4
Justification:
intraspecies factor 2.4
AF for remaining uncertainties:
5
Justification:
worker population factor of 5
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

The most appropriate endpoint for derivation of DNELs is the rat oral NOAEL of 150 mg/kgbw/day assumed from a well-conducted sub-chronic 90 day study, based on liver toxicity at higher doses. In all cases, calculations were based on default assumptions as defined in the REACH guidance document.


 


Based on the acute toxicity data, DNELs do not need to be derived for local or systemic effects for the worker population since DIDP has a low potential for acute toxicity. For worker long term exposure – local effects, DNELs do not need to be derived since no significant local effects were noted during the repeated dose studies.


 


Worker long term exposure – systemic effects, (inhalation) DNELs were calculated from the rat oral NOAEL of 150 mg/kg-bw/day. Assumptions on absorption rate differences for route to route extrapolation were 50% absorption via oral exposure, 100% absorption via inhalation, and 4% absorption via dermal exposure.


 


The corrected worker dermal starting point was 2500 mg/kg-bw/day and was derived from the NOAEL observed in rabbits. The value was divided by an adjustment factor of 60 (subchronic study factor of 2, intraspecies factor of 2.4, interspecies factor of 2.5, and the worker population factor of 5), leading to a DNEL of 41.67 mg/kg-bw-day.


 


The corrected worker inhalation starting point was 132.24 mg/m3 and was derived from the NOAEL multiplied by the inverse of the standard respiratory volume of the rat during an 8 hour period (2.63) multiplied by the absorption ratio of the oral absorption rate of the rat (50%) to the inhalation absorption rate of humans (100%) and finally multiplied by the ratio of standard respiratory volume for humans to the 8 hour worker standard respiratory volume: 150 * (2.62) * (50/100) * 0.67. The corrected starting point was adjusted by a factor of 25 (subchronic study factor of 2, interspecies factor of 2.5 and a worker factor of 5). This results in a calculated DNEL of 5.29 mg/m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
65.22 mg/m³
AF for differences in duration of exposure:
2
Justification:
subchronic study
AF for other interspecies differences:
2.5
AF for intraspecies differences:
2.4
AF for remaining uncertainties:
10
Justification:
general population factor of 10
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:
20.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
2
Justification:
subchronic study factor of 2
AF for other interspecies differences:
2.5
AF for intraspecies differences:
2.4
AF for remaining uncertainties:
10
Justification:
general population factor of 10
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:
0.75 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
AF for differences in duration of exposure:
2
Justification:
subchronic study factor of 2
AF for other interspecies differences:
2.5
AF for intraspecies differences:
4
AF for remaining uncertainties:
10
Justification:
general population factor
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

 


The most appropriate endpoint for derivation of DNELs is the rat oral NOAEL of 150 mg/kg-bw/ day assumed from a well-conducted sub-chronic 90 day study, based on liver toxicity at higher doses. In all cases, calculations were based on default assumptions as defined in the REACH guidance document.


 


Based on the acute toxicity data, DNELs do not need to be derived for local or systemic effects for the general population since DIDP has a low potential for acute toxicity. For general population long term exposure – local effects, DNELs do not need to be derived since no local effects were noted during the repeated dose studies.


 


General population long term exposure – systemic effects, (oral and inhalation) DNELs were calculated from the rat oral NOAEL of 150 mg/kg-bw/day. Assumptions on absorption rate differences for route to route extrapolation were 50% absorption via oral exposure, 100% absorption via inhalation, and 4% absorption via dermal exposure.


 


The corrected dermal general population starting point was 2500 mg/kg-bw/day and was derived from the rabbit NOAEL. The value was divided by an adjustment factor of 120 (subchronic study factor of 2, intraspecies factor of 2.4, interspecies factor of 2.5, and the general population factor of 10), leading to a DNEL of 20.83 mg/kg-bw-day.


 


The corrected general population inhalation starting point was 65.22 mg/m3 and was derived from the NOAEL multiplied by the inverse of the standard respiratory volume of the rat during a 24 hour period (0.87) multiplied by the absorption ratio of the oral absorption rate of the rat (50%) to the inhalation absorption rate of humans (100%): 150 * (0.87) * (50/100) = 65.22. The corrected starting point was adjusted by a factor of 50 (subchronic study factor of 2, interspecies factor of 2.5 and a general population factor of 10). This results in a calculated DNEL of 1.3 mg/m3.


 


The corrected general population oral starting point is 150 mg/kg-bw-day since we assume the oral absorption rate of humans is equivalent to rats. An adjustment factor of 200 is applied (subchronic study factor of 2, intraspecies factor of 4, interspecies factor of 2.5, and a general population factor of 10) leading to a DNEL of 0.75 mg/kg-bw/day.