Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

1.     Introduction:

In this dossier, all the toxicological information on 1-(2-tert-butyl cyclohexyloxy)-2-butanol are examined and analyzed in order to define a DNEL (s)/DMEL (s) for each human health endpoints if possible. The followed method is that proposed in the guidance for the implementation of REACH (Chapter R.8: Characterisation of dose (concentration)-response for human health, December 2010).

 

2.     Classification according to the Directive 67/548/EEC and to the CLP Regulation (Regulation (EC) No. 1272/2008):

 

There is no harmonized classification of 1-(2-tert-butyl cyclohexyloxy)-2-butanol for human health according to the Regulation (EC) No. 1272/2008 including the ATP2 draft. However, based on the available toxicological data, a self classification is proposed as Eye Irrit. 2 (H319, Causes serious eye irritation) according to the criteria of the Annex VI of the CLP Regulation (1272/2008 ATP2). No additional self-classification is proposed for the other toxicological endpoint.

3.     DNELs derivation according to the toxicological profile of 1-(2-tert-butyl cyclohexyloxy)-2-butanol:

In the sub-acute repeated oral toxicity study and the one-generation study for the toxicity to the reproduction with 1-(2-tert-butyl cyclohexyloxy)-2-butanol, changes in the liver and in the kidney were observed in the highest dose group animals (1000 mg/kg bw/d in the subacute study and 500 mg/kg bw/d in the one-generation study). However these effects had tendency to recover after the 2-week recovery period in the sub-acute toxicity study.

In both studies, it is assumed that the observed centrilobular hepatocyte enlargement occurs as an induction of the microsomal drug metabolizing enzyme systems caused by the treatment and is considered as cellular adaptation phenomena in the absence of associated inflammatory or degenerative changes. The adaptation response to the treatment with Amber core was very important at the highest dose (1000 mg/kg bw/d) in the 28-day repeated oral dose toxicity study as described in this dossier (see § 7.5.1). Moreover, the observation of cholangitis (inflammatory effect) associated to cholestasis in both sexes at the highest dose of Amber core in the sub-acute repeated oral toxicity study showed that the substance induced systemic toxicity. Therefore, even if this effect had tendency to recover after withdrawal (2-week recovery period), the highest dose of 1000 mg/kg bw/d was considered as a LOAEL. In the one-generation study, histopathological examinations of liver didn’t show any associated inflammatory changes in the liver at 500 mg/kg bw/d as it was observed (cholangitis associated to cholestase) in the sub-acute toxicity study at 1000 mg/kg bw/d. Therefore, histopathology at 20 or 100 mg/kg bw/day were not performed even if increased absolute and relative liver weights in males were recorded assuming that in the absence of any other effect, the liver weight changes were likely related to cellular adaptation phenomena as already demonstrated at the highest dose (500 mg/kg bw/d).

For the changes of both the renal tubular epithelium and basophilic tubules in both studies, these lesions are known to be spontaneous in male rats only and are not observed in other species. Therefore, this effect is specific to male rat, and is not considered as relevant for the risk assessment in human.

Consequently, it can be assumed that no test substance related effect was observed in the highest dose group of adult animals in the one-generation study considering that the changes observed in the liver resulted from cellular adaptation phenomena. Therefore, it is assumed that the highest dose (500 mg/kg bw/d) is a NOAEL for systemic effects in the adult animals treated up to 18 weeks in the one-generation study.

Therefore, the NOAEL of 500 mg/kg bw/d from the one-generation study was considered to calculate the DNEL by oral and dermal route, by inhalation. Hence, extrapolation of the DNEL long term for systemic effects is useful to protect human health (worker and general population). No acute DNEL was calculated as no local and/or systemic adverse effects were observed after a single exposure.

For the eye irritating properties of 1-(2-tert-butyl cyclohexyloxy)-2-butanol, no DNEL was calculated as a qualitative approach is followed to protect the worker. For the general population, the active substance has to be present in the final product at a concentration lower than 10% (generic concentration limit for classification considering the CLP regulation) or 20% (generic concentration limit for classification considering the Directive 1999/45/EC).

 

3.1      DNEL for long-term exposure – systemic effects:

Both inhalation and dermal routes were the relevant routes of exposure for assessing occupational risk in workers.

3.1.1      Dermal route:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was performed. In the absence of specific data and on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation (see Guidance Document, Chapter R.8, pp 19).

Thus, the dose corrected descriptor for dermal route is 500 mg/kg bw/day for workers.

The following table 3.1/1 indicates the calculation of the inhalation DNEL-long term for systemic effects for Amber core.

Worker

Long term DNEL / dermal /systemic effects

Step a : determination of the critical dose

Key study

Fulcher, 2010, OECD 415, Key study, oral one generation study

Relevant dose descriptor

NOAEL =  500 mg/kg bw/d

Step b : Correct starting point – factor for uncertainties

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

1

(oral to dermal)

Modification for exposure

(experiment in animal and human)

Not applicable

Modification for the respiratory volume

Not applicable

Correct starting point = relevant dose descriptor / overall factor for uncertainties

500 mg/kg bw/d

Step c : assessment factors

Interspecies differences

 

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

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 

 

4

 

 

2.5

 

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(18 weeks of exposure for males and 10 weeks for females)

Issues related to dose-response

1

(NOAEL)

Quality of the whole database

1

Overall assessment factor

100

DNEL calculation

5.0 mg/kg bw/d

 

The long term dermal DNEL for systemic effects is 5.0 mg/kg bw/d for the worker.

3.1.2      Inhalation route:

For potential inhalation exposure, route-to-route extrapolation from the oral NOAEL value was performed.

In the absence of specific data for both the starting route (oral) and the end route (inhalation), worst case assumptions have to be 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.

Finally, 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 441 mg/m3 for workers.

The following Table 3.1/2 indicates the calculation of the dermal DNEL-long term for systemic effects for Amber core

Worker

Long term DNEL / inhalation /systemic effects

Step a : determination of the critical dose

Key study

Fulcher, 2010, OECD 415, Key study, oral one-generation study

Relevant dose descriptor

NOAEL =  500 mg/kg bw/d

Step b : Correct starting point – factor for uncertainties

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

1/2

Oral to inhalation

Modification for exposure

(experiment in animal and human)

Not applicable

Modification for the respiratory volume

(1/0.38)

 (standard respiratory volume animal/human)

(6.7/10)

 (respiratory rate difference under standard conditions and under conditions of light activity for 8 hours)

Correct starting point = relevant dose descriptor / overall factor for uncertainties

441 mg/m3

Step c : assessment factors

Interspecies differences

 

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

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 

 

-

(not applicable)

 

2.5

 

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(18 weeks of exposure for males in study)

Issues related to dose-response

1

(NOAEL)

Quality of the whole database

1

Overall assessment factor

25

DNEL calculation

17.6 mg/m3

The long term DNEL by inhalation for systemic effects is 17.6 mg/m3 for the worker.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.35 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

1.     Introduction:

In this dossier, all the toxicological information on 1-(2-tert-butyl cyclohexyloxy)-2-butanolare examined and analyzed in order to define a DNEL (s)/DMEL (s) for each human health endpoints if possible. The followed method is that proposed in the guidance for the implementation of REACH (Chapter R.8: Characterisation of dose (concentration)-response for human health, December 2010).

 

2.     Classification according to the Directive 67/548/EEC and to the CLP Regulation (Regulation (EC) No. 1272/2008):

 

There is no harmonized classification of 1-(2-tert-butyl cyclohexyloxy)-2-butanol for human health according to the Regulation (EC) No. 1272/2008 including the ATP2 draft. However, based on the available toxicological data, a self classification is proposed as Eye Irrit. 2 (H319, Causes serious eye irritation) according to the criteria of the Annex VI of the CLP regulation (1272/2008 ATP2). No additional self-classification is proposed for the other toxicological endpoint.

3.     DNELs derivation according to the toxicological profile of 1-(2-tert-butyl cyclohexyloxy)-2-butanol:

In the sub-acute repeated oral toxicity study and the one-generation study for the toxicity to the reproduction with 1-(2-tert-butyl cyclohexyloxy)-2-butanol, changes in the liver and in the kidney were observed in the highest dose group animals (1000 mg/kg bw/d in the subacute study and 500 mg/kg bw/d in the one-generation study). However these effects had tendency to recover after the 2-week recovery period in the sub-acute toxicity study.

In both studies, it is assumed that the observed centrilobular hepatocyte enlargement occurs as an induction of the microsomal drug metabolizing enzyme systems caused by the treatment and is considered as cellular adaptation phenomena in the absence of associated inflammatory or degenerative changes. The adaptation response to the treatment with Amber core was very important at the highest dose (1000 mg/kg bw/d) in the 28-day repeated oral dose toxicity study as described in this dossier (see § 7.5.1). Moreover, the observation of cholangitis (inflammatory effect) associated to cholestasis in both sexes at the highest dose of Amber core in the sub-acute repeated oral toxicity study showed that the substance induced systemic toxicity. Therefore, even if this effect had tendency to recover after withdrawal (2-week recovery period), the highest dose of 1000 mg/kg bw/d was considered as a LOAEL. In the one-generation study, histopathological examinations of liver didn’t show any associated inflammatory changes in the liver at 500 mg/kg bw/d as it was observed (cholangitis associated to cholestase) in the sub-acute toxicity study at 1000 mg/kg bw/d. Therefore, histopathology at 20 or 100 mg/kg bw/day were not performed even if increased absolute and relative liver weights in males were recorded assuming that in the absence of any other effect, the liver weight changes were likely related to cellular adaptation phenomena as already demonstrated at the highest dose (500 mg/kg bw/d).

Consequently, it can be assumed that no test substance related effect was observed in the highest dose group of adult animals in the one-generation study considering that the changes observed in the liver resulted from cellular adaptation phenomena. Therefore, it is assumed that the highest dose (500 mg/kg bw/d) is a NOAEL for systemic effects in the adult animals treated up to 18 weeks in the one-generation study.

The NOAEL of 500 mg/kg bw/d from the one-generation study was considered to calculate the DNEL by oral and dermal routes and by inhalation. Hence, extrapolation of the DNEL long term for systemic effects is useful to protect human health (worker and general population). No acute DNEL was calculated as no local and/or systemic adverse effects were observed after a single exposure.

 

For the eye irritating properties of 1-(2-tert-butyl cyclohexyloxy)-2-butanol, no DNEL was calculated as a qualitative approach is followed to protect the worker. For the general population, the active substance has to be present in the final product at a concentration lower than 10% (generic concentration limit for classification considering the CLP regulation) or 20% (generic concentration limit for classification considering the Directive 1999/45/EC).

3.1      DNEL for long-term exposure – systemic effects:

3.1.1      Dermal route:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was performed. In the absence of specific data And on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation (see Guidance Document, Chapter R.8, pp 19).

Thus, the corrected dose descriptor for dermal route is 500 mg/kg bw/day for general population.

 

The following Table 3.1/3 indicates the calculation of the dermal DNEL-long term for systemic effects for Amber core

General population

Long term DNEL / dermal / systemic effects

Step a : determination of the critical dose

Key study

Fulcher, 2010, OECD 415, Key study, oral one-generation study

Relevant dose descriptor

NOAEL =  500 mg/kg bw/d

Step b : Correct starting point – factor for uncertainties

Differences in absorption depending on route of exposure (route-to-route extrapolation, human/animal)

1

(oral to dermal)

Modification for exposure

(experiment in animal and human)

Not applicable

Modification for the respiratory volume

Not applicable

Correct starting point = relevant dose descriptor / overall factor for uncertainties

500 mg/kg bw/d

Step c : assessment factors

Interspecies differences

 

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

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 

 

4

 

 

2.5

 

Intraspecies differences

10

(consumer)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(18 weeks of exposure for males in study)

Issues related to dose-response

1

(NOAEL)

Quality of the whole database

1

Overall assessment factor

200

DNEL calculation

2.5 mg/kg bw/d

The long term dermal DNEL for systemic effects is 2.5 mg/kg bw/d for the general population.

3.1.2     Inhalation route:

For potential inhalation exposure, route-to-route extrapolation from the oral NOAEL value was performed.

In the absence of specific data for both the starting route (oral) and the end route (inhalation), worst case assumptions have to be 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.

Finally, 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).

 

The following table 3.1/4 indicates the calculation of the inhalation DNEL-long term for systemic effect for Amber core

General population

Long term DNEL / inhalation /systemic effects

Step a : determination of the critical dose

Key study

Fulcher, 2010, OECD 415, Key study, oral one-generation study

Relevant dose descriptor

NOAEL =  500 mg/kg bw/d

Step b : Correct starting point – factor for uncertainties

Differences in absorption depending on route of exposure (route-to-route extrapolation, human/animal)

1/2

Oral to inhalation

Modification for exposure

(experiment in animal and human)

-

(Not applicable)

Modification for the respiratory volume

(1/1.15)

 (standard respiratory volume animal/human)

Correct starting point = relevant dose descriptor / overall factor for uncertainties

217 mg/m3

Step c : assessment factors

Interspecies differences

 

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

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 

 

-

(not applicable)

 

2.5

 

Intraspecies differences

10

(general population)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(18 weeks of exposure for males in study)

Issues related to dose-response

1

(NOAEL)

Quality of the whole database

1

Overall assessment factor

50

DNEL calculation

4.35 mg/m3

The long term DNEL by inhalation for systemic effects is 4.35 mg/m3 for the general population.

3.1.3      Oral route:

The oral NOAEL value was used as the dose descriptor for DNEL long-term for oral route derivation.

 

The following Table 3.1/5 indicates the calculation of the oral DNEL-long term for systemic effects for Amber core.

General population

Long term DNEL / oral / systemic effects

Step a : determination of the critical dose

Key study

Fulcher, 2010, OECD 415, Key study

Relevant dose descriptor

NOAEL =  500 mg/kg bw/d

Step b : Correct starting point – factor for uncertainties

Differences in absorption depending on route of exposure (route-to-route extrapolation, human/animal)

1

(same route of exposure)

Modification for exposure

(experiment in animal and human)

Not applicable

Modification for the respiratory volume

Not applicable

Correct starting point = relevant dose descriptor / overall factor for uncertainties

500 mg/kg bw/d

Step c : assessment factors

Interspecies differences

 

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

 

-      Remaining differences (toxicokinetics and toxicodynamics)

 

 

 

4

 

 

2.5

 

Intraspecies differences

10

(consumer)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(18 weeks of exposure for males in study)

Issues related to dose-response

1

(NOAEL)

Quality of the whole database

1

Overall assessment factor

200

DNEL calculation

2.5 mg/kg bw/d

The long term DNEL by oral route for systemic effects is 2.5 mg/kg bw/d for the general population including Human exposed via the environment.