3-Cyclohexene-1-methanol, α,4-dimethyl-α-(4-methyl-3-penten-1-yl)-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

18

Modified dose descriptor starting point:

NOAEC

Value:

176 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

according to R8 ECHA 2008. The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

according to R8 ECHA 2008.

AF for other interspecies differences:

1

Justification:

see discussion

AF for intraspecies differences:

3

Justification:

see discussion

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

according to R8 ECHA 2008. The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

according to R8 ECHA 2008.

AF for other interspecies differences:

1

Justification:

see discussion

AF for intraspecies differences:

3

Justification:

see discussion

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

560 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

other: 5600 µg/cm2

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

560 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: 5600 µg/cm2

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

General
DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010). 

Workers – Hazard via inhalation route

Long term, systemic inhalation DNEL

Occupational exposure to the test substance occurs mainly by dermal route, whereas inhalation exposure is less likely due to the low vapour pressure of racemic (+/-) alpha-Bisabolol. However, a long term systemic inhalation DNEL has been derived via route-to-route extrapolation. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Selection of the relevant dose descriptor (starting point): 
For risk characterisation an inhalation NOAEC was derived by route to route extrapolation. The key study for repeated dose toxicity, i.e. a subacute dermal repeated dose toxicity study acc. to OECD 410 and GLP (BASF 1996; 33S0144/95020) was considered as key value for the chemical safety assessment and therefore, most relevant starting point. In this study, transient effects of (+/-) alpha-Bisabolol on the treated skin (moderate erythema, diffuse scale formation) were seen in some high dose females. Body weight change and food efficiency were impaired transiently in high dose males and females. Although the effects were observed only transiently, a substance-relationship cannot be excluded with certainty. Thus, the no observed adverse effect level under the conditions of this study was therefore 200 mg/kg body weight/day.This value has been used as conservative point of departure, considering, that NOAELs derived from present oral repeated dose toxicity studies were higher (NOAEL = 1 ml/kg bw/d; approx. 930 mg/kg bw/d) and effective toxic doses in these studies were well above the limit dose of 1000 mg/kg bw/d.

 

Route to route extrapolation:

Indications for a high dermal penetration potential of (+/-) alpha-Bisabolol are available from non-guideline studies. Based on the physicochemical properties (+/-) alpha-Bisabolol is considered to become highly bioavailable via the dermal and oral route. On the basis of the low vapour pressure, the exposure with (+/-) alpha-Bisabolol via inhalation as a vapour is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to assess the route-to-route extrapolation between der dermal and the inhalation route case by case. Since a high dermal uptake and penetration enhancing capacities have been attributed to (+/-) alpha-Bisabolol, a twofold higher inhalative than dermal uptake has been considered, i.e 50% dermal and 100% inhalation absorption.

   

Modification into a correct starting point: 

Modification of starting point:	50%/100%         0.38 m3/kg bw         6.7 m3/10 m3		Ratio of dermal (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2)     Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)     Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

 

NOAEC corrected = 200*(1/0.38)*(50/100)*(6.7/10) = 176 mg/m3

 
Use of assessment factors: 18 

Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation
Remaining differences	1	Substance specific assessment factor: Adverse systemic effects of (+/-) alpha Bisabolol were only transient and not organ specific, i.e. impaired food efficiency and decreased body weight changes. On the basis of these transient findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling (not relevant, see above). Overall, based on these mild systemic effects, no additional AF for remaining differences is considered mandatory.
Intraspecies	3	Substance specific assessment factor: Due to the transient general systemic effects observed in the key repeated dose toxicity study, i.e. impaired food efficiency and body weight gains, the default assessment factor for intraspecies variability for systemic toxicity after repeated dosing has been amended to a less conservative value. These findings are not considered to have a very high variation within the human population and do not represent severe specific organ toxicity. The derivation of (+/-) alpha Bisabolol specific assessment factors are guided by the following information: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95th percentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 can be taken for the general population with a lower factor of 3 (i. e. closer to the 90th percentile) for the more homogenous worker population.
Exposure duration	6	Data from subacute study was taken into account

 

Overall, it needs to be pointed out, that several factors of conservatism have been applied to the systemic DNEL derivation made. Next to the use of the 90-95th percentile concerning intraspecies variability, the multiplicatory principle of AF together with a conservative choice of the NOAEL as point of departure provide a sufficient degree of conservatism.

In conclusion, long term systemic inhalation DNEL, workers = 9.8 mg/m³  

Acute/short term, systemic inhalation DNEL

(+/-) alpha-Bisabolol is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral, dermal and inhalation toxicity. Thus, no DNEL for sytemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for sytemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic inhalation effects.

 

Acute/short term and long term, local inhalation DNEL

No data on respiratory irritation or repeated inhalation toxicicity is available. However, as (+/-) alpha-Bisabolol is not classified as skin and eye irritating also no local adverse effects on i.e. the respiratory system are to be expected (in accordance with "Guidance on information requirements and chemical safety assessments, chapter R8"). Thus, no DNEL for local effects after acute or long term inhalation exposure is required.

 

 

Workers - Hazard via dermal route

Long term, systemic dermal DNEL

Selection of the relevant dose descriptor (starting point)

The NOAEL of 200 mg/kg bw/day, obtained from a subactue dermal toxicity study (BASF 1996; 33S0144/95020) was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

 

Use of assessment factors: 72

Allometric scaling	4	Assessment factor for allometric scaling (rat to human) according to R8 ECHA 2008
Remaining differences	1	Substance specific assessment factor: Adverse systemic effects of (+/-) alpha Bisabolol were only transient and not organ specific, i.e. impaired food efficiency and decreased body weight changes. On the basis of these transient findings, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling. Overall, based on these mild systemic effects, no additional AF for remaining differences is considered mandatory.
Intraspecies	3	Substance specific assessment factor: Due to the transient general systemic effects observed in the key repeated dose toxicity study, i.e. impaired food efficiency and body weight gains, the default assessment factor for intraspecies variability for systemic toxicity after repeated dosing has been amended to a less conservative value. These findings are not considered to have a very high variation within the human population and do not represent severe specific organ toxicity. The derivation of (+/-) alpha Bisabolol specific assessment factors are guided by the following information: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95th percentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 can be taken for the general population with a lower factor of 3 (i. e. closer to the 90th percentile) for the more homogenous worker population.
Exposure duration	6	Data from subacute study was taken into account

 

In conclusion, long term systemic dermal DNEL, workers = 2.8 mg/kg bw/day

Acute/short-term systemic dermal DNEL 

(+/-) alpha-Bisabolol is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral, dermal and inhalation toxicity. Thus, no DNEL for sytemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for sytemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

Acute/short-term and Long term local dermal DNEL

 

For (+/-) alpha-Bisabolol, it is not possible to exclude the possibility of potential skin sensitisation. This conclusion is based on the positive results in mice and guinea pigs (LLNA and GPMT). However, in available human tests and the Bühler test in guinea pigs, no skin sensitizing potential was observed for alpha-Bisabolol or Chamomile oil, and the data from the well conducted human repeated insult patch test are taken into account for a quantitative risk assessment and respective DNEL derivation.

 

Based on the outcome of the LLNA, i.e. an EC3 value of 17.9%, (+/-) alpha-Bisabolol, is considered to be a weak skin sensitizer.

The EC3 [%] is converted to EC3 [µg/cm2]:

EC3 [%] * 250 [µg/cm2/%] = EC3 [µg/cm2] = 17.9 * 250 = 4475 µg/cm2

 

A NOEL from a well performed HRIPT will (even if higher) have precedence over all other NOELs (including LLNA EC3 value of 17.9% (4475 µg/cm²)). The HRIPT used as point of departure represents such a well performed study. 107 subjects received 9 applications of 0.2 ml aliquot of 10% (+/-) alpha-Bisabolol in 3:1 DEP: EtOH (estimated to be 5600 µg/cm2) for 24 hours in 3 successive weeks. Approximately 2 weeks after the last induction application, a 24 h challenge application with 10% (+/-) alpha-Bisabolol in 3:1 DEP: EtOH was made to a naive site. When reactions to challenge were read 24 h, and 72 h post application, no skin sensitizing effects were observed.

 

Both the LLNA and the HRIPT studies lead to similar dose descriptors showing a substance specific comparability of effect levels in the different test systems used. Since no species specific differences in potencies are indicated between the murine test and human subjects, the use of an additional interspecies assessment factor is not plausible. Furthermore, based on the ECHA guidance document (R8 p.23) no extrapolation and no assessment factor is necessary for interspecies differences in sensitivity, where human data are used as the starting point for risk characterization.

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). Overall, an assessment factor of 10 for intraspecies differences is applied to adequately address the combined influence of these effects.

 

Therefore, a DNEL for skin sensitization was set at 560 µg/cm2. The derived DNEL on the basis of skin sensitization is considered sufficient to cover local effects observed after acute and long term dermal exposure.

 

References  (not included as endpoint study record)  

- ECHA (2008). Guidance on information requirements and chemical safety assessment - Chapter R.8: Characterisation of dose [concentration]-response for human health.

- Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier.March 15, 2006 (revised May 2006).

- Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008).Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23

Worker - Hazard for the eyes

According to the EU (DSD and GHS) criteria for classification and labelling requirements for dangerous substances and preparations (+/-) alpha Bisabolol does not have to be classified and has no obligatory requirements for eye irritation.

References  (not included as endpoint study record)  

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.  

- ECHA (2010). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. May 2008  

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.  

 

 

 

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

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:

no hazard identified

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

Since all relevant uses contain concentrations <0.1% or are outside the scope of REACH and inside the scope of the regulation EC 1223/2009 on cosmetic products, no DNELS have been derived for the general population according to “Guidance on information requirements and chemical safety assessment (Chapter R8). Hazard identification and risk characterisation has been covered by the respective regulation.