3a,4,7,7a-tetrahydro-4,7-methanoindene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.058 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

26.45 mg/m³

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into inhalation NOAEC human (in mg/m³) by using a default respiratory volume for the rat corresponding to the daily duration of human exposure, followed by a correction for differences in absorption between routes, and a correction for differences in inhalation absorption between rats and humans. For workers an additional correction was applied for the difference between respiratory rates under standard conditions and under conditions of light activity.

Corrected inhalatory NOAEC

= oral NOAEL x (1 / sRV_rat) x (ABS_oral-rat / ABS_inh-human) x (sRV_human / wRV)

= 30 mg/Kg bw/day x (1/0.38 m³/kg/day) x (1/2) x (6.7 m³ (8h) /10 m³ (8h))

Corrected inhalatory NOAEC = 26.45 mg/m³

ABS: Absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume

Note: A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8:

Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor - allometric scaling factor not applied (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assesment factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.31 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECETOC, 2003; 2010

Dose descriptor:

NOAEC

Justification:

default for subchronic to chronic

Justification:

allometric scaling is not necessary for the inhalation route if derived from an inhalation study (R8)

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). Furthermore, data available for 3a,4,7,7a-tetrahydro-4,7-methanoindene, together with information available for chemically-related structures , do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.

Justification:

There are no data to quantify variability in susceptibility to the effects of exposure to 3a,4,7,7a-tetrahydro-4,7-methanoindene 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.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

160.23 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECETOC: 2003, 2010

Dose descriptor starting point:

NOAEC

Justification:

Allometric scaling is not necessary for the inhalation route if derived from an inhalation study (R8).

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). Furthermore, data available for 3a,4,7,7a-tetrahydro-4,7-methanoindene, together with information available for chemically-related structures , do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.

Justification:

There are no data to quantify variability in susceptibility to the effects of exposure to 3a,4,7,7a-tetrahydro-4,7-methanoindene 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.

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into dermal NOAEL rat (in mg/Kg bw/day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans.

Corrected dermal NOAEL

= oral NOAEL x (ABS_oral-rat/ ABS_dermal-rat) x (ABS_dermal-rat/ABS_dermal-human)

= 30 mg/Kg bw/day x (ABS_oral-rat/ ABS_dermal-human)

= 30 mg/Kg bw/day x (1/1)

Corrected dermal NOAEL = 30 mg/Kg bw/day

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8:Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

For workers, as standard procedure for threshold effects, a default assessment factor of 5 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

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:

low hazard (no threshold derived)

Additional information - workers

I] DNEL Worker long-term lnhalation-systemic

 

Dose descriptor: A NOAEL of 30 mg/Kg bw/day will be used as the starting point.

 

Modification of dose descriptor

 

A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

 

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects) (no allometric scaling factor applied)
Intraspecies	5 (for worker)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	25

 

DNEL Worker long-term-systemic via inhalation route = 26.45 / 25 = 1.058 mg/m³

II] DNEL Worker long-term Inhalation-local

 

Dose descriptor: A NOAEL of 30 mg/Kg bw/d will be used as the starting point.

 

Modification of dose descriptor

A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

 

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	1 (for local effects) (no allometric scaling factor applied)
Intraspecies	5 (for worker)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	10

 

DNEL Worker long-term-local via inhalation route = 26.45 / 10 = 2.645 mg/m³

III] DNEL Worker long-term Dermal-systemic

Dose descriptor: A NOAEL of 30 mg/Kg bw/day will be used as the starting point.

 

Modification of dose descriptor

Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation.

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

 

Long-term DNEL Assessment Factors (Dermal)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects)   4 (allometric scaling factor for rats)
Intraspecies	5 (for worker)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	100

 

DNEL Worker long-term-systemic via dermal route = 30 / 100 = 0.30 mg/Kg bw/day

DNEL Worker Acute lnhalation-systemic

LOA does not believe that an acute inhalation DNEL for systemic effects is required as a Systemic NOAEC of 46 ppm (248.74 mg/m³) for irregular breathing and stereotypic behaviour in rats and mice is available in the current dossier.

Key studies assessing the acute (6 hour) inhalation toxicity of dicyclopentadiene exposure in rats and mice have been reported (Bushy Run, 1981).  In the rat study, groups of Fischer 344 rats were exposed for 6 hours to vapours containing 46, 130, 260 or 557 ppm and then observed daily for up to 14 days.  The 6 hour LC50 was 284 ppm for males and 353 ppm for females, equivalent to 1723 mg/m³(male/female). Conversion of this result using Haber's rule (n=3) gives a 4 hour LC50 equivalent of 1972 mg/m³for males and females.  Clinical signs included loss of righting reflex, impaired gait, stereotypic behaviour, laboured breathing, nasal discharge and convulsions. The NOAEC for irregular breathing and stereotypic behaviour was 46 ppm (248.74 mg/m³).  In the mouse study, groups of B6C3F1 mice were exposed for 6 hours to the same vapour concentrations of dicyclopentadiene and then observed daily for up to 14 days.  The 6 hour LC50 was 143 ppm for males and 126 ppm for females, equivalent to 738.5 mg/m³(male/female).  Clinical signs included loss of righting reflex, impaired gait, stereotypic behaviour, laboured breathing, clear nasal discharge, loss of coordination and convulsions prior to death. The NOAEC for irregular breathing and stereotypic behaviour was 46 ppm (248.74 mg/m³). 

As noted in the CSR (section 5.11.2 Inhalation, acute, local effects) an acute inhalation DNEL for local effects of 160.23 mg/m³ was derived, based upon the NOAEC (6 h) for irregular breathing, stereotypic behaviour in rats and mice at 46 ppm (248.74 mg/m³), which is related to local irritation of the respiratory tract. Inhalation is a relevant route of exposure for human peak exposure. The NOAEC was modified to 15 minutes (717.5 mg/m³) using the modified Haber's Law (n=3), and multiplication by 0.67 to define the point of departure: 717.5 * 0.67 = 480.7 mg/m³. 

Human exposure to vapours of dicyclopentadiene is considered likely to result in respiratory and ocular irritation.  The human odour threshold of DCPD vapour appears to be slightly below a corrected concentration of 0.003 ppm.  In another study the odour threshold of DCPD was 0.0057 ppm. The ratio of the DCPD TLV (5 ppm) to the odour threshold was 870-fold. Thus, human subjects exposed to DCPD vapour will detect its odour at air concentrations well below (>8000 fold) the NOAEC for irregular breathing and stereotypic behaviour in rats and mice (46 ppm). LOA argues that acute systemic effects have been accounted for in the derivation of the acute inhalation DNEL for local effects. Consequently, LOA does not consider that a derivation of an acute inhalation DNEL for systemic effects is necessary as systemic effects have already been taken into account in the NOAEC of 46 ppm (248.74 mg/m³) for irregular breathing and stereotypic behaviour in rats and mice.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.26 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

13.04 mg/m³

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into inhalation NOAEC human (in mg/m³) by using a default respiratory volume for the rat corresponding to the daily duration of human exposure, followed by a correction for differences in absorption between routes, and a correction for differences in inhalation absorption between rats and humans.

Corrected inhalatory NOAEC

= oral NOAEL x (1 / sRV_rat) x (ABS_oral-rat / ABS_inh-human)

= 30 mg/Kg bw/day x (1/1.15 m³/Kg bw/day) x (1/2)

Corrected inhalatory NOAEC = 13.04 mg/m³

Note: A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8:

Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor of 1 applied – no Allometric scaling factor for rats compared to humans (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.652 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor:

NOAEC

Value:

13.04 mg/m³

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor of 1 applied – no Allometric scaling factor for rats compared to humans (page 62, Example B3, of the ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version
2.1, November 2012).

Justification:

Additional factor of 1 for other interspecies differences; local effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

143.4 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECETOC: 2003, 2010

Dose descriptor starting point:

NOAEC

Justification:

Allometric scaling is not necessary for the inhalation route if derived from an inhalation study (R8)

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). Furthermore, data available for 3a,4,7,7a-tetrahydro-4,7-methanoindene, together with information available for chemically-related structures , do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.

Justification:

There are no data to quantify variability in susceptibility to the effects of exposure to 3a,4,7,7a-tetrahydro-4,7-methanoindene 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.

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Converted oral NOAEL rat (in mg/Kg bw/day) into dermal N(L)OAEL rat (in mg/Kg bw/day) by correcting for differences in absorption between routes as well as for differences in dermal absorption between rats and humans.

Corrected dermal NOAEL

= oral NOAEL x (ABS_oral-rat / ABS_dermal-rat) x (ABS_dermal-rat / ABS_dermal-human)

= 30 mg/Kg bw/day x (ABS_oral-rat / ABS_dermal-human)

= 30 mg/Kg bw/day x (1/1)

Corrected dermal NOAEL = 30 mg/Kg bw/day

Note: Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

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:

0.15 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification necessary (assuming 100% absorption for both routes in both species)

Corrected Oral NOAEL= 30 mg/Kg bw/day

Note: 100% absorption for both routes in both species assumed (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor of 2 applied when extrapolating duration of exposure from sub-chronic to chronic (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Allometric scaling factor for rats compared to humans (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Additional factor of 2.5 for other interspecies differences; systemic effects (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

For general population, as standard procedure for threshold effects, a default assessment factor of 10 was applied (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Justification:

Default assessment factor applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements (ECHA Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012).

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25.6 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECETOC: 2003, 2010

Modified dose descriptor starting point:

other: LD50

Value:

512 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable

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). Furthermore, data available for 3a,4,7,7a-tetrahydro-4,7-methanoindene, together with information available for chemically-related structures , do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.

Justification:

There are no data to quantify variability in susceptibility to the effects of exposure to 3a,4,7,7a-tetrahydro-4,7-methanoindene 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.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

I] DNEL General Population long-term Inhalation-systemic

 

Dose descriptor

A NOAEL of 30 mg/Kg bw/d will be used as the starting point.

 

Modification of dose descriptor

A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

 

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects) (no allometric scaling factor applied)
Intraspecies	10 (for General population)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	50

 

DNEL General Population long-term-systemic via inhalation route = 13.04 / 50 = 0.26 mg/m³

II] DNEL General Population long-term Inhalation-local

 

Dose descriptor

A NOAEL of 30 mg/Kg bw/d will be used as the starting point.

 

Modification of dose descriptor

 

A default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route)

introduced in the case of oral-to-inhalation extrapolation. The inclusion of this factor 2 means for example that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation.

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

 

Long-term DNEL Assessment Factors (Inhalation)
Assessment Factor	Worker
Interspecies	1 (for local effects) (no allometric scaling factor applied)
Intraspecies	10 (for General population)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	20

 

DNEL General Population long-term-local via inhalation route = 13.04 / 20 = 0.652 mg/m³

III] DNEL General Population long-term Dermal-systemic

Dose descriptor: A NOAEL of 30 mg/Kg bw/day will be used as the starting point.

 

Modification of dose descriptor

Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation.

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

 

Long-term DNEL Assessment Factors (Dermal)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects)   4 (allometric scaling factor for rats)
Intraspecies	10 (for General Population)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	200

 

DNEL General Population long-term-systemic via dermal route = 30 / 200 = 0.15 mg/Kg bw/day

IV] DNEL General Population long-term Oral-systemic

 

Dose descriptor: A NOAEL of 30 mg/Kg bw/day will be used as the starting point.

 

Modification of dose descriptor

Dermal absorption assumed not be higher than oral absorption, therefore no default factor (i.e. factor 1) introduced when performing oral-to-dermal extrapolation.

 

Assessment factors (ECHA Guidance Chapter R8, Table R8-6, November 2012

 

Long-term DNEL Assessment Factors (Oral)
Assessment Factor	Worker
Interspecies	2.5 (for systemic effects)   4 (allometric scaling factor for rats)
Intraspecies	10 (for General Population)
Exposure duration	2 (sub-chronic to chronic)
Issues related to reliability of the dose-response	1
Issues related to completeness and consistency of the available data	1
Overall AF	200

 

DNEL General Population long-term-systemic via Oral route = 30 / 200 = 0.15 mg/Kg bw/day