Diisotridecyl phthalate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44.08 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

6

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:

312.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

24

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat subchronic NOAEL.

 

The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:

 

• Although "residual" interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.

 

• Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.

 

Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that "Care should be taken to avoid double counting several aspects when multiplying the individual factors." Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in "double counting", and if used inappropriately, would lead to a large, conservative overall assessment factor.

 

In order to retain the scientific credibility in its DNEL setting process, we will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs.

 

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These "peaks" are normally associated with inhalation exposure but are less common for skin contact and ingestion (Appendix R.8-8). DTDP is not classified for acute toxicity; oral, dermal or inhalation. It does not present an acute hazard following skin and exposure via the oral route is not relevant for workers. 

 

Irritation

DTDP is not classified as an irritant and does not require the derivation of a DNEL for this endpoint. 

 

Long-term systemic effects

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity testing. The following DNELs are conservative by nature and are protective of all adverse effects; such as carcinogenicity and reproductive/developmental effects.  

For DTDP, the following NOAEC, presented in the IUCLID dossier, is deemed to be substantially protective of all potential adverse effects. 

 

Oral:
subchronic effects for DIDP: rat NOAEL = 150 mg/kg bw/d

 

Inhalation (no systemic effects):

route-to-route extrapolation from oral NOAEL

 

Dermal (no systemic effects):

route-to-route extrapolation from oral NOAEL

 

Dermal

DTDP, like other high molecular weight phthalates, is anticipated to have 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 150 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 = 150 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 = 150 mg/kg/day * (100/2)

dermal NOAEL = 7500 mg/kg/day

 

Assessment factors ¿ Based on ECETOC guidance document #86

Uncertainty	AF	Justification
Allometric scaling	4	default for the rat
Subchronic study	2	subchronic to chronic extrapolation
Intraspecies differences	3	default AF for workers
Overall AF	24

DNEL worker dermal= 7500 mg/kg bwt/d / 24

= 312.50 mg/kg bwt/d

 

Inhalation

Due to its extremely low vapour pressure, DTDP vapour phase concentrations are unlikely to attain high levels, even at high temperatures used in some industrial conditions. At high temperatures and mechanical pressures, aerosol formation is expected with DTDP like with other phthalates. Exposure to aerosol is therefore possible in any situation where pure DTDP is heated or materials containing DTDP are heated under influence of mechanical pressure. Exposure to DTDP 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 150 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 = 150 mg/kg/day

 

Assumptions

100% oral absorption regardless of species

100% inhalation absorption regardless of species

 

Modification of dose descriptor calculation B.3 in ECHA Guidance R.8

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

inhalatory NOAEC= 150 * (1/0.38) * (100/100) * (6.7 / 10)

inhalatory NOAEC = 264.47 mg/m³

 

Assessment factors - Based on ECETOC guidance document #86

Uncertainty	AF	Justification
subchronic study	2	subchronic study
workers	3	default workers
Overall AF	6

DNEL worker inhalation      = 264.47 mg/m³/ 6

                                             = 44.08 mg/m³

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.04 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

10

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:

187.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DMEL (Derived Minimum Effect Level)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.75 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat subchronic NOAEL.

 

The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:

 

• Although ¿residual¿ interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.

 

• Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.

 

Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that "Care should be taken to avoid double counting several aspects when multiplying the individual factors." Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in "double counting", and if used inappropriately, would lead to a large, conservative overall assessment factor.

 

In order to retain the scientific credibility in its DNEL setting process, we will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs.

 

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These "peaks" are normally associated with inhalation exposure but are less common for skin contact and ingestion (Appendix R.8-8). DTDP is not classified for acute toxicity; oral, dermal or inhalation. It does not present an acute hazard following skin and exposure via the oral route is not relevant for workers. 

 

Irritation

DTDP is not classified as an irritant and does not require the derivation of a DNEL for this endpoint. 

 

Long-term systemic effects

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity testing. The following DNELs are conservative by nature and are protective of all adverse effects; such as carcinogenicity and reproductive/developmental effects.  

For DTDP, the following NOAEC, presented in the IUCLID dossier, is deemed to be substantially protective of all potential adverse effects. 

 

Oral:
subchronic effects for DIDP: rat NOAEL = 150 mg/kg bw/d

 

Inhalation (no systemic effects):

route-to-route extrapolation from oral NOAEL

 

Dermal (no systemic effects):

route-to-route extrapolation from oral NOAEL

Inhalation

Due to its extremely low vapour pressure, DTDP vapour phase concentrations are unlikely to attain high levels, even at high temperatures used in some industrial conditions. At high temperatures and mechanical pressures, aerosol formation is expected with DTDP like with other phthalates. Exposure to aerosol is therefore possible in any situation where pure DTDP is heated or materials containing DTDP are heated under influence of mechanical pressure. Exposure to DTDP 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 150 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 = 150 mg/kg/day

 

Assumptions

100% oral absorption regardless of species

100% inhalation absorption regardless of species

 

Modification of dose descriptor calculation B.3 in ECHA Guidance R.8

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

inhalatory NOAEC= 150 * (1/1.15) * (100/100) * (6.7 / 10)

inhalatory NOAEC = 130.43 mg/m³

Assessment factors - based on ECETOC Guidance document #86

Uncertainty	AF	Justification
subchronic study	2	subchronic to chronic extrapolation
workers	5	default population
Overall AF	10

DNELpopulation inhalation = 130.43 mg/m³/ 10

= 13.04 mg/m³

Oral

Dose descriptor 

rat oral NOAEL = 150 mg/kg/day

 

Modification of dose descriptor

No modification is required (daily dosing)

 

Assessment factors - Based on ECETOC guidance document #86

Uncertainty	AF	Justification
subchronic study	2	subchronic to chronic extrapolation
Interspecies differences	4	default for rat
Intraspecies differences	5	default AF for general population
Overall AF	40

DNEL population oral = 150 mg/kg bwt/d / 40

 = 3.75 mg/kg bwt/d

Dermal

DTDP, like other high molecular weight phthalates, is anticipated to have 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 150 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 = 150 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 = 150 mg/kg/day * (100/2)

dermal NOAEL = 7500 mg/kg/day

Assessment factors - Based on ECETOC guidance document #86

Uncertainty	AF	Justification
Allometric scaling	4	default for the rat
Subchronic study	2	subchronic to chronic extrapolation
Intraspecies differences	5	default AF for population
Overall AF	40

DNEL population dermal = 7500 mg/kg bwt/d / 40

= 187.50 mg/kg bwt/d