Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
700 mg/m³
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 400 mg/m³
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
700 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 400 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 016 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
Explanation for the modification of the dose descriptor starting point:
The IOELV (mg/m3) was converted into a human dermal NOAEL (mg/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (REACH Guidance, Appendix R.8-2, Example B.4)
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for intraspecies differences:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used without modification (ECHA Guidance, Appendix R.8-13)
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:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Introduction

In accordance with REACH guidance (Appendix R.8-13) and since no new scientific information has obtained under REACH which does not support the use of the IOELV for this purpose, the established IOELV of 200 ppm (700mg/m3) – 8 hr TWA will be proposed for the inhalation DNEL for workers. The IOELV was published in Directive 2006/15/EC of 7 February 2006. It is of note that neither a 15-minute STEL nor skin notation were recommended.

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). Cyclohexane does not present an acute hazard following ingestion or skin contact hence a DNEL will be proposed for the inhalation route only. In accordance with REACH guidance (Appendix R.8-13) and since no new scientific information has obtained under REACH which does not support the use of the IOELV for this purpose, the established IOELV (SCOEL (2001); published as Directive 2006/15/EC) of 200 ppm (700 mg/m3) - 8 hr TWA will be proposed for the acute inhalation DNEL for workers. The 8-hr TWA value is viewed as conservative and protective for acute exposure (local and systemic effects).

In addition, cyclohexane is classified STOT – single exposure Category 3 (H336) and Aspiration toxicity Category 1 (H304) under CLP. These acute endpoints will be addressed using Qualitative Risk Characterisation.

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. No dose/response information can be derived from data available for cyclohexane and DNELs cannot therefore be determined. However past decisions from the C&L work group indicate that cyclohexane is irritating to the skin hence appropriate RMM and OCs should be employed. Cyclohexane is not irritating to the eye. Information on the respiratory irritation potential of cyclohexane is available from a human volunteer study which reported mild effects on eye and throat after 4 hr exposure. However these observations were subjective and the SCOEL (2001) review did not indicate the need for a STEL (15 minutes).

Long-term systemic effects

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose (neuro)toxicity and reproductive (fertility, developmental) testing.

For information (not for DNEL derivation), for cyclohexane the following NOAECs are presented in the IUCLID dossier:

sub-chronic effects: mouse NOAEC = 6,880 mg/ m3

reproductive effects: rats NOAEC = 24,080 mg/ m3

developmental toxicity: rat/rabbit NOAEC = 24,080 mg/ m3

Dermal

The dermal NOAEC is extrapolated from the IOELV. The IOELV is adjusted for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4). It is assumed that uptake of cyclohexane after inhalation is 100% while dermal absorption is only 5% (as concluded in the EU RAR (2004), as derived from Jeffcott, 1996).

correctedDermal NOAEL = IOELV x sRVhuman 8hr x [ABSinhal-human/ABSdermal-human]

correctedDermal NOAEL = 700 mg/m3 x wRV8-hour x [100% / 5%]

correctedDermal NOAEL = 700 x 0.144 x 20 = 2016 mg/kg bw/d

Note: worker respiratory volume (wRV) is 50% greater than the resting standard respiratory volume of 0.2 L/min/kg bw (wRV8-hour = (0.2 L/min/kg bw x 1.5 x 60 x 8) / 1000 = 0.144 m3/kg bw).

No assessment factor is necessary

DNELl-t dermal = 2016 mg/kg bwt/d

Inhalation

The IOELV will be used without any modification

DNELl-t inhalation = 700 mg/m3

Long-term local effects

Information on local effects associated with repeated exposure to cyclohexane is limited to results from a mouse repeated dose inhalation study, where no adverse local effects were reported.

Inhalation

It is considered that the long term systemic effect DNEL for inhalation is protective for local effects and therefore no specific DNEL for long-term local effects is derived here.

Dermal

No information is available to characterise the repeated local effects of cyclohexane on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. However cyclohexane is classified H315 - Skin irritant Cat 2 according to the CLP regulation hence risk management measures and other occupational controls designed to limit skin irritation will protect against long term local skin effects also.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
206 mg/m³
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance; ECETOC (2003, 2010)
Overall assessment factor (AF):
1.7
Modified dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for intraspecies differences:
1.7
Justification:
The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
412 mg/m³
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance; ECETOC (2003, 2010)
Overall assessment factor (AF):
1.7
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
Explanation for the modification of the dose descriptor starting point:
None applied
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for intraspecies differences:
1.7
Justification:
The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
206 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance; ECETOC (2003, 2010)
Overall assessment factor (AF):
1.7
Dose descriptor:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for intraspecies differences:
1.7
Justification:
The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
412 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance; ECETOC (2003, 2010)
Overall assessment factor (AF):
1.7
DNEL extrapolated from long term DNEL
Dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for intraspecies differences:
1.7
Justification:
The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 186 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance; ECETOC (2003, 2010)
Overall assessment factor (AF):
1.7
Modified dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
Explanation for the modification of the dose descriptor starting point:
The IOELV (mg/m3) was converted into a human dermal NOAEL (mg/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (REACH Guidance, Appendix R.8-2, Example B.4)
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for intraspecies differences:
1.7
Justification:
The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
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:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
59.4 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance; ECETOC (2003, 2010)
Overall assessment factor (AF):
1.7
Modified dose descriptor starting point:
other: SCOEL/SUM/13, May 2001; Dir 2006/15/EC
Explanation for the modification of the dose descriptor starting point:
The IOELV (mg/m3) was converted into a human oral NOAEL (mg/kg bwt/d) by adjusting for differences in uptake between the two routes of exposure (REACH Guidance, Appendix R.8-2, Example B.4)
AF for dose response relationship:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for differences in duration of exposure:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for interspecies differences (allometric scaling):
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for other interspecies differences:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for intraspecies differences:
1.7
Justification:
The worker IOELV has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The magnitude of the IOELV was further modified to take into account differences in duration of exposure experienced by workers and the general population. The IOELV has therefore been taken as a human 8-hr NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.
AF for the quality of the whole database:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
AF for remaining uncertainties:
1
Justification:
IOELV (8-hr) used as starting point (human NAEL)
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

Introduction

General population DNELs for cyclohexane have used the worker IOELV as their starting point. This is considered scientifically justifiable since information supporting the IOELV has been examined for consistency and biological plausibility by SCOEL, with only robust data used in the limit setting process. Importantly, results from human investigations played a key part in this process. It was also considered that the use of a common starting point (the IOELV) for both population groups would result in greater consistency in hazard (dose-response) identification than would be the case if different methods of assessment had been used for workers and the general population. The IOELV has therefore been taken as a human 8-hour no adverse effect level (NAEL) which, after modification (though use of an assessment factor), would be more broadly applicable to the general population.

The IOELV was modified to take into account differences in duration of exposure experienced by workers (8-hours) versus the chronic exposure experienced by the general population (24-hours).

An assessment factor (AF) was used to adapt the IOELV for use with the general population. As the IOELV relied heavily on human data, only a factor to account for human intra-species variation was considered necessary. In addition, since no particularly susceptible human sub-populations (including groups exhibiting polymorphisms or other predisposing factors) had been identified in the human literature for toluene, a factor reflecting the general relationship between the intra-species AF for workers and that for the general population was considered applicable.

An AFgeneral population = 1.7, reflecting the ratio between an intra-species AF = 5 for the general population and an intra-species AF = 3 for workers, was therefore applied to the IOELV to give a general population DNEL. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which indicated that the distribution of variability in toxicokinetic and toxicodynamic parameters for human populations of different ages, genders and disease states supports use of these AFs.

It is noted that a slightly larger AFgeneral population (AF = 2) would have resulted if intra-species defaults from REACH guidance had been used, however this would have had only a small effect on the magnitude of the DNEL.

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). Since cyclohexane does not present an acute hazard following ingestion or skin contact hence a DNEL will be derived for the inhalation route only. The IOELV will be used as the starting point for deriving a short-term inhalation DNEL for the general population. As no 15-min STEL was established under Directive 2006/15/EC, and since the 8-hr TWA value is viewed as conservative and protective against short-term systemic effects, the acute inhalation systemic DNEL is based on the IOELV with no modification.

Dose descriptor

IOELV = 700 mg/m3

Modification of dose descriptor

None required (human inhalation exposure)

NOAEL acute inhalation = IOELV = 700 mg/m3

Assessment factors

Assessment factors are not required when a worker DNEL is based upon an IOELV, however one is included here to reflect uncertainty when moving from the IOELV to the general population.

The worker IOELV-STEL has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV-STEL has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The IOELV-STEL has therefore been taken as a human 15-min NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV-STEL to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

DNELacute inhalation = 700 mg/m3 / 1.7 = 412 mg/m3

In addition, cyclohexane is classified STOT – single exposure Category 3 (H336) and Aspiration toxicity Category 1 (H304) under CLP. These acute endpoints will be addressed using Qualitative Risk Characterisation.

Irritation

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena. No dose/response information can be derived from data available for cyclohexane and DNELs cannot therefore be determined. However past decisions from the C&L work group indicate that cyclohexane is irritating to the skin hence appropriate RMM and OCs should be employed. Cyclohexane is not irritating to the eye. Information on the respiratory irritation potential of cyclohexane is available from a human volunteer study which reported mild effects on eye and throat after 4 hr exposure. However these observations were subjective and the SCOEL (2001) review did not indicate the need for a STEL (15 minutes).

Dose descriptor

IOELV = 700 mg/m3.

Modification of dose descriptor

Not modified (Haber’s law does not apply to local irritation effects)

Assessment factors

Assessment factors are not required when a worker DNEL is based upon an IOELV, however one is included here to reflect uncertainty when moving from the IOELV to the general population.

The worker IOELV-STEL has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV-STEL has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The IOELV-STEL has therefore been taken as a human 15-min NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV-STEL to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

DNELacute inhalation = 700 mg/m3 / 1.7 = 412 mg/m3

Long-term systemic effects

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose (neuro)toxicity and reproductive (fertility, developmental) testing.

For information (not for DNEL derivation, since this is based on the IOELV), for cyclohexane the following NOAECs are presented in the IUCLID dossier:

sub-chronic effects: mouse NOAEC = 6,880 mg/m3

reproductive effects: rats NOAEC = 24,080 mg/m3

developmental toxicity: rat/rabbit NOAEC = 24,080 mg/m3

Oral

The oral NOAEL is extrapolated from the IOELV

Dose descriptor

IOELV of 700 mg/m3 will be used as the starting point.

Modification of dose descriptor

Correct the IOELV to adjust for differences in duration of exposure; then convert the corrected inhalation value into an oral NOAEL (mg/kg bwt/d) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

Adjustment is made for the fact that the IOELV is an 8-hr TWA and the general population may be exposed for 24-hr each day.

It is assumed that uptake of cyclohexane after inhalation and oral exposure is equivalent.

corrected oral NOAEL = IOELV x wRV8-hour x [ABSinhal-human/ABSoral-human]

Note: worker respiratory volume (wRV) is 50% greater than the resting standard respiratory volume of

0.2 L/min/kg bw (wRV8-hour = (0.2 L/min/kg bw x 1.5 x 60 x 8) / 1000 = 0.144 m3/kg bw)

corrected oral NOAEL = 700 x 0.144 x 1

corrected oral NOAEL = 101 mg/kg bwt/d

Assessment factors

Assessment factors are not required when a worker DNEL is based upon an IOELV, however one is included here to reflect uncertainty when moving from the IOELV to the general population.

The worker IOELV-STEL has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV-STEL has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The IOELV-STEL has therefore been taken as a human 15-min NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV-STEL to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

DNELl-t oral = 101 mg/kg bwt/d / 1.7 = 59.4 mg/kg bwt/d

Dermal

The dermal NOAEC is extrapolated from the IOELV

Dose descriptor

IOELV of 700 mg/m3 will be used as the starting point.

Modification of dose descriptor

The IOELV is adjusted for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.4).

It is assumed that uptake of cyclohexane after inhalation is 100% while dermal absorption is only 5% (as concluded in the EU RAR (2004), as derived from Jeffcott, 1996).

Adjustment is made for the fact that the IOELV is an 8-hr TWA and the general population may be exposed for 24-hr each day.

corrected dermal NOAEL = IOELV x wRV8-hourr x [ABSinhal-human/ABSdermal-human]

corrected dermal NOAEL = 700 x 0.144 x 20 = 2016 mg/kg bwt/d

Assessment factors

Assessment factors are not required when a worker DNEL is based upon an IOELV, however one is included here to reflect uncertainty when moving from the IOELV to the general population.

The worker IOELV-STEL has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV-STEL has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The IOELV-STEL has therefore been taken as a human 15-min NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV-STEL to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

DNELl-t dermal = 2016 mg/kg bwt/d / 1.7 = 1186 mg/kg bwt/d

Inhalation

Dose descriptor

The IOELV of 700 mg/m3 will be used.

Modification of dose descriptor

Adjustment is made for the fact that the IOELV is an 8-hr TWA and the general population may be exposed for 24-hr each day.

Inhalation NOAEL = IOELV x (wRV8-hour / sRV24-hour)

Note: standard respiratory volume – human (sRV) 0.2 L/min/kg bw; sRV24-hour = (0.2 L/min/kg bw x 60 x 24) / 1000 = 0.288 m3/kg bw

Inhalation NOAEL = 700 x (0.144 / 0.288)

Inhalation NOAEL = 350 mg/m3

Assessment factors

Assessment factors are not required when a worker DNEL is based upon an IOELV, however one is included here to reflect uncertainty when moving from the IOELV to the general population.

The worker IOELV-STEL has been used as the starting point when deriving this DNEL for the general population. This is considered scientifically justifiable since information supporting the IOELV-STEL has been examined for consistency and biological plausibility by Scientific Committee on Occupational Exposure Limits (SCOEL), with only robust data used in the limit setting process. Furthermore, the use of a common starting point for both population groups also results in greater consistency in outcome than would be the case if different starting points and methods of assessment had been used. The IOELV-STEL has therefore been taken as a human 15-min NAEL, which (after modification through use of an assessment factor) would be broadly applicable to the general population. An assessment factor of 1.7 (reflecting the ratio between an intra-species AF of 5 for the general population and an intra-species AF of 3 for workers), was used to adapt the IOELV-STEL to the general population. Selection of these assessment factors was based on analyses of the scientific literature conducted by ECETOC (2003, 2010), which concluded that their magnitude was adequate to account for the distribution of variability in toxicokinetic and toxicodynamic parameters present in human populations of different ages, genders and disease states.

DNELl-t inhal = 350 mg/m3 / 1.7 = 206 mg/m3

Long-term local effects

Information on local effects associated with repeated exposure to cyclohexane is limited to results from a mouse repeated dose inhalation study, where no adverse local effects were reported. It is considered that the long term systemic effect DNEL for inhalation is protective for local effects and therefore no specific DNEL for long-term local effects is derived here.

Dermal

No information is available to characterise the repeated local effects of cyclohexane on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. However cyclohexane is classified H315 - Skin irritant Cat 2 according to the CLP regulation hence risk management measures and other occupational controls designed to limit skin irritation will protect against long term local skin effects also.