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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
51.72 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
23
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
366 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

General remarks

The most appropriate endpoint for derivation of DNELs is the rat oral NOAEL of 88 mg/kg-bw/day assumed from a well-conducted chronic / carcinogenicity rat study according to GLP (Moore, 1998), based on liver toxicity at higher doses consisting of hepatic biochemical changes (increased ALT, AST), of liver weight increase in both sexes concurrently with histopathological findings, and increased kidney weight in both sexes. This NOAEL is conservative by nature since the mechanism of toxicity, peroxisome proliferation via PPARα, is not relevant to humans. In all cases, calculations were based on default assumptions as defined in the REACH guidance document

WORKERS

Inhalation

Due to its extremely low vapour pressure, DINP vapour phase concentrations are unlikely to attain high levels, even at high temperatures used in some industrial conditions. At 20ºC, DINP has a vapour pressure of 6E10-5 Pa and a calculated saturated vapour concentration of 10 µg/m3. 

At high temperatures and mechanical pressures, aerosol formation is observed with DINP like with other phthalates. Exposure to aerosol is therefore possible in any situation where pure DINP is heated or materials containing DINP are heated under influence of mechanical pressure. Exposure to DINP aerosol is likely to result in limited absorption through the lungs and is more likely to result in oral absorption due to mucocilliary clearance. The protective value used to calculate and inhalation DNEL is derived from the oral NOAEL 88 mg/kg/day as opposed to the data presented in the 2-week repeated dose study with aerosolized DIDP in which the limit dose was tested and no systemic effects were reported. 

Dose descriptor

rat oral NOAEL = 88 mg/kg/day

Assumptions

100% oral absorption regardless of species

100% inhalation absorption regardless of species

Modification of dose descriptorcalculation B.3 in ECHA Guidance R.8

 

inhalatory NOAEC = oral NOAEL * (1/ sRV rat 8h) * (ABS oral / ABS inh) * (sRV human / wRV)

inhalatory NOAEC= 88 * (1/0.38) * (100/100) * (6.7 / 10)

inhalatory NOAEC = 155.16 mg/m3

Assessment factors – Based on ECETOC guidance document #86

Uncertainty

AF

Justification

workers

3

default workers

Overall AF

3

 

DNELworker inhalation= 155.16 mg/m3/ 3

                                             = 51.72 mg/m3


Dermal

DINP, like other high molecular weight phthalates, has a very low dermal penetration rate (2-4%). While a repeated dose dermal study is available for DINP, it is not suitable for DNEL calculation due to several study limitations;it is an old study (1969) performed prior to GLP, a small number of animals were used (n=4 per group where 2 were abraded and 2 were not), there was an in-house infection in which animals in the control and treated groups died and the others required pharmacological intervention, an incomplete histopathological analysis was performed (only liver, kidney, and skin were examined).

 

A dermal DNEL will be calculated from route to route extrapolation from the rat oral NOAEL of 88 mg/kg/day. This value is expected to be protective since there are clear dose responses via the oral route of exposure and it is highly unlikely that enough material could be applied to animals, since the dermal penetration rate is so low (2%), to observe similar effects.

Dose descriptor 

rat oral NOAEL = 88 mg/kg/day.

Assumptions

100% oral absorption regardless of species

2% dermal absorption regardless of species

Modification of dose descriptor

Route-to-route extrapolation (calculation B.5 in ECHA Guidance R.8):

dermal NOAEL = oral NOAEL * (ABS oral / ABS dermal)

dermal NOAEL = 88 mg/kg/day * (100/2)

dermal NOAEL = 4400 mg/kg/day

Assessment factors – Based on ECETOC guidance document #86

Uncertainty

AF

Justification

Allometric scaling

4

default for the rat

Intraspecies differences

3

default AF for workers

Overall AF

12

 


DNELworker dermal
   = 4400 mg/kg bwt/d / 12

= 366 mg/kg bwt/d

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
15.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
220 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

General remarks

The most appropriate endpoint for derivation of DNELs is the rat oral NOAEL of 88 mg/kg-bw/day assumed from a well-conducted chronic / carcinogenicity rat study according to GLP (Moore, 1998), based on liver toxicity at higher doses consisting of hepatic biochemical changes (increased ALT, AST), of liver weight increase in both sexes concurrently with histopathological findings, and increased kidney weight in both sexes. This NOAEL is conservative by nature since the mechanism of toxicity, peroxisome proliferation via PPARα, is not relevant to humans. In all cases, calculations were based on default assumptions as defined in the REACH guidance document. 

GENERAL POPULATION

Inhalation

Due to its extremely low vapour pressure, DINP vapour phase concentrations are unlikely to attain high levels, even at high temperatures used in some industrial conditions. At 20ºC, DINP has a vapour pressure of 6E10-5 Pa and a calculated saturated vapour concentration of 10 µg/m3. 

At high temperatures and mechanical pressures, aerosol formation is observed with DINP like with other phthalates. Exposure to aerosol is therefore possible in any situation where pure DINP is heated or materials containing DINP are heated under influence of mechanical pressure. Exposure to DINP aerosol is likely to result in limited absorption through the lungs and is more likely to result in oral absorption due to mucocilliary clearance. The protective value used to calculate and inhalation DNEL is derived from the oral NOAEL 88 mg/kg/day as opposed to the data presented in the 2-week repeated dose study with aerosolized DIDP in which the limit dose was tested and no systemic effects were reported. 

Dose descriptor

rat oral NOAEL = 88 mg/kg/day

Assumptions

100% oral absorption regardless of species

100% inhalation absorption regardless of species

Modification of dose descriptorcalculation B.3 in ECHA Guidance R.8

 

inhalatory NOAEC = oral NOAEL * (1/ sRV rat 24h) * (ABS oral / ABS inh)

inhalatory NOAEC= 88 * (1/1.15) * (100/100) * (6.7 / 10)

inhalatory NOAEC = 76.52 mg/m3

Assessment factors – based on ECETOC Guidance document #86

Uncertainty

AF

Justification

workers

5

default population

Overall AF

5

 

DNELpopulation inhalation            = 76.52 mg/m3/ 5

                                              = 15.30 mg/m3


Dermal

DINP, like other high molecular weight phthalates, has a very low dermal penetration rate (2-4%). While a repeated dose dermal study is available for DINP, it is not suitable for DNEL calculation due to several study limitations;it is an old study (1969) performed prior to GLP, a small number of animals were used (n=4 per group where 2 were abraded and 2 were not), there was an in-house infection in which animals in the control and treated groups died and the others required pharmacological intervention, an incomplete histopathological analysis was performed (only liver, kidney, and skin were examined).

 

A dermal DNEL will be calculated from route to route extrapolation from the rat oral NOAEL of 88 mg/kg/day. This value is expected to be protective since there are clear dose responses via the oral route of exposure and it is highly unlikely that enough material could be applied to animals, since the dermal penetration rate is so low (2%), to observe similar effects.

Dose descriptor 

rat oral NOAEL = 88 mg/kg/day.

Assumptions

100% oral absorption regardless of species

2% dermal absorption regardless of species

Modification of dose descriptor

Route-to-route extrapolation (calculation B.5 in ECHA Guidance R.8):

dermal NOAEL = oral NOAEL * (ABS oral / ABS dermal)

dermal NOAEL = 88 mg/kg/day * (100/2)

dermal NOAEL = 4400 mg/kg/day

Assessment factors

Uncertainty

AF

Justification

Allometric scaling

4

default for the rat

Intraspecies differences

5

default AF for population

Overall AF

20

 


DNELpopulation dermal=
 4400 mg/kg bwt/d / 20

= 220 mg/kg bwt/d

Oral

Dose descriptor 

rat oral NOAEL = 88 mg/kg/day

Modification of dose descriptor

No modification is required (daily dosing)

Assessment factors – Based on ECETOC guidance document #86

Uncertainty

AF

Justification

Interspecies differences

4

default for rat

Intraspecies differences

5

default AF for general population

Overall AF

20

 

DNELl-t oral            = 88 mg/kg bwt/d / 20

= 4.4 mg/kg bwt/d