Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA, 2010; ECETOC, 2003, 2010
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
DNEL value:
264.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
The rat oral rat NOAEL was converted into a corrected inhalation NOAEC according to ECHA guidance (Chapter R.8: Characterisation of dose [concentration]-response for human health, Figure R. 8-3)
AF for dose response relationship:
1
Justification:
No toxicologically relevant findings when tested up to a limit dose of 1000 mg/kg bw/d
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for sub-acute to chronic extrapolation (ECHA guidance, Chapter R. 8)
AF for interspecies differences (allometric scaling):
1
Justification:
Default assessment factor for the inhalation route (ECHA guidance, Chapter R. 8)
AF for other interspecies differences:
1
Justification:
An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51).
AF for intraspecies differences:
3
Justification:
There are no data to quantify variability in susceptibility to the effects of exposure to 2,4,4-trimethylpentene in the human population. However the population exposed in the workplace is highly homogeneous and the health of the work force is typically good (healthy worker effect) while metabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since compensating mechanisms (including alternative pathways of elimination) are often present (ECETOC, 2003, 2010). Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 3 (i.e. the 90th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within workers.
AF for the quality of the whole database:
1
Justification:
No issues regarding quality of whole database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties present
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:
2.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA, 2010; ECETOC, 2003, 2010
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
DNEL value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The rat oral rat NOAEL was converted into a corrected dermal NOAEL after correcting for differences in uptake between the two routes of exposure.

AF for dose response relationship:
1
Justification:
No toxicologically relevant findings when tested up to an oral limit dose of 1000 mg/kg bw/d
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for sub-acute to chronic extrapolation (ECHA guidance, Chapter R. 8)
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in the rat (ECHA guidance, Chapter R. 8)
AF for other interspecies differences:
1
Justification:
An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51).
AF for intraspecies differences:
3
Justification:
There are no data to quantify variability in susceptibility to the effects of exposure to 2,4,4-trimethylpentene in the human population. However the population exposed in the workplace is highly homogeneous and the health of the work force is typically good (healthy worker effect) while metabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since compensating mechanisms (including alternative pathways of elimination) are often present (ECETOC, 2003, 2010). Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 3 (i.e. the 90th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within workers.
AF for the quality of the whole database:
1
Justification:
No issues regarding quality of whole database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties present
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 toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not necessary if no acute toxicity hazard leading to classification has been identified. Animal data for 2,4,4-trimethylpentene demonstrate that the acute oral (HLS, 1996a) and dermal (HLS, 1996b) LD50 values are greater than 2000 mg/kg bw, while the inhalation LC50 (WIL Research Laboratories, 2006a) is in excess of 19,171 mg/m3, the highest vapour concentration tested. No acute DNELs will therefore be derived for these routes of exposure.

Other information suggests that 2,4,4-trimethylpentane may cause transient CNS depression after ingestion, while a low kinematic viscosity (0.611 mm2/s at 40 degrees C) is consistent with a potential to damage the lungs if swallowed, with classification triggered in both instances. Qualitative risk characterisation will be conducted to address these endpoints as neither is suited to derivation of a quantitative DNEL.

Irritation/Sensitisation

2,4,4-Trimethylpentene is not irritating to skin (HLS, 1996c; WIL Research Laboratories, 2005a) or eye (HLS, 1996d; WIL Research Laboratories, 2005b), nor does it induce or elicit sensitisation after skin contact (HLS, 1997a). No quantitative DNELs or qualitative risk characterisation are therefore necessary for these endpoints.

Repeated dose toxicity

Results from oral sub-acute repeated dose toxicity testing of 2,4,4-trimethylpentene according to OECD Guideline 407 demonstrate no adverse systemic effects following gavage administration at 300 mg/kg bw/d for up to 28 days; higher treatments (1000 mg/kg bw/d) were associated with increased liver and kidney weights, however no accompanying histopathological alterations were present (HLS, 1997b). Findings of alpha-2u-globulin nephropathy described in other studies (HLS, 1997c; Swenberg and Schoonhoven, 2004) are not relevant to human risk assessment or to the derivation of long-term DNELs.

Genetic toxicity

Adequate information exists to characterise the genetic toxicity of 2,4,4-trimethylpentene. Results of bacterial mutation assays (HLS, 1996e; BioReliance, 2005) demonstrate an absence of mutagenic potential towards strains of Salmonella typhimurium when tested in the absence or presence of exogenous metabolic activation, while no evidence of clastogenicity was found in vitro after treatment of human lymphocytes (HLS, 1997d) or CHO cells (BioReliance, 2006) in the absence and in the presence of S9 fraction. No increase in micronucleated polychromatic erythrocytes was found in rats following a single 4-hr exposure to 19,171 mg/m3 2,4,4-trimethylpentene (WIL Research Laboratories, 2006a) ).

Reproductive / developmental toxicity

Results from an OECD 421 screening study showed no adverse effects on reproductive or developmental performance in rats (HLS, 1997c).

Mode of Action Considerations

For studies relevant to the setting of DNELs, a threshold mode of action was assumed.

Modification of Relevant Dose Descriptors to the Correct Starting Point

Relevant dose descriptors were developed for the different routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). In the absence of information on the extent of absorption of 2,4,4-trimethylpentene, uptake by the oral, dermal and inhalation routes has been assumed to be 50%, 100% and 100%, respectively (see Guidance Document, Chapter R.8, R.8.4.2b). The values are provided below.

Dermal route:

The corrected dermal NOAEL is:

dermal NOAEL = oral NOAEL * (ABSoral-rat/ABSderm-human)

dermal NOAEL = 300 * (50/100)

dermal NOAEL = 150 mg/kg/d

Thus, the corrected dose descriptor for dermal route is 150 mg/kg/day.

Inhalation route:

To convert oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3for an 8-h exposure period).

The corrected inhalation NOAEC for workers is:

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

inhalatory NOAEC= 300 * (1/0.38) * (50/100) * (6.7 / 10)

inhalatory NOAEC = 264.5 mg/m3

Thus, the corrected dose descriptor for inhalation is 264.5 mg/m3 for workers.

Application of Assessment Factors to the Corrected Dose Descriptors

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC 2003; 2010).

ECETOC (2003). Derivation of Assessment Factors for Human Health Risk Assessment, Technical Report 86, Brussels, February 2003.

ECETOC (2010). Guidance on assessment factors to derive a DNEL. Technical report No. 110, ECETOC, Brussels, October 2010

 

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

Worker

Differences in metabolic rate per b. w. (allometric scaling)

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

3

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

72

 

Long-term DNEL Assessment Factors (Inhalation)

Assessment Factor

Worker

Differences in metabolic rate per b. w. (allometric scaling)

-

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

3

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

18

 

Testing for OECD 408, OECD 414 (Rat and Rabbit) is being proposed. The testing proposals for the same can be accessed in Sections 7.5.1. and 7.8.2., respectively. The DNELs will be revised once testing is complete and data available for the OECD 408 and 414 studies.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA, 2010; ECETOC, 2003, 2010
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
DNEL value:
130.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
The rat oral rat NOAEL was converted into a corrected inhalation NOAEC according to ECHA guidance (Chapter R.8: Characterisation of dose [concentration]-response for human health, Figure R. 8-3)
AF for dose response relationship:
1
Justification:
No toxicologically relevant findings when tested up to a limit dose of 1000 mg/kg bw/d
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for sub-acute to chronic extrapolation (ECHA guidance, Chapter R. 8)
AF for interspecies differences (allometric scaling):
1
Justification:
Default assessment factor for the inhalation route (ECHA guidance, Chapter R. 8)
AF for other interspecies differences:
1
Justification:
An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51).
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of exposure to 2,4,4-trimethylpentene in the human population. However an analysis of assessment factors conducted by ECETOC (2003, 2010) showed that metabolic differences due to genetic polymorphisms do not to automatically require an increased assessment factor since alternative pathways of elimination are often present. Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 5 (i.e. the 95th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within the general population.
AF for the quality of the whole database:
1
Justification:
No issues regarding quality of whole database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties present
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:
1.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA, 2010; ECETOC, 2003, 2010
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The rat oral rat NOAEL was converted into a corrected dermal NOAEL after correcting for differences in uptake between the two routes of exposure
AF for dose response relationship:
1
Justification:
No toxicologically relevant findings when tested up to a limit dose of 1000 mg/kg bw/d
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for sub-acute to chronic extrapolation (ECHA guidance, Chapter R. 8)
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in the rat (ECHA guidance, Chapter R. 8)
AF for other interspecies differences:
1
Justification:
An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51).
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of exposure to 2,4,4-trimethylpentene in the human population. However an analysis of assessment factors conducted by ECETOC (2003, 2010) showed that metabolic differences due to genetic polymorphisms do not to automatically require an increased assessment factor since alternative pathways of elimination are often present. Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 5 (i.e. the 95th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within the general population.
AF for the quality of the whole database:
1
Justification:
No issues regarding quality of whole database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties present
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:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA, 2010; ECETOC, 2003, 2010
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
No toxicologically relevant findings when tested up to a limit dose of 1000 mg/kg bw/d
AF for differences in duration of exposure:
6
Justification:
Default assessment factor for sub-acute to chronic extrapolation (ECHA guidance, Chapter R. 8)
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor for allometric scaling in the rat (ECHA guidance, Chapter R. 8)
AF for other interspecies differences:
1
Justification:
An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51).
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of exposure to 2,4,4-trimethylpentene in the human population. However an analysis of assessment factors conducted by ECETOC (2003, 2010) showed that metabolic differences due to genetic polymorphisms do not to automatically require an increased assessment factor since alternative pathways of elimination are often present. Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 5 (i.e. the 95th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within the general population.
AF for the quality of the whole database:
1
Justification:
No issues regarding quality of whole database
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties present
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 toxicity

ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity are not necessary if no acute toxicity hazard leading to classification has been identified. Animal data for 2,4,4-trimethylpentene demonstrate that the acute oral (HLS, 1996a) and dermal (HLS, 1996b) LD50 values are greater than 2000 mg/kg bw, while the inhalation LC50 (WIL Research Laboratories, 2006a) is in excess of 19,171 mg/m3, the highest vapour concentration tested. No acute DNELs will therefore be derived for these routes of exposure.

Other information suggests that 2,4,4-trimethylpentane may cause transient CNS depression after ingestion, while a low kinematic viscosity (0.611 mm2/s at 40 degrees C) is consistent with a potential to damage the lungs if swallowed, with classification triggered in both instances. Qualitative risk characterisation will be conducted to address these endpoints as neither is suited to derivation of a quantitative DNEL.

Irritation/Sensitisation

2,4,4-Trimethylpentene is not irritating to skin (HLS, 1996c; WIL Research Laboratories, 2005a) or eye (HLS, 1996d; WIL Research Laboratories, 2005b), nor does it induce or elicit sensitisation after skin contact (HLS, 1997a). No quantitative DNELs or qualitative risk characterisation are therefore necessary for these endpoints.

Repeated dose toxicity

Results from oral sub-acute repeated dose toxicity testing of 2,4,4-trimethylpentene according to OECD Guideline 407 demonstrate no adverse systemic effects following gavage administration at 300 mg/kg bw/d for up to 28 days; higher treatments (100 mg/kg bw/d) were associated with increased liver and kidney weights, however no accompanying histopathological alterations were present (HLS, 1997b). Findings of alpha-2u-globulin nephropathy described in other studies (HLS, 1997c; Swenberg and Schoonhoven, 2004) are not relevant to human risk assessment or to the derivation of long-term DNELs.

Genetic toxicity

Adequate information exists to characterise the genetic toxicity of 2,4,4-trimethylpentene. Results of bacterial mutation assays (HLS, 1996e; BioReliance, 2005) demonstrate an absence of mutagenic potential towards strains of Salmonella typhimurium when tested in the absence or presence of exogenous metabolic activation, while no evidence of clastogenicity was found in vitro after treatment of human lymphocytes (HLS, 1997d) or CHO cells (BioReliance, 2006) in the absence and in the presence of S9 fraction. No increase in micronucleated polychromatic erythrocytes was found in rats following a single 4-hr exposure to 19,171 mg/m3 2,4,4-trimethylpentene (WIL Research Laboratories, 2006a) ).

Reproductive / developmental toxicity

Results from an OECD 421 screening study showed no adverse effects on reproductive or developmental performance in rats (HLS, 1997c).

Mode of Action Considerations

For studies relevant to the setting of DNELs, a threshold mode of action was assumed.

Modification of Relevant Dose Descriptors to the Correct Starting Point

Relevant dose descriptors were developed for the different routes of exposure (see Guidance Document, Chapter R.8, Appendix R.8-2). In the absence of information on the extent of absorption of 2,4,4-trimethylpentene, uptake by the oral, dermal and inhalation routes has been assumed to be 50%, 100% and 100%, respectively (see Guidance Document, Chapter R.8, R.8.4.2b). The values are provided below.

Dermal route:

The corrected dermal NOAEL is:

dermal NOAEL = oral NOAEL * (ABSoral-rat/ABSderm-human)

dermal NOAEL = 300 * (50/100)

dermal NOAEL = 150 mg/kg/d

Thus, the corrected dose descriptor for dermal route is 150 mg/kg/day.

Inhalation route:

To convert oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h). The corrected inhalation NOAEC for general population is:

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

inhalatory NOAEC= 300 * (1/1.15) * (50/100)

inhalatory NOAEC = 130.4 mg/m3

Thus, the corrected dose descriptor for inhalation is 130.4 mg/m3 for general population.

Application of Assessment Factors to the Corrected Dose Descriptors

Endpoint-specific DNEL values were derived from the corrected dose descriptors after application of assessment factors (AF). The AFs were based on the procedures described by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC 2003; 2010).

ECETOC (2003). Derivation of Assessment Factors for Human Health Risk Assessment, Technical Report 86, Brussels, February 2003.

ECETOC (2010). Guidance on assessment factors to derive a DNEL. Technical report No. 110, ECETOC, Brussels, October 2010.

 

Long-term DNEL Assessment Factors (Oral)

Assessment Factor

General Population

Differences in metabolic rate per b. w. (allometric scaling)

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

120

 

Long-term DNEL Assessment Factors (Dermal)

Assessment Factor

General Population

Differences in metabolic rate per b. w. (allometric scaling)

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

120

  

Long-term DNEL Assessment Factors (Inhalation)

Assessment Factor

General Population

Differences in metabolic rate per b. w. (allometric scaling)

-

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1

Intraspecies differences

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

6 (sub-chronic)

Issues related to dose-response

1

Quality of whole database

1

Overall AF

30

 

Testing for OECD 408, OECD 414 (Rat and Rabbit) is being proposed. The testing proposals for the same can be accessed in Sections 7.5.1. and 7.8.2., respectively. The DNELs will be revised once testing is complete and data available for the OECD 408 and 414 studies.