Cyclohexanemethanol, 4-(1-methylethyl)-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.63 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

165.74 mg/m³

Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested on page 19 of Guidance Document, Chapter R.8 (2012). To convert the 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 m3 for an 8-h exposure period). Thus, the corrected dose descriptor for inhalation is [188 mg/kg bw/day] / [0.38 m3/kg bw/day] X [6.7 m3/10m3] /2. Thus, the corrected dose descriptor for inhalation is 165.74 mg/m3 for workers.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

2

Justification:

Default factor for a sub-chronic study. Table R.8-5 ECHA REACH Guidance

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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:

1.88 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

2

Justification:

Default factor for a sub-chronic study. Table R.8-5 ECHA REACH Guidance

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The available dose-descriptors per endpoint as a result of hazard assessment are listed in the table below:

Endpoint	Dose-descriptor (from study report)	Associated effect	Relevance of effects
OECD 408 Repeated dose toxicity – sub-chronic (oral, diet)	3000 ppm 188 / 220 mg/kg bw/day (M/F)	evidence of systemic exposure but no effects which were deemed to be adverse	No adverse effect observed
OECD 407 Repeated dose toxicity – sub-acute (oral, gavage)	100 mg/kg bw/day	changes in the liver (moderate and marked periportal hepatocyte vacuolation associated with slight disturbances in plasma biochemistry) and sperm (decreased motility)	Liver effects considered to be non-adverse adaptive changes; Sperm effects due to oxidative stress
OECD 414 Developmental and maternal toxicity (oral, gavage)	300 mg/kg bw/day	Non-adverse minor effects at 300 mg/kg bw/day associated with slightly reduced food consumption in the dams The highest dose level was selected as one that would not induce excessive reductions in weight gain of the females, thereby avoiding concomitant confounding effects on fetal development. The data confirm the validity of the dose selection	No adverse effect observed
OECD 421 Reproductive toxicity – screening –reproductive toxicity (oral, gavage)	150 mg/kg bw/day	effects on sperm motility at the higher dose level of 300 mg/kg/day	Sperm effects due to oxidative stress
OECD 421 Reproductive toxicity – screening –developmental toxicity (oral, gavage)	50 mg/kg bw/day	effects on the post natal survival of pups and reductions in Day 1 pup body weights in the higher dose groups	Effects on pup weight and survival considered to be secondary to modest effects on female food consumption and maternal behaviour.

 

The effects on sperm motility observed in the OECD 407 and 421 studies are considered to be due to oxidative stress occurring as a result of testicular metabolism of the substance made possible by high plasma levels of the substance and its metabolites following oral gavage administration of a large bolus dose. This hypothesis is supported by the results of the OECD 408 dietary study, in which no testicular toxicity was observed up to the highest dose level tested, 3000 ppm (equivalent to 188 mg/kg/day in males and 220 mg/kg/day in females). [Cf. IU section 7.5 & 7.8 for further details]. In consequence, the effect is subject to a threshold that cannot be exceeded under normal exposure conditions for humans and is therefore on no toxicological relevance.

 

Regarding the liver effects observed in the OECD 407, given the lack of any degenerative changes in the liver, and the absence of similar effects in the OECD 408, it is considered that the liver findings at 300 mg/kg/day do not represent a significant toxicity. It is concluded that the liver findings represent an adaptive, non-adverse, change. [Cf. IU section 7.6 for further details].

 

In the OECD 421, the NOAEL was considered by the study director to be 50 mg/kg bw/day since at 150 mg/kg/day the live birth index was slightly lower than in Controls, and there was one litter with several pup deaths where offspring bodyweights on Day 1 of age were lower than expected, and this was also seen at 300 mg/kg/day. However, the reduction in the live birth index seen at 150 mg/kg bw/day is not statistically significant and there was no similar reduction at 300 mg/kg bw/day, therefore the effects are not considered to be toxicologically relevant. The hypothesis mentioned in the report for the litter which had the most pup deaths, was a possible adverse effect on this litter in utero. However, in the OECD 414 study there were no effects on pup development up to 300 mg/kg bw/day. The OECD 414 results confirm that the effects seen at 150 mg/kg bw/day in the OECD 421 study are not related to in utero exposure, and are not a direct toxic effect of the substance. Based on this, the NOAEL (developmental toxicity) for the OECD 421 can be set to 150 mg/kg bw/day. The reductions in post natal survival and growth of the offspring at 300 mg/kg bw/day are most likely associated with the reduced maternal food consumption recorded at the start of lactation, and/or the presence of the substance in the milk affecting pup suckling behaviour (unpleasant taste to the milk), which may explain why a number of pups in several litters at 300 mg/kg/day were observed with no milk in the stomach. A reasonable speculation could be made that there could well be an effect of the fragrance ingredient on the maternal behaviour of the dams towards the pups. [Cf. IU section 7.8 for further details]

 

 

Overall conclusion for dose-descriptor selection:

The quantitative dose-descriptor selected for DNEL assessment is the lowest actual NOAEL (188 mg/kg bw/day in males) from the study with the longest exposure duration, i.e. the sub-chronic 90-day study.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.63 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

81.74 mg/m³

Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route( inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested on page 19 of Guidance Document, Chapter R.8 (2012). To convert the 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). Thus, the corrected dose descriptor for inhalation is [188 mg/kg bw/day] / [1.15 m3/kg bw/ day] /2. Thus, the corrected dose descriptor for inhalation is 81.74 mg/m3 for consumers.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

2

Justification:

Default factor for a sub-chronic. Table R.8-5 ECHA REACH Guidance

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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:

0.94 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

2

Justification:

Default factor for a sub-chronic study. Table R.8-5 ECHA REACH Guidance

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.94 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

188 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

2

Justification:

Default factor for a sub-chronic study. Table R.8-5 ECHA REACH Guidance

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

1

Justification:

Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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

The available dose-descriptors per endpoint as a result of hazard assessment are listed in the table below:

 

Endpoint	Dose-descriptor (from study report)	Associated effect	Relevance of effects
OECD 408 Repeated dose toxicity – sub-chronic (oral, diet)	3000 ppm 188 / 220 mg/kg bw/day (M/F)	evidence of systemic exposure but no effects which were deemed to be adverse	No adverse effect observed
OECD 407 Repeated dose toxicity – sub-acute (oral, gavage)	100 mg/kg bw/day	changes in the liver (moderate and marked periportal hepatocyte vacuolation associated with slight disturbances in plasma biochemistry) and sperm (decreased motility)	Liver effects considered to be non-adverse adaptive changes; Sperm effects due to oxidative stress
OECD 414 Developmental and maternal toxicity (oral, gavage)	300 mg/kg bw/day	Non-adverse minor effects at 300 mg/kg bw/day associated with slightly reduced food consumption in the dams. The highest dose level was selected as one that would not induce excessive reductions in weight gain of the females, thereby avoiding concomitant confounding effects on fetal development. The data confirm the validity of the dose selection	No adverse effect observed
OECD 421 Reproductive toxicity – screening –reproductive toxicity (oral, gavage)	150 mg/kg bw/day	effects on sperm motility at the higher dose level of 300 mg/kg/day	Sperm effects due to oxidative stress
OECD 421 Reproductive toxicity – screening –developmental toxicity (oral, gavage)	50 mg/kg bw/day	effects on the post natal survival of pups and reductions in Day 1 pup body weights in the higher dose groups	Effects on pup weight and survival considered to be secondary to modest effects on female food consumption and maternal behaviour.

The effects on sperm motility observed in the OECD 407 and 421 studies are considered to be due to oxidative stress occurring as a result of testicular metabolism of the substance made possible by high plasma levels of the substance and its metabolites following oral gavage administration of a large bolus dose. This hypothesis is supported by the results of the OECD 408 dietary study, in which no testicular toxicity was observed up to the highest dose level tested, 3000 ppm (equivalent to 188 mg/kg/day in males and 220 mg/kg/day in females). [Cf. IU section 7.5 & 7.8 for further details]. In consequence, the effect is subject to a threshold that cannot be exceeded under normal exposure conditions for humans and is therefore on no toxicological relevance.

 

Regarding the liver effects observed in the OECD 407, given the lack of any degenerative changes in the liver, and the absence of similar effects in the OECD 408, it is considered that the liver findings at 300 mg/kg/day do not represent a significant toxicity. It is concluded that the liver findings represent an adaptive, non-adverse, change. [Cf. IU section 7.6 for further details].

 

In the OECD 421, the NOAEL was considered by the study director to be 50 mg/kg bw/day since at 150 mg/kg/day the live birth index was slightly lower than in Controls, and there was one litter with several pup deaths where offspring bodyweights on Day 1 of age were lower than expected, and this was also seen at 300 mg/kg/day. However, the reduction in the live birth index seen at 150 mg/kg bw/day is not statistically significant and there was no similar reduction at 300 mg/kg bw/day, therefore the effects are not considered to be toxicologically relevant. The hypothesis mentioned in the report for the litter which had the most pup deaths, was a possible adverse effect on this litterin utero. However, in the OECD 414 study there were no effects on pup development up to 300 mg/kg bw/day. The OECD 414 results confirm that the effects seen at 150 mg/kg bw/day in the OECD 421 study are not related toin uteroexposure, and are not a direct toxic effect of the substance. Based on this, the NOAEL (developmental toxicity) for the OECD 421 can be set to 150 mg/kg bw/day. The reductions in post natal survival and growth of the offspring at 300 mg/kg bw/day are most likely associated with the reduced maternal food consumption recorded at the start of lactation, and/or the presence of the substance in the milk affecting pup suckling behaviour (unpleasant taste to the milk), which may explain why a number of pups in several litters at 300 mg/kg/day were observed with no milk in the stomach. A reasonable speculation could be made that there could well be an effect of the fragrance ingredient on the maternal behaviour of the dams towards the pup [Cf. IU section 7.8 for further details]

 

Overall conclusion for dose-descriptor selection:

The quantitative dose-descriptor selected for DNEL assessment is the lowest actual NOAEL (188 mg/kg bw/day in males) from the study with the longest exposure duration, i.e. the sub-chronic 90-day study.