Screening Assessment for the Challenge
1-Naphthalenepropanol, α-ethenyldecahydro-2-hydroxy-α,2,5,5,8α-pentamethyl-, [1R-[1α(R*),2β,4αβ,8αα]]-
(Sclareol)
Chemical Abstracts Service Registry Number
515-03-7

Environment and Climate Change Canada
Health Canada

October 2017

(PDF Format-425KB)

Table of Contents

Table of Figures

Synopsis

Pursuant to section 74 of the Canadian Environmental Protection Act, 1999 (CEPA), the Minister of the Environment and the Minister of Health have conducted a screening assessment of 1-Naphthalenepropanol, α-ethenyldecahydro-2-hydroxy-α,2,5,5,8α-pentamethyl-, [1R-[1α(R*),2β,4αβ,8αα]]-, hereinafter referred to as sclareol. The Chemical Abstracts Service Registry Number (CAS RNFootnote 1) for sclareol is 515-03-7. Sclareol was identified as a priority for assessment as it met the categorization criteria under subsection 73(1) of CEPA.

Sclareol is naturally produced as a component in the essential oil of several genera (e.g., Salvia and Stachys) in the mint family, Lamiaceae. The essential oil containing sclareol may be produced by plants to protect themselves from pathogens (i.e., bacteria and/or fungi), foraging herbivores and/or influence the growth of neighbouring plants. Sclareol has been isolated in various plant species, such as Salvia sclarea, Salvia officinalis, Salvia judaica, Salvia palaestina, Juniperus phoenicea, Cistus creticus, and Astragalus brachystachys, including some 25 tobacco species, such as Nicotiana glutinosa, Nicotiana tabacum.

In Canada, sclareol is not reported to be imported or manufactured above the 100 kg reporting threshold or used above the 1000 kg threshold by any single company for the reporting years 2005 and 2006. However, a total estimated quantity of 76 to 1350 kg sclareol is currently used in Canada per year. Sclareol is a component of the clary sage essential oil, which was reported to be present in cosmetics, flavouring agents, aromatherapy products, and fragrances in Canada.

It is expected that sclareol, when produced by plants, will likely be degraded by soil bacteria or other fungal species, as a number of studies have shown that soil micro-organisms are capable of metabolizing sclareol. However, when the essential oil containing sclareol is extracted from these plants and incorporated into cosmetics, down-the-drain releases are likely to occur via wastewater treatment system effluent into the aquatic environment, where degradation is expected to occur much more slowly.

Sclareol has low water solubility and has a tendency to partition to sediments if released to surface waters. On the basis of its physical and chemical properties, modelled data and a limited amount of experimental data, sclareol is expected to persist in water and sediment. Modelled data relating to its partitioning between octanol and water indicate that sclareol has a high potential to accumulate in the lipid tissues of organisms (bioconcentration factor [BCF]and bioaccumulation [BAF] factor values range from 4247 to 31 890). Modelled toxicity data for sclareol suggest that the substance can cause acute harm to aquatic organisms. Experimental microbial toxicity data also suggest that sclareol causes harm to bacteria and fungi.

Given the relatively small amounts of sclareol known to be in commerce in Canada and its uses, which can lead to disperse releases to the environment, ecological exposure to sclareol is expected to be low. Considering all available lines of evidence presented in this screening assessment, there is low risk of harm to organisms and the broader integrity of the environment from sclareol. It is concluded that sclareol does not meet the criteria under paragraph 64(a) or (b) of CEPA as it is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends.

On the basis of the available information, exposure of the general population to sclareol is expected to be negligible given the low reports of use of sclareol in Canada in 2006. The general population is expected to be exposed predominantly via the dermal route from the presence of sclareol, a component of clary sage essential oil, in cosmetics. On the basis of the available information on health effects of sclareol, it was not considered to have high hazard potential. A comparison of conservative upper-bounding estimates of dermal exposure to sclareol from the presence of clary sage essential oil in cosmetics to a level at which no adverse effects were observed in experimental animals, resulted in margins of exposure that were considered adequate to address uncertainties in the health effects and exposure databases. On the basis of the available information, it is concluded that sclareol does not meet the criteria in paragraph 64(c) of CEPA, as it is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

On the basis of the information available, it is concluded that sclareol does not meet any of the criteria set out in section 64 of CEPA.

1. Introduction

The Canadian Environmental Protection Act, 1999 (CEPA) (Canada 1999) requires the Minister of the Environment and the Minister of Health to conduct screening assessments of substances that have met the categorization criteria set out in the Act to determine whether these substances present or may present a risk to the environment or to human health.

On the basis of the information obtained through the categorization process, the Ministers identified a number of substances as high priorities for action. These include substances that:

The Ministers therefore published a notice of intent in the Canada Gazette, Part I, on December 9, 2006 (Canada 2006a), that challenged industry and other interested stakeholders to submit, within specified timelines, specific information that may be used to inform risk assessment, and to develop and benchmark best practices for the risk management and product stewardship of those substances identified as high priorities.

The substance, 1-Naphthalenepropanol, α-ethenyldecahydro-2-hydroxy-α,2,5,5,8α-pentamethyl-, [1R-[1α(R*),2β,4αβ,8αα]]-, was identified as a priority for assessment as it met categorization criteria under subsection 73(1) of CEPA (ECCC, HC [modified 2007]). The "Challenge" for this substance was published in the Canada Gazette on December 26, 2009 (Canada 2009a, 2009b). A substance profile was released at the same time. The substance profile presented the technical information available prior to December 2005 that formed the basis for categorization of this substance. No submissions of information pertaining to the properties, bioaccumulation potential, persistence, hazard, uses, or exposure of the substance were received under the Challenge.

Screening assessments focus on information critical to determining whether a substance meets the criteria as set out in section 64 of CEPA. Screening assessments examine scientific information and develop conclusions by incorporating a weight-of-evidence approach and precaution.Footnote 2

This screening assessment includes consideration of information on chemical properties, hazards, uses and exposure, including the additional information submitted under the Challenge. Data relevant to the screening assessment of this substance were identified in original literature, review and assessment documents, and stakeholder research reports and from literature searches up to August 2010 for ecological and health sections of the screening assessment. In February 2017, a rapid search of the literature did not identify any significant new information that could influence the outcome of this assessment. Key studies were critically evaluated and modelling results may have been used to reach conclusions.

When available and relevant, information presented in hazard assessments from other jurisdictions was considered.

This screening assessment was prepared by staff in the Existing Substances Programs at Health Canada and Environment and Climate Change Canada and incorporates input from other programs within these departments. The ecological and human health portions of this assessment have undergone external written peer review/consultation. Approaches used in the screening assessments under the Challenge have been reviewed by an independent Challenge Advisory Panel. Additionally, the draft of this screening assessment was subject to a 60-day public comment period. No external comments were received on the draft screening assessment. The final content and outcome of the screening assessment remain the responsibility of Health Canada and Environment and Climate Change Canada.

The critical information and considerations upon which the screening assessment is based are summarized below.

2. Substance identity

2.1 Substance name

For the purposes of this document, 1-Naphthalenepropanol, α-ethenyldecahydro-2-hydroxy-α,2,5,5,8α-pentamethyl-, [1R-[1α(R*),2β,4αβ,8αα]]- will be referred to as sclareol, its common name.

Table 2 -1. Substance identity for sclareol
Chemical Abstracts Service Registry Number (CAS RN)515-03-7
DSL name[a]1-Naphthalenepropanol, α-ethenyldecahydro-2-hydroxy-α,2,5,5,8α-pentamethyl-, [1R-[1α(R*),2β,4αβ,8αα]]-
National Chemical Inventories (NCI) names[3b]1-naphthalenepropanol, α-ethenyldecahydro-2-hydroxy-α,2,5,5,8α-pentamethyl-, (αR,1R,2R,4αS,8αS)- (TSCA, PICCS, ASIA-PAC, NZIoC)
1-Naphthalenepropanol, α-ethenyldecahydro-2-hydroxy-α,2,5,5,8α-pentamethyl-, [1R-[1α(R*),2β,4αβ,8αα]]- (AICS)
[1R-[1α(R*),2β,4αβ,8αα]]-2-hydroxy-α,2,5,5,8α-pentamethyl-α-vinyldecahydronaphthalene-1-propan-1-ol (EINECS)
Sclareol (PICCS)
Other names(-)-Sclareol;Labd-14-ene-8,13-diol; (13R)-{1R-[1α(R*),2β,4αβ,8αα]}-2-Hydroxy-α,2,5,5,8α-pentamethyl-α-vinyldecahydronaphtalene-1-propan-1-ol
Chemical group
(DSL stream)
Discrete organics
Major chemical class or useBicyclic diterpenes
Major chemical sub-classLabdane diterpene diols
Chemical formulaC20H36O2
Chemical structure 
SMILES[c]OC(C=C)(CCC(C(C(C(CC1)(C)C)CC2)(C1)C)C2(O)C)C
Molecular mass308.51 g/mol

a Domestic Substances List.
b National Chemical Inventories (NCI). 2007: AICS (Australian Inventory of Chemical Substances); ASIA-PAC (Asia-Pacific Substances Lists); EINECS (European Inventory of Existing Commercial Chemical Substances); PICCS (Philippine Inventory of Chemicals and Chemical Substances); NZIoC (New Zealand Inventory of Chemicals); and TSCA (Toxic Substances Control Act Chemical Substance Inventory).
c Simplified molecular-input line entry system.

3. Physical and chemical properties

Table 3-1 contains experimental and modelled physical and chemical properties of sclareol that are relevant to its environmental fate. Sclareol is a white crystalline powder. The modelling program ACD/pKaDB (2005) predicts a primary acid dissociation constant (pKa1) of 15.5 and a secondary acid dissociation constant (pKa2) of 14.5. The substance ionizes little in water under environmentally relevant conditions and can therefore be evaluated using mass balance and quantitative structure-activity relationship (QSAR) models based on the properties of the neutral species.

QSAR models were used to generate data for some of the physical and chemical properties of sclareol. These models (except WSKOWWIN 2008) are based mainly on fragment addition methods, i.e., they rely on the structure of a chemical. Since these models only accept the neutral form of a chemical as input (in SMILES form), the modelled values shown in Table 3-1 are for the neutral form of sclareol.

Table 3 -1. Physical and chemical properties for sclareol
PropertyTypeValue[a]DescriptorReference
Melting point (°C)Experimental104-105NAJermstad 1927
Melting point (°C)Experimental106[b]NARIFM 1992
Boiling point (°C)Experimental218–220[b] (at 19 mmHg)NASigma-Aldrich MSDS 2010
Boiling point (°C)Experimental>340NARIFM 1992
Density (g/cm3)Experimental0.954NALookchem 2010
Vapour pressure (Pa)Experimental<0.1333[b]
( < 0.001 mmHg)
25RIFM 1992
Vapour pressure (Pa)Modelled0.3
(0.00212 mmHg)
NAEPIsuite 2008
Henry's law constant (Pa·m3/mol)Modelled (Bond method)0.32
(3.11 × 10−6
atm•m3/mole)
NAHENRYWIN 2008
Henry's law constant (Pa·m3/mol)Modelled (Group method)Not calculableNAHENRYWIN 2008
log Kow (octanol-water partition coefficient) (dimensionless)Modelled6.0[b]NAKOWWIN 2008
Log Kow (octanol-water partition coefficient) (dimensionless)Modelled3.29NATOPKAT 2004
Log Kow (octanol-water partition coefficient) (dimensionless)Modelled4.93NAALOGPS c2001-2009
Log Koc (organic carbon-water partition coefficient) (dimensionless)Modelled3.1–3.4NAKOCWIN 2008
log Koa (octanol-air partition coefficient) (dimensionless)Modelled9.9NAKOAWIN 2008
Water solubility (mg/L)Modelled0.05[b]25WSKOWWIN 2008
pKa (acid dissociation constant) (dimensionless)ModelledpKa1 = 15.5
pKa2 = 14.5
(acid form)
NAACD/pKaDB 2005

a Values in parentheses represent the original ones as reported by the authors or as estimated by the models.
b Values selected in modelling with EPI Suite (2008).
NA = Not available.

4. Sources

Sclareol is naturally produced as a component in the essential oil of sage. This essential oil may be produced by the plant to protect itself from pathogens (i.e., bacteria and/or fungi), herbivores and/or influence the growth of neighbouring plants (Sirikanataramas et al. 2008). For example, the upper leaf surface of sage is covered with glandular hairs that secrete the essential oils that typically give the plant its distinct aroma. When the hairs are rubbed or brushed, some of the oil-bearing cells are ruptured, releasing the oil. This often results in the plant being unattractive to grazing animals and some insects.

Salvia sclarea, commonly known as clary sage, is the plant species most commonly used commercially for the extraction of sclareol. Abiennial or perennial shrub with an aromatic smell (Pitarokili et al. 2002; Souleles and Argyriadou 1997; Tutin et al. 1972), Salvia sclarea was introduced into the United States and has been designated as a noxious weed by the US federal government and/or individual states as it is considered to pose a threat to forage production and plant biodiversity by displacing less competitive, more desirable species (NRCS 2010; NWCB 2008).

One of several genera commonly referred to as "sage," Salvia is the largest genus of plants in the mint family (Lamiaceae), with approximately 700 to 900 species of shrubs, herbaceous perennials and annuals. Forty-eight species within the Lamiaceae family are considered naturalized in Canada, several of which (i.e., Salvia sylvestris, Stachys arvenis, Stachys palustris) have been designated as invasive species in Canada (CFIA 2008). Salvia sylvestris is listed as native to Ontario, introduced (i.e., as a result of human activity, either deliberate or accidental) in British Columbia, Alberta, and Manitoba, and extirpated (i.e., native but eradicated) in Saskatchewan (Brouillet et al. 2010). Salvia sclarea (found in Ontario) and Salvia officinalis (found in Ontario and Quebec) are listed as ephemerals (i.e., not established permanently, but recurring in the wild on a near-annual basis, usually from cultivation) (Brouillet et al. 2010). Of the 48 species in the Lamiaceae family considered naturalized in Canada, only Salvia sclarea and Salvia officinalis are currently known to produce sclareol in their essential oil.

In addition to Salvia sclarea, sclareol may also be found in Salvia officinalis (also known as "common sage" or Dalmatian sage) and its cultivars, Salvia judaica (Judean sage) (Boszomenyi et al. 2009), Salvia palaestina (Senatore et al. 2005), Salvia poculata (Kolak et al. 2009), Salvia desoleana (Soković et al. 2008), in some species of the genus Stachys, such as S. ionica, S. sylvatica, and S. swainsonii ssp. scyronica (Piozzi and Bruno 2009), in the essential oils of the leaves and berries of Juniperus phoenicea (El-Sawi et al. 2007), in the leaves of Cistus creticus (Demetzos et al. 1990) and in the plant Astragalus brachystachys (Choudhary et al. 2006). The leaves of some tobacco species, such as Nicotiana glutinosa, Nicotiana tabacum and 23 other Nicotiana species, also contain sclareol (Cutler et al. 1977; Kennedy et al. 1992).

The essential oils are extracted from plants by steam distillation or with organic solvents, typically for use as flavour or fragrance ingredients. The amount of sclareol in an essential oil extracted from a given plant varies depending on the section of the plant from which the essential oil is extracted (i.e., flower, leaves), the developmental stage of the plant (i.e., full blossom, at seed formation, full seed formation) (Farkas et al. 2005), the cultivation conditions (Peana et al. 1999), the country of origin (Schmiderer et al. 2008), and the extraction technique. Clary sage can be extracted for its essential oil or its "concrete." Concrete, in perfumery, is a semi-solid mass obtained by solvent extraction of fresh plant material. Essential oils are obtained by means of hydro-distillation of the plant material (Souleles and Argyriadou 1997), while the concrete is obtained by solvent extraction (Schmiderer et al. 2008; Lawrence 1986). Sclareol may be present at varying percentages (ranging from 0.06 to 20%) in the essential oil of various Salvia species, with higher percentages found in Salvia palaestina (~20%). While levels of sclareol can be more concentrated in concrete ( >70% in Salvia sclarea) (Senatore et al. 2005; Schmiderer et al. 2008; Esteban et al. 1996; Lawrence 1986), it is rarely used as fragrance in the cosmetic industry (Surburg and Panten 2006).

Historically, during the Domestic Substances List (DSL) nomination process (based on the years 1984 to 1986), the DSL use codes for "fragrance/perfume/deodorizer/flavouring agent" were identified for sclareol. The quantity reported was in the 1000 to 10 000 kg range (Environment Canada 1988), with fewer than four notifiers.

For the 2005 calendar year, no manufacture or import of sclareol above the 100 kg threshold, or use above the 1000 kg threshold, by any single company in Canada was reported in response to a CEPA section 71 survey notice (Canada 2006b; Environment Canada 2006). However, two companies identified themselves as having a stakeholder interest in the substance.

For the 2006 calendar year, no manufacture or import of sclareol above the 100 kg threshold or use above the 1000 kg threshold by any single company, was were reported in Canada in response to a CEPA section 71 survey notice (Canada 2009b; Environment Canada 2010). One company identified itself as a having a stakeholder interest in the substance.

Additional investigations (personal communications from the Canadian Federation of Aromatherapists and other associations, 2011; unreferenced) indicated that sclareol is currently used in Canada. Using a combination of reported information and conservative assumptions, lower and upper estimates of the quantity of sclareol in commerce were made. It is estimated that between 76 and 1350 kg of sclareol is used (see Table 4-1) in Canada per year. The total quantity of sclareol imported/used in Canada was estimated by summing the estimates of use in the fragrance, flavouring agents, cosmetics and aromatherapy industries. This may result in some double counting, as some aromatherapy products may be considered cosmetics and some fragrances may be used in the formulation of cosmetics. This information was taken into consideration for the assessment.

The following assumptions were used in calculating the quantity estimates in Canada:

The commercial significance of clary sage essential oil or sclareol to industry, particularly companies involved in aromatherapy, is considered low to moderate. Many companies indicated low use quantities, low sales and the use of alternative substances (personal communications from Canadian Federation of Aromatherapists and other associations, 2011; unreferenced).

Table 4 -1. Total extrapolated quantity data for sclareol (CAS 515-03-7) per year
Sector/ product categoryTotal (pure substance) (kg)Total (pure substance or in clary sage essential oil) (kg)
Fragrances/Cosmetics14–15962–507
Flavour4–404–40
AromatherapyNA10–802
TobaccoNANA
Total18–19976–1350

NA = not available

5. Uses

In Canada, notification of fragrance components to Health Canada is not a requirement and sclareol, as such, was not identified in the Cosmetic Notification System (CNS). However, it is a component of the essential oil in Salvia sclarea, and approximately 800 cosmetic products containing this essential oil in concentrations varying between 0.1% and 30% were identified in the CNS (CNS 2010). Sclareol is not included on the List of Prohibited and Restricted Cosmetic Ingredients (more commonly referred to as the Cosmetic Ingredient Hotlist or simply the Hotlist), an administrative tool that Health Canada uses to communicate to manufacturers and others that certain substances, when present in a cosmetic, may contravene the general prohibition found in section 16 of the Food and Drugs Act or a provision of the Cosmetic Regulations (Health Canada 2011).

Clary sage essential oil is used as fragrance in insect repellents, insecticides, indoor flea and tick treatments for domestic animals, and carpet sanitizers (personal communication from the Pest Management Regulatory Agency, Health Canada, to Risk Management Bureau, Health Canada, dated November 2010; unreferenced). Sclareol is not listed as an approved food additive in the lists of permitted food additives under the Food and Drugs Act (Health Canada 2013).

The Flavor and Extract Manufacturers Association (FEMA) of the United States has listed sclareol as one of the 236 new flavouring ingredients generally recognized as safe (Smith et al. 2009). As sclareol is used as a food flavour in the United States and elsewhere (Smith et al. 2009; European Commission 2002; Ash and Ash 2003, 2006), it is possible that sclareol is used as a flavour in foods that are offered for sale in Canada. In Canada, food flavours are not regulated as food additives and are not required under the Food and Drug Regulations to undergo pre-market review. Flavouring ingredients can be added to any food that does not have a standard of identity and composition in the Food and Drug Regulations and to those foods that have a standard of identity and composition that allows for the addition of flavours to the food. Similarly, plant materials such as leaves, stems, and seeds containing sclareol may be added to foods without a regulatory standard and to foods having a standard where there is provision for the addition of spices or seasonings. Sclareol was not identified in food packaging applications or in formulations of incidental additives (personal communication from Food Directorate, Health Canada, to the Risk Management Bureau, Health Canada, dated August 2010; unreferenced).

Sclareol is not listed in the Drug Product Database, the Therapeutic Products Directorate's internal Non-Medicinal Ingredient Database, the Natural Health Products Ingredients Database (NHPID) or the Licensed Natural Health Products Database (LNHPD) as a medicinal or a non-medicinal ingredient present in final pharmaceutical products, natural health products or veterinary drugs (DPD 2017; NHPID 2017; LNHPD 2017; personal communication from the Therapeutic Products Directorate, Natural Health Products Directorate and Veterinary Drugs Directorate, Health Canada, to the Risk Management Bureau, Health Canada, dated August 2010; unreferenced). Clary sage essential oil, which naturally contains sclareol, is listed in the NHPID with a medicinal role because it is classified as an NHP substance under item 2 (extract) of Schedule 1 to the Natural Health Products Regulations and is listed as a medicinal ingredient in the NNHPD Aromatherapy – Essential Oils for use at concentrations up to 5% for topical application, to a maximum of 8% for local application (i.e., up to 10% of body surface area). It is also listed with a non-medicinal role for oral use as flavour enhancer or for topical use as fragrance ingredient in natural health products (NHPID 2017). It is listed in the Licensed Natural Health Products Database (LNHPD) as being present as such, a medicinal or non-medicinal ingredient, in currently licensed natural health products in Canada (LNHPD 2017). Salvia sclarea and other plant species and their preparations that naturally contain sclareol are also listed in the NHPID with a medicinal and/or non-medicinal role and in the LNHPD as being present as such in currently licensed natural health products in Canada (LNHPD 2017; NHPID 2017.

Salvia sclarea is native to southern Europe and is commonly cultivated in southern France, Russia, Hungary, Italy, the United Kingdom and the United States (Pitarokili et al. 2002). Extracts of the whole plant, of which sclareol is a constituent, have been used in a variety of applications. Upon hydro-distillation, the flowering inflorescence yields an essential oil that is used in the preparation of various alcoholic beverages (Dzamic et al. 2008). The extract of the aerial part of the S. sclarea plant also has a broad spectrum of uses in traditional medicine: analgesic, anti-inflammatory, antioxidant, antifungal, and antibacterial. Fresh leaves of the plant are used in soups (Lattoo et al. 2006). In Greece, S. sclarea is known by the common name "agiannitis" and is used locally for coughs, colds, blood cleaning, on wounds and sore eyes, and as a diuretic (Pitarokili et al. 2002).

Sclareol itself is used as a fragrance ingredient in decorative cosmetics, fine fragrances, creams, lotions, shampoos, toilet soaps, and other toiletries, as well as other products used by consumers, such as household cleaners and detergents (Bhatia et al. 2008; Farkas et al. 2005; Ash and Ash 2003, 2006). It has been used for antibacterial activity, fungal-growth regulation (i.e., rust fungi) and plant-growth inhibition (Dimas et al. 2007; Choudhary et al. 2006; Lattoo et al. 2006; Jasinski et al. 2001; Ulubelen et al. 1994; Bailey et al. 1975). Sclareol is used commercially as a fixative in perfumery (ambergris), as a tobacco flavour additive, in foods and beverages, as a synthon for the synthesis of a series of amber odorants, and in traditional medicine (Choudhary et al. 2006; Dimas et al. 2007; Bailey et al. 1975; McChesney and Kouzi 1990; Pitarokili et al. 2002; Kutney and Chen 1994; Leung 1980). Patents have also been developed for the use of sclareol in inducing weight loss and increasing lipolysis (Peele and Dilip 2006). Sclareol is also a precursor for sclareolide, which is another tobacco flavour additive, salt enhancer and a precursor of ambrox, an ambergris-like product used in perfumery (Kutney and Chen 1994; Leung 1980). The Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) has published a specification for sclareol as a food flavouring agent (JECFA 2010a).

6. Releases to the environment

There were no reports of use, import or manufacture of sclareol in Canada in 2006 at or above the reporting thresholds specified in the CEPA section 71 notice (Canada 2009b). However, a total estimated quantity of between 76 and 1350 kg sclareol is currently used in Canada per year (see Table 4-1). It is known that sclareol is in commerce in Canada as a component of the clary sage essential oil in cosmetics. The concentration of sclareol in clary sage essential oil has been measured at concentrations ranging from 0.06% to 6%. However, no measured data has been identified for the concentrations of sclareol in cosmetic products. Bhatia et al. have estimated the sclareol concentration in cosmetic products to be 0.03% (2008).

It is expected that the plants producing essential oils containing sclareol will likely be degraded by soil bacteria or other fungal species, as a number of studies have shown soil microorganisms are capable of metabolizing sclareol (see section on Persistence) in its natural terrestrial habitat. However, if sclareol or the essential oil containing sclareol is chemically extracted from these plants and incorporated into various products available to consumers, then down-the-drain releases are likely to occur via wastewater treatment systemsFootnote3 (WWTS) effluent into the aquatic environment, where degradation is not likely to occur (see section 7.1).

7. Environmental fate

The results of Level III fugacity modelling (Table 7-1) based on the physical and chemical properties of sclareol (Table 3-1) suggest that sclareol is expected to predominantly reside in air, soil or sediment, depending on the compartment of release. These results represent the partitioning of the substance in a hypothetical evaluative environment resulting from intermedia partitioning and loss by both advective transport (out of the modelled region) and degradation/transformation processes. The partitioning values shown in Table 7-1 represent the net effect of these processes under conditions of continuous release when a non-equilibrium "steady-state" has been achieved.

Table 7 -1. Results of the Level III fugacity modelling (EQC 2003) for the percentage of sclareol partitioning into each compartment
Substance released to:AirWaterSoilSediment
Air (100%)99.90.0050.0040.12
Water (100%)0.024.10.000000796
Soil (100%)600.003400.07

If released to air, high amounts of the substance are expected to reside in air. Given the moderate experimental vapour pressure of 0.1333 Pa and moderate estimated Henry's Llaw constant of 0.315 Pa·m3/mol, sclareolis considered to be moderately volatile. Therefore, if released solely to air, sclareol will almost completely reside in this compartment.

If released to water, sclareol is expected to adsorb to suspended solids and sediment given the moderate estimated log Koc value of 3.1 to 3.4. Volatilization from water surfaces is expected to be a less important fate process because of sclareol's estimated moderate Henry's law constant (0.315 Pa·m3/mol). Thus, if water is a receiving medium, sclareol is expected to partition mainly to sediment.

If released to soil, sclareol is expected to have moderate adsorptivity to soil (i.e., may have some mobility in soil pore waters) given its estimated log Koc (3.1 to 3.4). Because of its estimated Henry's law constant, volatilization from moist soil surfaces seems to be an important fate process. Therefore, if released to soil, sclareol will reside in soil as well as volatilize to air, as illustrated by the results of the Level III-fugacity modelling.

7.1 Environmental persistence

Few experimental data are available for sclareol. Consequently, an attempt was made to identify a number of analogues to use in a read-across approach to help determine the persistence and bioaccumulation properties of sclareol. However, no acceptable analogues with measured properties or experimental data were identified.

The structural classes of sclareol (i.e., aliphatic carbons, olefinic carbons, alcohols) are amenable to model predictions as they are considered to be "in the model domain of applicability (e.g., within structural and/or property parameter domains of the model database). Therefore, the applicability of QSAR models to sclareol is considered appropriate.

Empirical biodegradation in air data for sclareol was available. Vlad and Aryku (1992) investigated the ozonolysis of sclareol under various conditions, such as in ethyl acetate in the presence of pyridine and in ethyl acetate with decomposition of the ozonide in water. The percent yield of the reaction products from 1 g of sclareol ranged from 30% to 52% at temperatures of 18 to 70 °C and an ozonation time of 60 minutes. However, it should be noted that these conditions are not environmentally relevant.

Since few experimental data on the degradation of sclareol are available, a QSAR-based weight-of-evidence approach (Environment Canada 2007) was also applied using the degradation models shown in Table 7-2 below. Sclareol is expected to be released to the water compartment and, given the ecological importance of the water compartment and the fact that most of the available models apply to water; biodegradation in water was primarily examined. Table 7-2 summarizes the results of available QSAR models for degradation in various environmental media.

Table 7-2. Modelled data for degradation of sclareol
Fate processTypeModel and model basisModel result and predictionExtrapolated half-life (days)
Atmospheric oxidationAbioticAOPWIN 2008[a]t ½ =
0.182 days
<2
Ozone reactionAbioticAOPWIN 2008[a]t ½ =
6.5 days
≥ 2
HydrolysisAbioticHYDROWIN 2008[a]NA[b]NA
Biodegradation (aerobic)PrimaryBIOWIN 2008[a]
Sub-model 4: Expert Survey
(qualitative results)
2.8[c]
"does not biodegrade fast"
≤ 182
Biodegradation (aerobic)UltimateBIOWIN 2008[a]
Sub-model 3:
Expert Survey
(qualitative results)
1.7[c]
"biodegrade slowly"
≥ 182
Biodegradation (aerobic)UltimateBIOWIN 2008[a]
Sub-model 5:
MITI linear probability
0.31[d]
"31[d]
"does not biodegrade fast"
≤ 182
Biodegradation (aerobic)UltimateBIOWIN 2008[a]
Sub-model 6:
MITI non-linear probability
0.06[d]
"biodegrade very slowly"
≥ 182
Biodegradation (aerobic)UltimateTOPKAT 2004
Probability
0[d]
"biodegrade very slowly"
≥ 182
Biodegradation (aerobic)UltimateCATABOL 2004–2008: % BOD
(biological oxygen demand)
0.3
"biodegrade slowly"
≥ 182

a From EPI Suite (2008), using SMILES notation in Table 2.1 for sclareol
b Model does not provide an estimate for this type of chemical structure.
c Output is a numerical score from 0 to 5 related to a predicted biodegradation rate.
d Output is a probability score.

In air, a predicted atmospheric oxidation half-life value of 0.182 days (see Table 7-2) demonstrates that this substance is likely to be rapidly oxidized. The substance is not expected to react appreciably with other photo-oxidative species in the atmosphere, such as O3, nor is it likely to degrade via direct photolysis given the predicted ozone reaction half-life of 6.5 days (see Table 7-2, AOPWIN 2008). It is therefore expected that reactions with hydroxyl radicals will be the important fate process in the atmosphere for sclareol. With a half-life of 0.182 days via reactions with hydroxyl radicals as the rate-limiting factor overriding the half-life of 6.5 days via ozone reaction, sclareol is considered not to persist in air.

In water, the hydrolysis half-life was not calculable, as no chemicals of structural comparability are contained in the training set of HYDROWIN 2008. In addition, sclareol does not contain functional groups expected to undergo hydrolysis. However, other fate processes in water need to be considered to determine overall persistence in this medium. The empirical 28-day ready biodegradation test result is 1.5% (CHRIP c2008). Most of the biodegradation models suggest that biodegradation is very slow and that the half-life in water would be ≥ 182 days. The substance contains structural features associated with chemicals that are not easily biodegraded (e.g., C-C bonds). Therefore, considering the model results and the structural features of sclareol, there is sufficient evidence to indicate that the biodegradation mineralization half-life of sclareol is >182 days in water.

Using an extrapolation ratio of 1:1:4 for a water:soil:sediment biodegradation half-life (Boethling et al. 1995), the half-life in soil is also ≥ 182 days and the half-life in sediments is ≥  365 days. This indicates that sclareol is expected to persist in soil and sediment.

A number of studies have shown that soil micro-organisms are capable of metabolizing sclareol. Kouzi and McChesney (1990, 1991a, 1991b) showed that sclareol was metabolized by six Cunninghamella species (mold), three Aspergillus species (mold), one Chaetomium (mold), Mucor species (mold), Bacillus cereus (fungus), Septomyxa (mold) and Sporobolomyces species (fungus). A total of 400 to 600 mg sclareol was dissolved in ethanol, and after 3 to 8 days, the suspensions were filtered and analyzed. Metabolite yields ranged from 28% to 50%. Abraham (1994) showed that many strains of fungi (n=60) and bacteria (n=40) were capable of transforming sclareol, with fungi showing higher metabolic activities than bacteria. Bacillus sphaericus ATCC 13805 (fungus) converted 20 mg sclareol over a 72-h period to two metabolites with yields of 5% and 20%. Cunninghamella elegans DSM 1908 (mold) converted 200 mg of sclareol after 120 h to five metabolites with yields of 40.5%, 6%, 10%, 2.5%, and 18.5%. Diplodia gossypina ATCC 10936 (fungus) converted 10 mg sclareol after 96 h with 20% yields for four metabolites. Aranda et al. (1991) showed the microbial transformation of sclareol by the fungus Mucor plumbeus, where 92% to 99% sclareol (up to 0.5 g/L) was consumed within 2 to 4 days. Hanson et al. (1994) showed that the fungus Cephalosporium aphidicola microbially transformed sclareol after 12 days into 5 metabolites. Diez et al. (2005) showed the microbial oxidation of 100 mg of sclareol by Rhizopus stolonifer (mold) after 5 to 8 days at 30 °C under varying chemical conditions. The best chemical condition (2.5 g/L K2HPO4; 2.5 g/L NH4NO3; 0.25 g/L MgSO4; 10−4 M CaCl2·6H2O; 1.5x10−5 M FeSO4; 10−5 M MnCl2, and 100 mg of sclareol dissolved in ethanol) resulted in the transformation of 87% to 88% of the sclareol after 5 days and 98% of the sclareol after 8 days. Therefore, most of these studies (except for Diez et al. 2005) indicate that the presence of sclareol in soils may be mitigated by the metabolic activities of bacterial and fungal species. However, it should be noted that all of these studies were laboratory-based using media (e.g., liquid medium, agar) other than soil. The described degradation rates may therefore be slower under field conditions.

If sclareol or the essential oil containing sclareol is chemically extracted from these plants and incorporated into various products available to consumers, then down-the-drain releases are likely to occur via wastewater treatment systems into the aquatic environment. No information has been found to indicate that organisms capable of degrading sclareol, similar to those found in soil, are present in surface waters. In addition, under potential anaerobic conditions, such as in sediment, there may be a lack of sufficient aerobic bacteria to facilitate aerobic or anaerobic degradation.

The Transport and Persistence Level III Model (TaPL3) (TaPL3 2000) was used to estimate the characteristic travel distance (CTD), defined as the maximum distance traveled in air by 63% of the substance. Beyer et al. (2000) have proposed CTDs of >2000 km as representing high long-range atmospheric transport potential (LRATP), 700 to 2000 km as moderate LRATP, and <700 km as low LRATP. Given the CTD estimate of 91 km, the long-range atmospheric transport potential of sclareol is considered to be low. This means that sclareol is not expected to be transported a significant distance from its emission sources through the atmosphere.

The OECD Pov-LRTP Screening Model can also be used to help identify chemicals with high persistence and long-range transport potential (Scheringer et al. 2006). This is a global model that compartmentalizes the earth into air, water and soil. It is "transport-oriented" rather than "target-oriented," as it simply identifies the CTD without indicating specifically where a substance may be transported (Fenner et al. 2005). Klasmeier et al. (2006) have suggested that a threshold of 5098 km, based on the model's CTD estimate for PCB-180, can be used to identify substances with high long-range-transport potential. PCB-180 is empirically known to be found in remote regions. The CTD calculated for sclareol using the OECD model is 47 km, indicating that sclareol has a low potential for transport in air. The empirical and modelled data suggest that sclareol is highly persistent in water and sediment (half-life in water ≥ 182 days and half-life in sediment ≥ 365 days), but not in air (half-life in air ≤ 2 days) or soil (half-life ≤ 365).

7.2 Potential for bioaccumulation

Since no experimental bioaccumulation factor (BAF) or bioconcentration factor (BCF) data for sclareol were available, a predictive approach was applied using available BAF and BCF models as shown in Table 7-3 below.

As mentioned previously, the structural classes of sclareol (i.e., aliphatic carbons, olefinic carbons, alcohols) are amenable to model predictions as they are considered to be "in the model domain of applicability" (e.g., within structural and/or property parameter domains of the model database). Therefore, the applicability of QSAR models to sclareol is considered appropriate.

The modelled log Kow value from KOWWIN 2008 was used as it was deemed that this model has the best training set and likely coverage of chemicals similar in structure to sclareol. The modelled log Kow value of 6.0 for sclareol suggests that this chemical has high potential to bioaccumulate in biota (see Table 7-3).

Measures of BAF are the preferred metric for assessing bioaccumulation potential of substances. This is because BCF may not adequately account for the bioaccumulation potential of substances via diet, which predominates for substances with log Kow greater than ~4.0 (Arnot and Gobas 2003). Kinetic mass-balance modelling is, in principle, considered to provide the most reliable prediction method for determining the bioaccumulation potential because it allows for metabolism correction as long as the log Kow of the substance is within the log Kow domain of the model. BCF and BAF estimates, corrected for potential biotransformation, were generated using the BCFBAF model (EPI Suite 2008). Metabolic rate constants were derived using structure activity relationships described further in Arnot et al. (2008a, 2008b, and 2009). Since metabolic biotransformation rate constants are shown to be a function of body weight and temperature (Hu and Layton 2001; Nichols et al. 2006), the BCFBAFWIN model provides a "normalized" kM for a 10-g fish at 15 °C. For sclareol, this screening level kM-QSAR estimate is 0.062 /day. The middle trophic level fish was used to represent overall model output as suggested by the model developer and is generally representative of fish sizes likely to be consumed by most avian or terrestrial piscivores. If the kM for a 10-g fish is scaled to a representative middle trophic level fish (assumed mass ~184 g), the kMis about 0.03/day.

The available evidence indicates that sclareol is expected to bioaccumulate in fish because of its physical and chemical properties (i.e., low water solubility, high log Kow). Metabolism-corrected BCF and BAF values range from 4247 to 31 890. On the basis of the available kinetic-based modelled values corrected for metabolism, sclareol is considered to have a high potential to bioaccumulate in fish.

Table 7-3. Modelled bioaccumulation data for sclareol
Test organismEndpointWet weight (L/kg)Reference
FishBCF4247BCFBAF 2008
FishBCF4445BCFBAF 2008
FishBAF31 890BCFBAF 2008

8. Potential to cause ecological harm

8.1 Ecological effects assessment

8.1.1 Aquatic compartment

There are no available experimental data for aquatic toxicity for this substance; modelled data were therefore used. The structural classes of sclareol (i.e., aliphatic carbons, olefinic carbons, alcohols) are amenable to model predictions as they are considered to be "in the model domain of applicability" (e.g., within structural and/or property parameter domains of the model database). Therefore, the applicability of QSAR models to sclareol is considered appropriate.

A range of aquatic toxicity values were obtained from the various QSAR models. However, a few values were considered to provide unreliable toxicity estimates for this substance, as the predictions indicated that acute effects would be expected at concentrations significantly above its water solubility (i.e., modelled water solubility value is 0.05 mg/L). Given that modelled concentrations for water solubility are often uncertain (a single modelled value in this case), toxicity values that exceeded solubility estimates by up to a factor of 10 were considered to be acceptable. Therefore, the predicted values in Table 8-1 (as indicated) would be considered acceptable. Modelled data for sclareol indicate that this substance is expected to cause acute harm to aquatic organisms at low concentrations (acute median lethal concentrations [LC50s] are ≤ 1.0 mg/L).

Table 8-1. Modelled data for aquatic toxicity for sclareol
Test organismType of testEndpointValue(mg/L)Reference
FishAcute (96 hours)LC50[b]0.16[c]CPOPs 2008
FishAcuteLC50[b]0.04[c]AIEPS 2003–2007
Fish(96 hours)LC50[b]0.03[c][*]TOPKAT 2004
DaphniaAcute (48 hours)LC50[b]0.08[c]CPOPs 2008
DaphniaAcute (48 hours)LC50[b]0.4[c]AIEPS 2003–2007
DaphniaAcute (48 hours)EC5011.5TOPKAT 2004
AlgaeAcute (72 hours)EC50[a]7.94AIEPS 2003–2007

a EC50 - The concentration of a substance that is estimated to cause some effect on 50% of the test organisms.
b LC50 - The concentration of a substance that is estimated to be lethal to 50% of the test organisms.
c Acceptable - given that modelled concentrations for water solubility are often uncertain, toxicity values that exceeded solubility estimates by up to a factor of 10 were considered to be acceptable.
* Value selected for exposure modelling.

8.1.2 Other environmental compartments

Choudhary et al. (2006) reported that sclareol exhibits antibacterial activity, fungal growth regulating properties and plant growth inhibiting properties.

Bailey et al. (1974) assayed sclareol for fungal inhibition against Cladosporium cucumerinum on silica gel, on agar, and in liquid medium. The diterpene sclareol and 13-epi-sclareol were isolated as a eutectic mixture Footnote 4 from the leaves of the Nicotiana glutinosa plant. On the silica gel assay, Cladosporium cucumerinum growth inhibition occurred at > 0.10 mg sclareol. In addition, for the microscope slide assay, the authors found that sclareol up to 500 mg/L did not prevent the germination of spores of several species of fungi (Alternaria brassicicola, A. longipes, Aspergillus niger, Botrytis cinerea, Cladosporium cucumerinum and Colletotrichum lindemuthianum). However, when germinated spores of Alternaria sp. were incubated further, it was observed that the colonies produced on agar incorporating sclareol expanded slowly. The effect of sclareol on the growth of mycelium demonstrated that the radial growth rates of 16 species of fungi were significantly reduced at 20 mg/L sclareol. These results suggest that sclareol affects the growth regulatory systems of fungi.

Bailey et al. (1975) investigated the inhibition of fungal growth by an epimeric Footnote 5 mixture of the diterpenes, sclareol and 13-episclareol on Uromyces appendiculatus (French bean rust), Puccinia recondita f. sp. tritici (wheat leaf rust) and Uromyces viciae-fabae (broad bean rust). The germination of rust uredospores was assessed using the well slide test and a test with agar surfaces impregnated with concentrations of sclareol ranging from 5 to 1000 mg/L. Similar results were obtained with both tests. French bean rust was completely inhibited by 25 mg/L sclareol and its germ tubes were shortened at 5 mg/L. Broad bean rust produced small protuberances at the surface of the uredospores, and normal growth of the germ tube occurred only at levels below 25 mg/L sclareol. Wheat leaf rust had normal growth of the germ tube only if the concentration of sclareol was below 25 mg/L.

Kennedy et al. (1992) used a bioassay to evaluate the effect of sclareol, isolated from the cuticular leaf component of a variety of Nicotiana tobacco species (e.g., Nicotiana tabacum, Nicotiana glutinosa), on the germination of Peronospora tabacina (blue mold). Sclareol in acetone was then applied to leaf disks of Nicotiana tabacum, which were subsequently inoculated with blue mold sporangia. The IC50 for blue mold sporangia inhibition by sclareol was 0.0047 mg/cm2.

Ulubelen et al. (1994) obtained sclareol from an acetone extract of the whole plant Salvia sclarea and tested it for antimicrobial activity against standard bacterial strains (Staphylococcus aureus and Proteus mirabilis) and the yeast Candida albicans. Sclareol was found to be active against Staphylococcus aureus at 48.25 mg/L and the yeast (no concentration given) but was not active against Proteus mirabilis.

Table 8-2. Empirical microbial and fungal toxicity data for sclareol
Test organismType of testEndpointValue (mg/L unless otherwise indicated)Reference
Bacterium (Staphylococcus aureus)Acute (24 hours)Growth inhibition48.25Ulubelen et al. 1994
Fungus (Cladosporium cucumerinum)UnknownGrowth inhibition0.1 mg/cmBailey et al. 1974
Fungus (16 species)Chronic (10 days)Mycelium growth20Bailey et al. 1974
Fungal spores of Alternaria brassicicola, A. longipes, Aspergillus niger, Botrytis cinerea, Cladosporium cucumerinum, Colletotrichum lindemuthianum)Chronic (10 days)Spore germination>500Bailey et al. 1974
Fungus (Uromyces appendiculatus)UnknownSpore germination and growth5
(shortened germ tubes)
Bailey et al. 1975
Fungus (Uromyces appendiculatus)UnknownSpore germination and growth25
(complete inhibition)
Bailey et al. 1975
Fungus (Uromyces viciae-fabae)UnknownSpore germination and growth> 25Bailey et al. 1975
Fungus (Puccinia recondita f. sp. tritici)UnknownSpore germination and growth> 25Bailey et al. 1975
Blue mold (Peronospora tabacina)Acute (24 hours at 15°C)IC50[a]
(inhibition of sporangia germination)
0.0047 mg/cm2Kennedy et al. 1992

a IC50 – The inhibiting concentration for a specified percent effect. A point estimate of the concentration of a test substance that causes 50% reduction in a quantitative biological measurement such as growth rate.

8.2 Characterization of ecological risk

Sclareol is naturally widespread in the environment as a component in the essential oil of several plants. Sclareol is likely degraded by soil bacteria or other fungal species in their natural terrestrial habitat.

If sclareol or the essential oil containing sclareol is chemically extracted from these plants and then released to the environment through wastewater treatment system releases resulting from industrial and/or consumer uses (estimated total quantity of 76 to 1350 kg/year), sclareol will be found mainly in water and sediment where it is expected to be highly persistent. On the basis of modelled data, sclareol is also expected to have a high bioaccumulation potential in fish and is estimated to be highly hazardous to certain aquatic organisms.

When sclareol is released into a water body, it partitions to suspended particulate matter and to bottom sediments, where sediment-dwelling organisms would be exposed to the substance. However, no environmental monitoring data or toxicity data specific to sediment-dwelling organisms are available for this substance.

Substances that are persistent remain in the environment for a long time after being released, increasing the potential magnitude and duration of exposure. Substances that have long half-lives in mobile media (air and water) and partition into these media in significant proportions have the potential to cause widespread contamination. Releases of small amounts of bioaccumulative substances may lead to high internal concentrations in exposed organisms. Highly bioaccumulative and persistent substances are of special concern, since they may biomagnify in food webs, resulting in very high internal exposures, especially for top predators.

However, given the relatively small amounts known to be in commerce in Canada and its uses which are expected to lead to disperse releases to the environment, ecological exposure to sclareol is expected to be low. It is therefore concluded that sclareol is not currently causing ecological harm in Canada. On the basis of the information available, it is concluded that sclareol is not entering the aquatic environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute a danger to the environment on which life depends.

Although current use patterns and quantities in commerce are not of concern at current levels, there may be concerns if quantities were to increase in Canada, given the ecological effects associated with sclareol.

8.3 Uncertainties in evaluation of ecological risk

Given the use of this substance in other countries, it is possible that sclareol is entering the Canadian market as a component of manufactured items and/or products available to consumers (Pitarokili et al. 2002; Lattoo et al.; Choudhary et al. 2006; Dimas et al. 2007; Bailey et al. 1975; McChesney and Kouzi 1990). Information obtained from various information sources indicates that sclareol may be available in a limited number of these types of products in Canada. However, as no information is available on the quantity of sclareol in such imports, it is not possible to derive a quantitative estimate that would help determine the importance of this source.

9. Potential to cause harm to human health

9.1 Exposure assessment

9.1.1 Environmental media and food

Empirical data on concentrations of sclareol in environmental media in Canada were not identified. Sclareol was not reported above the reporting threshold by any single company in response to a CEPA section 71 survey notice for the years 2005 and 2006. However, it is estimated to be used in overall quantities between 76 and 1350 kg. The low use quantities of sclareol indicate that the release into the Canadian environment from industrial and consumer use would be low and exposure of the general population from environmental media is expected to be negligible.

Sclareol is a component of the essential oil in Salvia sclarea (clary sage) that may be used as a flavour ingredient in food. It may also be present in common sage, Salvia officinalis, which is used as a culinary herb. Several studies that analyzed the composition of common sage were identified in the literature (Santos-Gomes et al. 2001; Perry et al. 1999, 1996; Tucker et al. 1990). Only one study detected sclareol at levels up to 5% (Boszormenyi et al. 2009). JECFA (2010b) recently concluded on the basis of current estimated dietary exposure that sclareol does not pose a safety concern (JECFA 2004). The European Food Safety Authority also concluded that sclareol does not give rise to safety concerns at the level of dietary intake estimated by JECFA.

9.1.2 Products available to consumers

9.1.2.1 Cosmetics

Sclareol may be present in several species of sage, but it is predominantly found in Salvia sclarea or clary sage (Kuzma et al 2009; Bhatia et al 2008; Dzamic et al. 2008; Farkas et al. 2005; Fraternale et al. 2005; Pitarokili et al. 2002; Ronyai et al. 1999; Esteban et al. 1996; Lawrence 1994, 1986). In Canada, approximately 800 cosmetic products containing the essential oil of clary sage were identified in the Cosmetic Notification System (CNS 2010). According to the information in the CNS database, the concentration of the essential oil in cosmetics ranges from 0.1% to 30%.

The available literature indicates a wide range of sclareol concentrations in clary sage essential oil (from 0.06% [Dzamic et al. 2008] to 6% [Pitarokili et al. 2002]). However, most studies report concentrations of sclareol in essential oil well below 5% (personal communication from the Consumer Product Safety Directorate, Health Canada, to the Risk Management Bureau, Health Canada, dated August 2010; unreferenced). The assumption of 5% of sclareol in essential oil, which can be translated into a range of 0.005% to 1.5% sclareol in products, was used in estimating exposure of the general population from use of cosmetics in Canada. This assumption is considered conservative as information from a cosmetic manufacturer indicates that sclareol is present in cosmetic products at a much lower concentration. Bhatia et al. have estimated the sclareol concentration in cosmetic products to be 0.03% (2008).

Estimates of exposure of the general population of Canada to sclareol from use of cosmetics were derived using ConsExpo 4.1 (ConsExpo 2006).

The upper-bounding estimates of daily exposure from use of cosmetics containing sclareol are presented in Table 9-1, while the details of the exposure scenarios are summarized in Appendix A.

Sclareol has a low vapour pressure, and inhalation exposure is not considered likely except through the use of pump spray. The predominant route of exposure during the use of these products is considered to be dermal. For rinse-off products such as hair shampoo and conditioner, retention factors were applied as appropriate (refer to Appendix A for details). For products in Table 9-1, the predominant contribution to the aggregate exposure was from fragrance (6.06 × 10−4 to 0.404 mg/kg-bw [kilograms of body weight] per day).

Table 9 -1. Estimates of daily dermal exposure from frequently used cosmetics – adults [a]
ProductEssential oil concentration range (%)[b]Sclareol concentration range (%)[c]Frequency/yrEstimated daily dermal exposure (mg/kg-bw per day)
Fragrance[d]0.1–300.005–1.5730–10956.06×10−4–0.404
Skin moisturizer (face, hand and/or body)0.1–30.005–0.157301.69×10−3–0.389
Hair shampoo0.1–300.005–0.152601.02×10−3–0.301
Hair conditioner0.1–300.005–1.52606.95×10−4–0.209
Facial toner[e]0.1–300.005–0.15365–7308.46×10−4–0.106
Hair grooming[f]0.1–30.005–0.15274–4381.12×10−3–0.0611
Eye lotion0.1–100.005–0.53653.52×10−4–0.0352
Skin cleanser (face, hand and/or body: bar, liquid)0.1–300.005–1.5329–7308.38×10−6–0.0166
Deodorant (stick)0.1–10.005–0.054731.10×10−3–0.0110
Foot deodorant spray0.3–10.015–0.057300.0584–0.195
Foundation – female only0.1–0.30.005–0.0153655.64×10−4–0.0017
Leave-in hair protectant0.1–0.30.005–0.0152606.22×10−4–0.0019
Make up removal pads – female only<0.10.0057300.0004
Eye mascara – female only0.3–10.015–0.053655.29×10−5–0.0002
Shaving gel – male only0.1–10.005–0.053651.41×10−5–0.00014
TOTALN/AN/AN/A0.0058–1.73[g]

Abbreviations: N/A, not applicable.
a Modelled using ConsExpo 4.1 (RIVM 2006) with default assumptions unless otherwise noted in Appendix A.
b Concentrations of the essential oil from clary sage as reported on the Cosmetics Notification System (CNS 2010).
c This represents the concentration of sclareol in the cosmetic product, assuming the concentration of sclareol in the essential oil is 5%.
d Includes perfume (use frequency assumed to be 730 times per year) and eau de toilette (use frequency assumed to be 1095 times per year).
e Includes after shave lotion (use frequency assumed to be 365 times per year) and facial toner (use frequency assumed to be 730 times per year).
f Includes mousse (use frequency assumed to be 274 times per year), gel (use frequency assumed to be 358 times per year), hair spray (use frequency assumed to be 438 times per year). The exposure estimates for the hair detangler were added (use frequency assumed to be 438 times per year).
g This number does not represent a gender specific estimate. Taking this into account, the range of exposure estimate for female would be 0.0588 to 1.73 mg/kg-bw per day, and for male would be 0.0584 to 1.73 mg/kg-bw per day.

Estimates of exposure to sclareol from cosmetics used less frequently are summarized in Table 9-2. Since these products are used only occasionally, exposure to sclareol from use of these products is considered to be acute in duration. The highest exposure estimate is from use of massage oil, which ranged from 0.00564 to 1.69 mg/kg-bw per use.

Table 9-2. Estimates of acute dermal exposure from use of cosmetics – adult [a]
ProductEssential oil concentration range (%)[b]Sclareol concentration range (%)[c]Frequency/yrEstimated acute dermal exposure (mg/kg-bw)[d]
Massage oil0.1–300.005–1.5240.00564–1.69
Face mask0.1–100.005–0.51040.00141–0.141
Hair bleach<0.10.005100.141
Hair dye0.3–10.015–0.05100.0212–0.0705
Tanning preparation<0.10.005750.00705
Bath preparation (oil, foam salts)0.1–300.005–1.51049.17×10−6–2.75×10−4

a Modelled using ConsExpo 4.1 (RIVM 2006) with default assumptions unless otherwise noted in Appendix A.
b Concentrations of the essential oil from clary sage as reported on the Cosmetics Notification System (CNS 2010).
c Assuming the concentration of sclareol in the essential oil is 5%.
d Acute dermal exposure is reported per application.

Estimates of exposure to sclareol from use of cosmetics intended for infants and toddlers are presented in Table 9-3. The upper-bounding estimates of daily exposure ranged from 0.015 to 0.057 mg/kg-bw per day, while for a less frequently used product, i.e., massage oil, the upper-bounding estimate of acute exposure ranged from 0.023 to 0.099 mg/kg-bw.

Table 9-3. Estimates of chronic and acute dermal exposure from use of cosmetics – infants and toddlers[a], [b]
ProductAge groupEssential oil concentration range (%)[c]Frequency /yrDaily dermal exposure (mg/kg-bw per day)Estimated acute dermal exposure (mg/kg-bw)[d]
Baby massage oil0–6 month0.3–124N/A0.0296–0.0987
Baby massage oil0.5–4 years0.3-124N/A0.0232–0.0774
Baby shampoo0–6 month0.3–12600.0162–0.0539N/A
Baby shampoo0.5–4 years0.3-13650.0145–0.0483N/A
Baby body wash0–6 month0.3–13298.11×10−4–2.7×10−3N/A
Baby body wash0.5–4 years0.3–13296.38×10−4–2.13×10−3N/A
Kids hair detangler0–6 monthN/AN/AN/AN/A
Kids hair detangler0.5–4 years0.1–0.34380.0003–0.0009N/A
TOTAL0–6 month--0.017–0.057N/A
TOTAL0.5–4 years--0.015–0.051N/A

Abbreviations: N/A, not applicable, '-' no data available
a Infants are between 0 and 6 months of age and toddlers are between 0.5 and 4 years of age.
b Modelled using ConsExpo 4.1 (RIVM 2006) with default assumptions unless otherwise noted in Appendix A.
c Concentrations of the essential oil from clary sage as reported on the Cosmetics Notification System (CNS 2010). The concentration of sclareol in the oil was assumed to be 5%.
d Acute dermal exposure is reported per application.

Given the nature of the physical and chemical properties (log Kow, molecular weight, Kp) of sclareol, absorption through the skin is expected to be limited. Using an approach developed by Kroes et al. 2007, a default dermal absorption value of 10% was derived.

Lipstick products can contain the essential oil of clary sage at concentrations of 0.1% to 1% wet weight (w/w). Sclareol concentrations in lipstick were therefore estimated to be 0.005% to 0.05%, and daily oral exposure from use of lipstick was estimated to range from 2.82×10−5 to 2.82×10−4mg/kg-bw per day (details of the calculation are presented in Appendix A).

Given their use pattern, some cosmetics containing sclareol are considered to result in potential inhalation exposure. Estimates of mean concentration per event from use of products applied as a spray were derived (see Appendix A) and found to be low.

9.1.2.2 Other products

A limited number of natural health products were noted to contain clary sage essential oil as a non-medicinal ingredient. The cosmetic exposure scenarios assessed in the previous section are expected to be representative of exposures from natural health products, considering the conditions of use outlined in the NNHPD Aromatherapy – Essential Oils monograph.

A room mister containing clary sage essential oil as a fragrance ingredient has been identified (CNS 2010). The clary sage essential oil concentration in this product was reported to be 0.3% to 1%; hence the corresponding concentration of sclareol in the product is estimated to be 0.015–0.05%. Based on its use pattern, exposure from use of this product is expected to be mainly via inhalation and the mean event concentration was estimated to range from 2.1×10−4 mg/m−3 to 6.99×10−4 mg/m−3 (see Appendix B).

9.2 Health effects assessment

Appendix C summarizes the health effects information for sclareol and its analogue, sclareol glycol.

The acute toxicity of sclareol appears to be low, given that the lowest oral and dermal LD50 values identified were both greater than 5000 mg/kg-bw in rats and rabbits, respectively (RIFM 1979a, 1979b). Following administration of 100 mg/kg-bw, 316 mg/kg-bw or 1000 mg/kg-bw sclareol via a single intraperitoneal (i.p.) injection to male Sprague-Dawley rats, transient decreases in spontaneous motor activity, a decrease in respiratory rate and a compensatory increase in respiratory depth were observed (Malone et al. 1991).

Undiluted sclareol induced dermal irritation in rabbits at 5000 mg/kg-bw (RIFM 1979a, 1979b), but diluted sclareol did not induce dermal irritation in patch tests or semi-occlusive tests in either human volunteers or rabbits (RIFM 1975a, 1975b; RIFM 1979c; RIFM 1981; RIFM 1986). Sensitization was observed in only one of the human volunteer studies, in which the boiling point of sclareol was 84 to 90 °C, indicating that the purity of the test material was low (RIFM 1979c). Sclareol with a boiling point greater than 96 °C in the other identified sensitization tests in human volunteers did not induce sensitization (RIFM 1981, 1986). The International Fragrance Association (IFRA 2009) identified sensitization as the critical effect of sclareol and set the standard that sclareol used as a fragrance ingredient should have a minimum purity of 98%, on the basis of the results of sensitization tests in human volunteers showing a sensitizing potential for samples with low purity (i.e., low boiling point) and no sensitizing effects for samples with a minimum purity of 98%.

In terms of repeated-dose toxicity, a no-observed-adverse-effect level (NOAEL) of 8.8 mg/kg-bw per day was identified. This was based on the observation of an increase in mean kidney weight relative to brain weight in male rats and an increase in mean heart and spleen weights relative to brain weight in female rats, when animals were administered sclareol 7 days per week via oral intubation for 30 days at a single dose of 8.8 mg/kg-bw per day. Minimally but statistically increased protein, globulin and calcium concentrations were considered to be possible corroborative clinical chemistry findings with increase in the kidney-to-brain weight ratio for male rats treated with sclareol. These effects maybe treatment related, but were considered non-adverse with limited toxicological significance (RIFM 2006a). RIFM (2006a) identified 8.8 mg/kg-bw per day as a NOAEL because the findings were not consistent between the sexes, and any additional clinical pathological or histopathologic changes such as gross or microscopic alterations or increase in serum liver enzymes in male and female rats were absent.

Very limited genotoxicity data were available for sclareol. Sclareol induced DNA damage in human HCT116 colon cancer cells in vitro. Sclareol suppressed HCT116 tumour growth in immunodeficient male SCID mice that were injected subcutaneously with the maximum tolerated dose (MTD) of 275 mg/kg-bw, which was determined through administration of sclareol encapsulated into the lipid bilayer of liposomes for 5 days (Dimas et al. 2007). In a previous study, sclareol was also reported to induce DNA fragmentation and apoptosis in human leukemic cell lines (Dimas et al. 1999). However, in vitro genotoxicity assays were both negative in a Salmonella/Microsome reversion assay and in a Bacillus subtilis rec-assay on essential oils from clary sage (Salvia sclarea) oil, of which sclareol is a component (Zani et al. 1969; Leung 1980; Lawrence 1986).

After administration to male Wistar rats intravenously at doses of 100 mg/kg-bw and orally via gavage at 1000 mg/kg-bw, 0.02% and 9% of the administered dose was excreted unchanged in bile and feces after intravenous and oral exposure, respectively (Kouzi et al. 1993). Kouzi et al. (1993) also identified four biliary metabolites of sclareol in rats–i.e., 3-keto-sclareol, 3a-hydroxysclareol, 3b-hyroxysclareol and 18-hydroxysclareol–but there is no relevant empirical toxicity data for any of these metabolites.

Since limited health effects information was available for sclareol, information on an analogue substance was also considered. Sclareol glycol (CAS RN 55881-96-4) was found to have structural similarity with sclareol (using the Tanimoto association coefficient in ChemID, the similarity was quantified to be 87.33%).

Sclareol glycol stimulated the locomotor activity of male albino mice exposed to the test substance via a single dose of i.p. injection at 5, 25 or 50 mg/kg-bw, but at 100 mg/kg-bw, it decreased locomotor activity by 30% compared to the controls (Georgieva 1988). It was also reported that sclareol glycol significantly inhibited clonidine-induced aggressive behaviour in male albino mice (Georgieva 1989a). Sclareol glycol administered via i.p. injection stimulated the central nervous system and had dose-dependent effects on convulsive seizures (Georgieva 1987, 1989b). After administration at low dose (5 mg/kg-bw) via i.p. injection, sclareol induced clonic convulsions and myoclonic twitches of the head and forelimbs in 6 of 10 male albino mice (Georgieva 1989b). The route of administration of these studies was of limited relevance to human health risk assessment.

The outputs of predictive (Q)SAR models were considered using four different models, DEREK, TOPKAT, CASETOX and Leadscope Model Applier. The predictions for carcinogenicity, genotoxicity, developmental toxicity, and reproductive toxicity for sclareol were predominantly negative (DEREK 2008; TOPKAT 2004; CASETOX 2008; Leadscope c2005–2008). A summary of the model outputs is shown in Appendix D.

Overall, sclareol was not identified as having high hazard potential.

The confidence in the health effects database for sclareol is low. Only acute, short-term repeated toxicity, irritation and sensitization empirical data were available. No subchronic, chronic/carcinogenicity, in vivo genotoxicity, reproductive or developmental toxicity data were available. Only very limited health effects information was available for an analogue, and (Q)SAR outputs were predominantly negative.

9.3 Characterization of risk to human health

On the basis of the available information on use of sclareol, exposure of the general population from environmental media in Canada is expected to be negligible. Dietary exposure of the general population to sclareol is expected to be low and to result mainly from its naturally occurring presence in food.

Dermal exposure to sclareol from the use of cosmetics is considered to be the predominant route of exposure for the general population. Estimates of systemic exposure were derived using the dermal absorption value of 10%. Systemic daily exposure for adults ranges from 0.0058 to 0.173 mg/kg-bw per day. The systemic daily exposure for infants and toddlers ranges from 0.0015 to 0.0057 mg/kg-bw per day.

Comparing the estimates of exposure to sclareol from adult use of cosmetics (0.0058 to 0.173 mg/kg-bw per day) to a level at which no adverse effects were observed in experimental animals (8.8 mg/kg-bw per day) results in margins of exposure ranging from 50 to 1500. Considering that the exposure estimates are based on a series of conservative assumptions (i.e., 10% dermal absorption, 5% sclareol in essential oil coupled with a maximum of 30% essential oil in product, assumption that all types of products would be used on the same day, all containing sclareol at the maximum concentration), actual margins are expected to be much higher than those calculated. Margins would be higher when considering the estimate generated by the Research Institute for Fragrance Materials of 0.0008 mg/kg-bw per day for total human skin exposure from use of multiple cosmetic products containing sclareol (Bhatia et al. 2008). These margins of exposure are considered adequate to address uncertainties in the health effects and exposure databases.

Comparison of the estimates of systemic exposure from use of cosmetics intended for children (0.0015 to 0.0057 mg/kg-bw per day) to a level at which no adverse effects were observed in experimental animals (8.8 mg/kg-bw per day) results in margins of exposure ranging from 1500 to 5900. These margins are considered adequate to address uncertainties in the health effects and exposure databases.

Comparison of the upper-bounding estimates of acute dermal exposure from less frequent use of cosmetics for adults (0.00564 to 1.69 mg/kg-bw per use) and children (0.023 to 0.099 mg/kg-bw from use of massage oil) to the lowest acute dermal effect level (5000 mg/kg-bw per day based on dermal irritation) results in margins of exposure ranging from 2.96×103 to 8.87×105for adults and 5.05×104 to 2.17×105 for children. These margins were considered adequate to address uncertainties in the health effects and exposure databases.

Comparison of the upper-bounding estimates of oral exposure from lipstick products (2.82×10−5 to 2.82×10−4 mg/kg-bw per day) to a level at which no adverse effects were observed in experimental animals (8.8 mg/kg-bw per day) results in margins of exposure ranging from 9.94×103 to 5.2×107. These margins were considered adequate to address uncertainties in the health effects and exposure databases.

9.4 Uncertainties in evaluation of risk to human health

Confidence in the modelled estimates of exposure from products is low to moderate, as direct information on concentrations of sclareol in cosmetic products was not available. There is uncertainty associated with the assumption that sclareol is present in cosmetics mostly from clary sage essential oil. However, on the basis of information in the literature regarding typical use in the cosmetic industry, it is considered to be a reasonable assumption. Also, information regarding the presence of sclareol in food in Canada was not available. The default parameter values in ConsExpo (ConsExpo 2006) were based on upper-bounding scenarios that consider a general population that frequently uses products available to consumers. It is recognized that there is uncertainty with the use of default model parameters that are not Canadian-specific. Uncertainty is also recognized in the use of the approach described by Kroes et al. (2007) to characterize dermal absorption of sclareol once applied as a component in a cosmetic product. As conservative assumptions were used, it is considered likely that derived estimates of general population exposures are considered overestimates (e.g., given the large number of cosmetics on the market, the assumption that an individual would use products that all contained sclareol on the same day is highly conservative).

Because of the very limited empirical health effects database on sclareol and its analogue, and the use of qualitative structure-activity relationship models, confidence in the health effects database is low.

10. Conclusion

Considering all available lines of evidence presented in this screening assessment, there is low risk of harm to organisms and the broader integrity of the environment from sclareol. It is concluded that sclareol does not meet the criteria under paragraphs 64(a) or 64(b) of CEPA as it is not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends.

On the basis of the information available, it is concluded that sclareol does not meet the criteria in paragraph 64(c) of CEPA as it is not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

It is concluded that sclareol does not meet any of the criteria set out in section 64 of CEPA.

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Footnotes

Appendices

Appendix A – Upper bounding estimates of exposure to Sclareol in Cosmetics using ConsExpo 4.1 (ConsExpo 2006)

The following notes pertain to the data of the Appendices A-1 to A-6:

  1. The following assumptions were applied to all scenarios:
    • body weight of 70.9 kg for an adult
    • uptake fraction of 1 was used to account for external applied dose
    • exposure type of "direct dermal contact" for instant application (ConsExpo 2006)
    • concentrations of the essential oil as reported on the Cosmetics Notification System (CNS 2010)
    • concentration of sclareol in essential oil of 5%.
  2. Essential oil concentration range, Exposure frequency, Exposed area and Product amount applied are all default ConsExpo assumptions (RIVM 2006).
  3. The Exposed Area data is referenced from Health Canada 1995.
  4. External applied dose: Chronic external applied dose calculated through amortization over a year to estimate daily exposure dose.
  5. Retention factor was applied for rinse-off products (Cosmetics Exposure Workbook, New Substances Assessment and Control Bureau, Health Canada, 2006; unreferenced).
  6. Deposition factor of 10% was applied for those products used in the hair, but not directly on the scalp (ConsExpo 2006).
  7. The amounts of product applied for: Skin moisturizer, hair conditioner, skin cleanser for face, facial wash and leave-in hair protectant were calculated by multiplying the product amounts as stated in RIVM (2006) by the ratio of the surface area of the affected body surface as reported in Health Canada (1995) with that of RIVM (2006).

Appendix A-1. Chronic exposure estimates of adult exposure via the dermal route

  1. Fragrance- Perfume
    • Scenario: Fragrance
    • Assumptions:
      • Essential oil concentration (%): 0.1–30
      • Exposure frequency (times/year): 730–1095
      • Exposed area (cm2): 100 (Health Canada 1995)
      • Product amount applied (g): 100 (note: This scenario includes perfume (use frequency assumed to be 730 times per year and the amount of product applied is 0.43 g) and eau de toilette (use frequency assumed to be 1095 times per year and the amount of product applied is 0.64 g).
      • External applied dose (g): 0.43–0.64
    • External applied doseb (mg/kg-bw per day): 6.06 × 10−4–0.404
  2. Skin moisturizer face, hand and/or body cream
    • Scenario: skin moisturizer
    • Assumptions:
      • Essential oil concentration (%):0.1–3
      • Exposure frequency (times/year):730
      • Exposed area (cm2): (Health Canada 1995): 637–1.76E4
      • Product amount applied (g):1.2–9.2
    • External applied dose: 1.69 × 10−3–0.389
  3. Hair shampoo
    • Scenario: hair shampoo
    • Assumptions
      • Essential oil concentration (%): 0.1–30
      • Exposure frequency (times/year):260
      • Exposed area (cm2): 1.55E3 (Health Canada 1995)
      • Retention factor of 10% was applied
      • Product amount applied (g): 60
    • External applied dose: 1.02 × 10−3–0.301
  4. Hair conditioner
    • Scenario: hair conditioner
    • Assumptions
      • Essential oil concentration (%): 0.1–30
      • Exposure frequency (times/year): 260
      • Exposed area (cm2): 1.55E3 (Health Canada 1995)
      • Deposition factor of 10% was applied
      • Product amount applied (g): 54
    • External applied dose: 6.95 × 10−4–0.209
  5. Shaving preparation
    • Scenario: after shave lotion
    • Assumptions
      • Essential oil concentration (%): <0.1–0.1
      • Exposure frequency (times/year): 365
      • Exposed area (cm2): 319 (Health Canada 1995)
      • Product amount applied (g): 1.2
    • External applied dose: 8.46 × 10−4
  6. Facial toner
    • Scenario: cleansing lotion
    • Assumptions
      • Essential oil concentration (%): 0.1–3
      • Exposure frequency (times/year): 730
      • Exposed area (cm2): 637 (Health Canada 1995): 637
      • Product amount applied (g): 2.5
    • External applied dose: 3.52 × 10−3–0.106
  7. Hair spray
    • Scenario: hair spray
    • Assumptions
      • Essential oil concentration (%): 0.1–0.3
      • Exposure frequency (times/year): 438
      • Exposed area (cm2): (Health Canada 1995): 637
      • Retention factor of 20% was applied
      • Product amount applied (g): 0.6
    • External applied dose: 1.01 × 10−4–3.04 × 10−4
  8. Hair grooming
    • Scenario: hair gel
    • Assumptions
      • Essential oil concentration (%): 0.1–0.3
      • Exposure frequency (times/year): 274
      • Exposed area (cm2): 637 (Health Canada 1995)
      • Product amount applied (g): 0.3
    • External applied dose: 1.59 × 10−4–4.76 × 10−4
  9. Hair detangler
    • Scenario: hair spray with trigger bottle
    • Assumptions
      • Essential oil concentration (%): <0.1
      • Exposure frequency (times/year): 438
      • Exposed area (cm2): 637 (Health Canada 1995)
      • Product amount applied (g): 0.6
    • External applied dose: 1.04 × 10−3
  10. Hair grooming
    • Scenario: hair gel
    • Assumptions
      • Essential oil concentration (%): 0.1–3
      • Exposure frequency (times/year): 358
      • Exposed area (cm2): 637 (Health Canada 1995)
      • Product amount applied (g): 0.3
    • External applied dose: 2.07 × 10−4–0.061
  11. Eye lotion
    • Scenario: eye make-up remover
    • Assumptions
      • Essential oil concentration (%): 0.1–10
      • Exposure frequency (times/year): 365
      • Exposed area (cm2): (Health Canada 1995): 50
      • Product amount applied (g): 0.5
    • External applied dose: 3.52 × 10−4–0.0352
  12. Skin cleanser for face, hand and/or body (bar, liquid)
    • Scenario: skin cleanser
    • Assumptions
      • Essential oil concentration (%): 0.1–30
      • Exposure frequency (times/year): 329–730
      • Exposed area (cm2): 637-1.76E4cm2 (Health Canada 1995)
      • Retention factor of 1% as applied
      • Product amount applied (g): 1.78–26.2
    • External applied dose: 8.38 × 10−6–0.0166
  13. Deodorant stick
    • Scenario: Deodorant
    • Assumptions
      • Essential oil concentration (%): 0.1–1
      • Exposure frequency (times/year): 473
      • Exposed area (cm2): 240 (estimate) (Health Canada 1995)
      • Product amount applied (g): 1.2
    • External applied dose: 1.10 × 10−3 – 1.1 × 10−2
  14. Foot deodorant spray
    • Scenario: trigger spray
    • Assumptions
      • Essential oil concentration (%): 0.3–1
      • Exposure frequency (times/year): 730
      • Exposed area (cm2): 1280 (Health Canada 1995)
      • Product amount applied (g): 13.8
    • External applied dose: 0.0584–0.195
  15. Facial wash
    • Scenario: makeup removal pads
    • Assumptions
      • Essential oil concentration (%): < 0.1
      • Exposure frequency (times/year): 730
      • Exposed area (cm2): 637 (Health Canada 1995)
      • Retention factor of 10% was applied
      • Product amount applied (g): 2.5
    • External applied dose: 5.64 × 10−4–1.69 × 10−3
  16. Leave-in hair protectant
    • Scenario: hair conditioner (no retention factor)
    • Assumptions
      • Essential oil concentration (%): 0.1–0.3
      • Exposure frequency (times/year): 260
      • Exposed area (cm2): 1.44E3 cm2 (Health Canada 1995)
      • Deposition factor of 10% was applied
      • Product amount applied (g): 12.4
    • External applied dose: 6.22 × 10−4–1.9 × 10−3
  17. Face makeup – foundation
    • Scenario: facial makeup
    • Assumptions
      • Essential oil concentration (%): 0.1–3
      • Exposure frequency (times/year): 365
      • Exposed area (cm2): 637 (Health Canada 1995)
      • Product amount applied (g): 0.8
    • External applied dose: 3.52 × 10−4
  18. Eye mascara
    • Scenario: eye makeup
    • Assumptions
      • Essential oil concentration (%): 0.3–1
      • Exposure frequency (times/year): 365
      • Exposed area (cm2): 1.6 (Health Canada 1995)
      • Product amount applied (g): 0.025
    • External applied dose: 5.29 × 10−5 – 1.76 × 10−4
  19. Shaving preparation gel
    • Scenario: shaving cream
    • Assumptions
      • Essential oil concentration (%): 0.1–1
      • Exposure frequency (times/year): 365
      • Exposed area (cm2): 318 (Health Canada 1995)
      • Product amount applied (g): 2
    • External applied dose: 1.41 × 10−5 – 1.41 × 10−4

Appendix A-2. Acute exposure estimates of Adults via the dermal route

  1. Massage oil
    • Scenario: massage oil
    • Assumptions
      • Essential oil concentration (%): 0.1–30
      • Exposure frequency (times/year): 24
      • Exposed area (cm2): 1.68E4 (Health Canada 1995)
      • Product amount applied (g): 8
    • External applied dose (mg/kg-bw): 5.64 × 10−3–1.69
  2. Hair bleach
    • Scenario: hair bleach
    • Assumptions
      • Essential oil concentration (%): < 0.1
      • Exposure frequency (times/year): 10
      • Exposed area (cm2): 637 (Health Canada 1995)
      • Product amount applied (g): 200
    • External applied dose (mg/kg-bw): 0.141
  3. Purifying mask
    • Scenario: face mask
    • Assumptions
      • Essential oil concentration (%): 0.3–1
      • Exposure frequency (times/year): 104
      • Exposed area (cm2): 637 (Health Canada 1995)
      • Retention factor of 10% was applied
      • Product amount applied (g): 20
    • External applied dose (mg/kg-bw): 1.41 × 10−3– 0.141
  4. Hair dye
    • Scenario: hair dye
    • Assumptions
      • Essential oil concentration (%): 0.3–1
      • Exposure frequency (times/year): 10
      • Exposed area (cm2): 637 (Health Canada 1995)
      • Retention factor of 10% was applied
      • Product amount applied (g): 100
    • External applied dose (mg/kg-bw): 2.12 × 10−2– 0.0705
  5. Tanning preparation
    • Scenario: sunscreen lotion
    • Assumptions
      • Essential oil concentration (%): < 0.1–0.1
      • Exposure frequency (times/year): 75
      • Exposed area (cm2): 1.69E4 (Health Canada 1995)
      • Product amount applied (g): 10
    • External applied dose (mg/kg-bw): 7.05 × 10−3
  6. Bath products (oil, foam, salts)
    • Scenario: bath preparation
    • Assumptions
      • Essential oil concentration (%): 0.1–30
      • Exposure frequency (times/year): 104
      • Exposed area (cm2): 1.63E4 (Health Canada 1995)
      • Retention factor of 0.1% was applied
      • Product amount applied (g): 1.69E4
    • External applied dose (mg/kg-bw): 9.17 × 10−6–2.75 × 10−4

Appendix A-3. Estimates of adult exposure via the oral route

  1. Lipstick
    • Assumptions:
      • Essential oil concentration range (%) = 0.1–1
      • Exposure frequency (times/year): 1.46×103
      • Exposure type: Direct intake (ConsExpo 2006)
      • Amount product ingested (g): 0.01
      • Body weight (kg): 70.9
    • Estimated chronic exposure(mg/kg-bw per day): Chronic external oral dose calculated through amortization over a year = 2.82×10−5–2.82×10−4

Appendix A-4 Estimates of adult exposure via the inhalation route

  1. Deodorant – foot mist (pump spray)
    • Scenario: trigger spray
    • Assumptions
      • Essential oil concentration range (%)= 0.3–1
      • Amount of product applied (g): 13.8
      • Uptake fraction (%): 100
      • Body weight (kg): 70.9 (Health Canada 1995)
    • Estimated acute exposure (per application): Mean event concentration: 0.145–0.482 mg/m3
  2. Fragrance – perfume
    • Scenario: Fragrance
    • Assumptions
      • Essential oil concentration range (%) = 0.1–30
      • Amount of product applied (g): 0.43–0.64
      • Uptake fraction (%): 100
      • Body weight (kg): 70.9 (Health Canada 1995)
    • Estimated acute exposure (per application): Mean event concentration: 1.1×10−5–0.0033 mg/m3
  3. Hair spray
    • Scenario: hair spray
    • Assumptions
      • Essential oil concentration range = 0.1–0.3%
      • Amount of product applied: 0.6 g
      • Uptake fraction: 100%
      • Body weight 70.9 kg (Health Canada 1995)
    • Estimated acute exposure (per application): Mean event concentration: 6.91×10−5 – 2.07×10−4mg/m3
  4. Hair detangler
    • Scenario: Hair detangler with trigger spray
    • Assumptions
      • Essential oil concentration range = < 0.1–0.1%
      • Amount of product applied: 0.6 g
      • Uptake fraction: 100%
      • Body weight 70.9 kg (Health Canada 1995)
    • Mean event concentration: 3.65×10−6mg/m3

Appendix A-5. Infant exposure estimates via the dermal route

  1. Baby shampoo (chronic exposure)
    • Scenario: Hair shampoo
    • Assumptions
      • Essential oil concentration range = 0.3–1%
      • Exposure frequency (times/year): 260
      • Exposed area: 330 cm2 (Health Canada 1995)
      • Retention factor of 10% was applied
      • Amount of product applied: 34.1 g
    • Chronic external applied dose: (mg/kg-bw per day): 0.0162–0.0539
  2. Baby skin cleanser – body wash (chronic exposure)
    • Scenario: skin cleanser
    • Assumptions
      • Essential oil concentration range = 0.3–1%
      • Exposure frequency (times/year): 329
      • Exposed area: 3.02E3 cm2 (Health Canada 1995)
      • Retention factor of 1% was applied
      • Amount of product applied: 4.5 g
    • Chronic external applied dose: (mg/kg-bw per day): 8.11 × 10−4–2.7 × 10−3
  3. Baby massage oil (acute exposure)
    • Scenario: massage oil
    • Assumptions
      • Essential oil concentration range (%): 0.3–1
      • Exposure frequency (times/year): 24
      • Exposed area: 3020 cm2 (Health Canada 1995)
      • Amount of product applied (g): 1.48
    • Chronic external applied dose (mg/kg-bw per day): 0.0296–0.0987

Appendix A-6. Toddler exposure estimates

  1. Baby shampoo
    • Scenario 365, chronic dermal exposure
    • Assumptions
      • Essential oil concentration range (%): 0.3–1
      • Exposure frequency (times/year): 365
      • Exposed area: 435 cm2 (Health Canada 1995)
      • Retention factor of 10% was applied
      • Amount of product applied: 45 g
    • Chronic external applied dose: (mg/kg-bw per day): 0.0145–0.0483
  2. Baby skin cleanser – body wash
    • Scenario: Skin cleanser, chronic dermal exposure
    • Assumptions
      • Essential oil concentration range (%): 0.3–1
      • Exposure frequency (times/year): 329
      • Exposed area: 4.91E3 cm2 (Health Canada 1995)
      • Retention factor of 1% was applied
      • Amount of product applied (g): 7.32
    • Chronic external applied dose:6.38×10−4–2.13×10−3
  3. Baby massage oil
    • Scenario: massage oil, acute dermal exposure
    • Assumptions
      • Essential oil concentration range (%): 0.3–1
      • Exposure frequency (times/year): 24
      • Exposed area: 4910 cm2 (Health Canada 1995)
      • Amount of product applied (g): 2.4
    • Chronic external applied dose(mg/kg-bw per day): 0.0232–0.0774
  4. Kids hair detangler (inhalation route exposure)
    • Scenario: hair spray with trigger spray
    • Assumptions
      • Essential oil concentration range (%): 0.1–0.3
      • Amount of product applied (g): 0.6
      • Uptake fraction(%): 100
      • Body weight (kg): 15.5 (Health Canada 1995)
    • Estimated acute exposure (per application)Mean event concentration: 3.65×10−6 – 1.1×10−5mg/m3

Appendix B. Consumer products

  1. Room mister (upper-bounding estimates exposure, ConsExpo 4.1 (ConsExpo2006)

    • Assumptions
      • Essential oil concentration range = 0.3–1%
      • Uptake fraction: 100%
      • Inhalation Adapted from ConsExpo 4.1 Trigger spray (RIVM 2006)
    • Exposure to spray
      • Exposure duration: 240 min (estimated)
      • Room volume: 58 m3 (US EPA 1986)
      • Ventilation rate: 0.5 h−1 (US EPA 1986)
      • Mass generation rate: 0.75 g/sec (RIVM 2006)
      • Spray duration: 3 min (US EPA 1986)
      • Airborne fraction: 1 (RIVM 2006)
      • Weight fraction of non-volatile: 0.1
      • Density of non-volatile: 1.8 g/cm3 (RIVM 2006)
      • Room height: 2.5 m (estimated)
      • Inhalation cut-off diameter: 15 mm (RIVM 2006)
      • Inhalation rate = 16.2 m3/day (Health Canada 1995)
    • Estimated exposure:Mean event concentration: 2.1×10−4 – 6.99×10−4mg/m3

Appendix C. Summary of health effects information for sclareol

The following acronyms are used within the text that follows:

Acute toxicity [No acute inhalation studies identified]

Lowest oral LD50 >5000 mg/kg bw in rats (0/10 death) (RIFM 1979a, b
cited in Bhatia 2008).

[No additional acute oral studies identified]
Lowest dermal LD50 >5000 mg/kg bw in rabbits (0/6 death) (RIFM
1979a, b cited in Bhatia 2008)

[No additional acute dermal studies identified]
[Additional acute studies: Malone et al. 1991]

Short-term repeated-dose toxicity
Oral LOEL = 8.8 mg/kg-bw per day, based on increase in mean kidney weight relative to brain weight in male rats, increase in mean heart and spleen weights relative to the brain weight in female, in a study of 10 male and 10 female rats that were administered sclareol at dose of 8.8 mg/kg-bw per day 7 days per week via oral intubation for 30 days. No gross or microscopic alterations were observed (RIFM 2006a; cited in Bhatia et al. 2008).

No study was identified for the following endpoints:
Subchronic toxicity , chronic toxicity/ carcinogenicity, developmental toxicity, reproductive toxicity

Genotoxicity and related endpoints: in vitro

  1. Positive: Human leukemic cell line HL60, 20 µg/mL of sclareol, dose- and time- dependent DNA cleavage (Dimas et al. 1999).
  2. Positive: Human colon cancer HCT116 cell line, 100 µM sclareol induced DNA
    breaks as early as 4 hours after sclareol addition (Dimas et al. 2007).

Essential oils from clary sage (Salvia sclarea) containing sclareol:

  1. Gene mutation in bacteria: Negative: Salmonella typhimurium TA1535, TA1537, TA98 and TA100, with S9 (Zani et al. 1969).
  2. DNA damage: Negative: Bacillus subtilis strain PB 1652(trpC2, metB10, lys3, rec+) and PB 1791 (trpC2, metB10, recE4), 10–30 µL of Salvia sclarea L. (Zani et al. 1969).

Dermal Irritation

  1. Irritating: In rabbit, 5000 mg/kg produced irritant effects after an occluded application for 24 hours (RIFM 1979a, 1979b; cited in Bhatia et al. 2008).
  2. Not irritating: In 3 albino rabbits, 3% sclareol in petrolatum or 3% sclareol in alcohol SDA, applied with patches to clipped skin (RIFM 1975c, 1975d).

Experience with human exposure

  1. Dermal Irritation
    Not irritating: In 106 volunteers, 48-hour closed patch test with 10% in petrolatum on the backs of volunteers (RIFM 1979c, 1981, 1986; cited in Bhatia et al. 2008).
    Not irritating: In 35 volunteers, with 3% in alcohol SDA 39C, 48 hours, semi-occlusive (HRIPT induction) (RIFM 1975a; cited in Belsito et al. 2008).
  2. Not irritating: In 39 volunteers, with 3% in petrolatum, 48 hours, semi-occlusive (HRIPT induction) (RIFM 1975b; cited in Belsito et al. 2008).

Sensitization

  1. Sensitizing: In 29 and 26 volunteers, with 10% in petrolatum, sample no. 78-97 (melting point 84–90oC) produced 1/29 sensitization reactions, and produced 3/26 sensitization reactions on retesting (RIFM 1979c; cited in Bhatia et al. 2008).
  2. Not sensitizing: In 23 volunteers, with 10% in petrolatum, sample no. 80-91R (melting point 96–106) produced 0/23 sensitization reactions (RIFM 1981; cited in Bhatia et al. 2008).
  3. Not sensitizing: In 28 volunteers, with 10% in petrolatum, sample no. 1140-85 (melting point 98–101oC) produced 0/28 sensitization reactions (RIFM 1986; cited in Bhatia et al. 2008).

Acute neurotoxicity

Transient neurological effects (decrease in spontaneous motor activity, a decrease in respiratory rate and a compensatory increase in respiratory depth) were observed in male Sprague-Dawley rats (group size unknown) that were exposed to 0, 100, 316, or 1000 mg/kg-bw via a single intraperitoneal (i.p.) injection (of sclareol in sterile 0.25% aqueous agar) (Malone et al. 1991).

Acute neurotoxicity for analogue sclareol glycol

LOEL= 5 mg/kg, based on decrease of locomotor activity observed in groups of 8 male albino mice (strains unknown) that were exposed to 0, 5, 25, 50 or 100 mg/kg via a single i.p. injection. The locomotor activity was recorded at 5-minute intervals for 30 minutes after injection. Sclareol glycol stimulated the locomotor activity at 5, 25 and 50 mg/kg, but at 100 mg/kg, it decreased the locomotor activity by 30% compared to controls (Georgieva 1988).
[Other neurotoxicity studies: Georgieva 1987, 1989a, 1989b]

Appendix D – Summary of (Q)SAR prediction results for sclareol

Table D-1. (Q)SAR Predictions on carcinogenicity
Model/SpeciesMale miceFemale miceMale ratFemale ratRatMiceRodentMammal
Model ApplierNPPNNNN-
Multicase CasetoxNNNN----
TOPKATNDPIC*ND----
Derek-------NR

ND – Not in domain (the model indicates that the query chemical is outside of its applicability domain) "-" No model available in QSAR suite NR – Nothing to report N – Negative P – Positive IC*– Inconclusive (unreliable prediction, based on user-defined model-specific criteria other than the models' applicability domain)

Table D-2. (Q)SAR predictions on genotoxicity
Model/endpointsModel ApplierMulticase CasetoxTOPKAT
chromosomal aberrations.PN-
chromosomal aberrations - other rodentP--
chromosomal aberrations - ratND--
micronucleus miceNN-
micronucleus rodentP--
DrosophilaNND-
Drosophila heritable translocationsN--
Drosophila SLRLN--
mam. mutationN--
mam. mutation dominant lethalN--
UDSNND-
UDS human lymphocytesND--
UDS rat hepatocytesN--
mouse lymphoma mutNND-
S. cerevisiaeN--
yeastN--
HGPRTN--
E. coliN--
E coli wN--
microbialN--
SalmonellaNNN

MA – Model Applier CT – Multicase Casetox TK – TOPKAT ND – Not in domain (the model indicates that the query chemical to be outside of its applicability domain) "-" No model available in QSAR suite N – Negative P – Positive

Table D-3. (Q)SAR predictions on developmental toxicity - Model Applier
Endpoint/ SpeciesMiceRabbitRatRodent
RetardationNDNDNN
Weight decreaseNDNDPN
Fetal deathNDNDNN
Post implantation lossNDNDPN
Pre implantation lossNDNDNN
StructuralNDNDNN
VisceralNDNDNN

ND – Not in domain (the model indicates that the query chemical is outside of its applicability domain) N – Negative P – Positive

Table D-4 (Q)SAR Predictions on developmental toxicity - Multicase Casetox
Endpoint/SpeciesHamsterMammalMiscellaneous
Teratogenicity-NN
DevelopmentalND--

ND – Not in domain (the model indicates that the query chemical is outside of its applicability domain) "-" No model available in QSAR suite N – Negative

Table D-5. (Q)SAR Predictions on reproductive toxicity - Model Applier
Model/EndpointFemale MiceFemale ratFemale rodentMale miceMale ratMale rodent
SpeciesMiceRatRodentMiceRatRodent
ReproNDNDNDNDNDND
Sperm---NDNDND

ND – Not in domain (the model indicates that the query chemical is outside of its applicability domain) "-" No model available in QSAR suite

Table D-6. (Q)SAR Predictions on Reproductive Toxicity -Multicase Casetox
MiceRatRabbitHuman
NNNND

ND – not in domain (the model indicates that the query chemical is outside of its applicability domain) "-" no model available in QSAR suite N – Negative

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