- Email: [email protected]
Fragrance material review on tetrahydrolinalool
Food and Chemical Toxicology 46 (2008) S286–S288
Contents lists available at ScienceDirect
Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox
Fragrance material review on tetrahydrolinalool A. Lapczynski *, R.J. Foxenberg, S.P. Bhatia, C.S. Letizia, A.M. Api Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
a r t i c l e
i n f o
Keywords: Review Fragrance Tetrahydrolinalool
a b s t r a c t A toxicologic and dermatologic review of tetrahydrolinalool when used as a fragrance ingredient is presented. Ó 2008 Published by Elsevier Ltd.
Introduction In 2006, a complete literature search was conducted on tetrahydrolinalool. Online databases that were surveyed included Chemical Abstract Services and the National Library of Medicine. In addition, fragrance companies were asked to submit pertinent test data. All relevant references are included in this document. More details have been provided for unpublished data. Any papers in which the vehicles and/or the doses are not given have not been included in this review. The number of animals, sex and strain are always provided unless they are not given in the original report or paper. This individual Fragrance Material Review is not intended as a stand alone document. Please refer to A Safety Assessment of Cyclic and Non-Cyclic Terpene Alcohols When Used as Fragrance Ingredients (Belsito et al., 2008) for an overall assessment of this material. 1. Identification (Fig. 1) 1.1 Synonyms: 2,6-dimethyl-6-octanol; 3,7-dimethyloctan-3ol; 3-octanol, 3,7-dimethyl. 1.2 CAS Registry number: 78-69-3. 1.3 EINECS number: 201-133-9. 1.4 Formula: C10H22O. 1.5 Molecular weight: 158.29. 1.6 Council of Europe: Tetrahydrolinalool was included by the Council of Europe in the list of substances granted B-information requires 28 day oral study (COE No. 77) 1.7 Food and Drug Association (FDA): Tetrahydrolinalool was approved by the FDA as a flavor (21 CFR 172.515).
* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8090. E-mail address: [email protected] (A. Lapczynski). 0278-6915/$ - see front matter Ó 2008 Published by Elsevier Ltd. doi:10.1016/j.fct.2008.06.076
1.8 FEMA: Flavor and Extract Manufacturers’ Association states: Generally Recognized as Safe as a flavor ingredient – GRAS3 (3060). 1.9 JECFA: The Joint FAO/WHO Expert Committee on Food Additives (JECFA No. 357) concluded that the substance does not present a safety concern at current levels of intake when used as a flavoring agent. 2. Physical properties 2.1 Physical form: A colorless, oily liquid with a sweet, oily, delicately floral odor, less green-woody than linalool, more floral and powdery sweet-dry odor. 2.2 Boiling point: 311 °C. 2.3 Melting point: 11.77 °C. 2.4 Flash point: 185 °F; CC. 2.5 Log Kow (calculated): 3.6. 2.6 Henry’s law (calculated): 0. 0000547 atm m3/mol 25 °C. 2.7 Specific gravity: 0.83 g/ml. 2.8 Vapor pressure (calculated): 0.4 mm Hg at 20 °C. 2.9 Water solubility (calculated): 188.9 mg/l at 25 °C. 3. Usage (Table 1) Tetrahydrolinalool is a fragrance ingredient used in many fragrance compounds. It may be found in fragrances used in decorative cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non-cosmetic products such as household cleaners and detergents. Its use worldwide is in the region greater than 1000 metric tonnes per annum. The maximum skin level that results from the use of tetrahydrolinalool in formulae that go into fine fragrances has not been reported. A default value of 0.02% is used, assuming use of the fragrance oil at levels up to 20% in the final product. The 97.5 percentile use level in formulae for use in cosmetics in general has not
S287
A. Lapczynski et al. / Food and Chemical Toxicology 46 (2008) S286–S288 Table 2 Summary of acute toxicity studies
HO Fig. 1. Tetrahydrolinalool.
been reported. As such the default value of 0.02% is used to calculate the maximum daily exposure on the skin of 0.0005 mg/ kg for high end users of these products. 4. Toxicology data 4.1. Acute toxicity (Table 2) 4.1.1. Oral studies 4.1.1.1. Ten rats received a single oral dose of tetrahydrolinalool at 5.0 g/kg. The animals were observed for 14 days. The clinical signs included lethargy. The LD50 exceeded 5.0 g/kg based on 0/10 deaths on that dose (RIFM, 1976a). 4.1.1.2. Ten male and female CF-1 mice, weighing 17–25 g received a single oral dose of undiluted tetrahydrolinalool. The animals were observed for 72 h. The calculated LD50 was 6.233 g/ kg ± 0.498 g/kg (RIFM, 1967). 4.1.2. Dermal studies 4.1.2.1. The acute dermal LD50 in rabbits exceeded 5.0 g/kg based on 0/10 deaths at that dose. Ten rabbits received a single dermal application of neat tetrahydrolinalool at 5.0 g/kg. The rabbits were observed for 14 days. No clinical effects were observed (RIFM, 1976a).
Route
Species
Number of animals/dose group
LD50
References
Oral Oral Dermal
Rats Mice Rabbits
10 10 10
>5.0 g/kg 6.233 g/kg >5.0 g/kg
RIFM (1976a) RIFM (1967) RIFM (1976a)
Table 3 Summary of human irritation studies Method
Dose (%)
Results
References
48 h closed patch test 24–48 h closed patch test
4% in petrolatum
0/5
RIFM (1976b)
0.05–0.5% in base cream or 99% ethanol
0/46
Takenaka et al. (1986)
guinea pigs (5/group). Applications of tetrahydrolinalool at concentrations of 5, 10, 30 or 50% in acetone were made on the right and the left side of all the animals. Immediately after application, one side was covered with aluminum foil, while the other side was subject to irradiation. Reactions were assessed at 24 and 48 h after irradiation using the Draize scale. No reactions were observed at concentrations up to 30%. At 50% slight irritation reaction was observed in 1/5 animals (RIFM, 1999). 4.2.2.2. A primary dermal irritation study was conducted using three rabbits per dose group. Each animal received a single dermal application of 5% in diethyl phthalate or neat tetrahydrolinalool on intact and abraded skin sites. Observations were made at 24 and 72 h after application. A dose of 5% produced very slight erythema, in 1/3 rabbits at 24 h. Neat test material produced very slight erythema in 2/3 rabbits at 72 h (RIFM, 1967).
4.2. Skin irritation (Table 3) 4.2.1. Human studies 4.2.1.1. In a pre-test for a maximization study, no reactions were observed to 4% tetrahydrolinalool in petrolatum when applied for 48 h under occlusion on the backs of 32 healthy volunteers (RIFM, 1976b). 4.2.1.2. Tetrahydrolinalool at 0.05–0.5% was utilized in a closed patch test on the back or forearm of 46 subjects for 24–48 h. No irritation was observed (Takenaka et al., 1986). 4.2.2. Animal studies (Table 4) 4.2.2.1. As part of an associated phototoxicity study, tetrahydrolinalool was evaluated for primary irritation in female Hartley albino
4.2.2.3. As part of the associated LD50 study, irritation to neat tetrahydrolinalool was evaluated in ten rabbits. Moderate (9/10) to slight erythema (1/10) and moderate (9/10) to slight edema (1/ 10) was observed (RIFM, 1976a). 4.3. Mucous membrane (eye) irritation 4.3.1.1. The eye irritation potential of tetrahydrolinalool was evaluated in 3 rabbits using the Draize procedure. A 0.1 ml aliquot of tetrahydrolinalool at 5% in DEP or 100% was instilled into conjunctival sac of all the animals with no further treatment. Fluorescein was injected to check for corneal damage. Reactions were assessed at 0–4 h and 1–3 days after the instillation. Tetrahydrolinalool at 100% produced well defined to moderate conjunctival redness,
Table 1 Calculation of the total human skin exposure from the use of multiple cosmetic products containing tetrahydrolinalool Type of cosmetic product
Grams applied
Applications per day
Retention factor
Mixture/Product
Ingredient/Mixturea
Ingredient mg/kg/dayb
Body lotion Face cream Eau de toilette Fragrance cream Antiperspirant Shampoo Bath products Shower gel Toilet soap Hair spray Total
8.00 0.80 0.75 5.00 0.50 8.00 17.00 5.00 0.80 5.00
0.71 2.00 1.00 0.29 1.00 1.00 0.29 1.07 6.00 2.00
1.000 1.000 1.000 1.000 1.000 0.010 0.001 0.010 0.010 0.010
0.004 0.003 0.080 0.040 0.010 0.005 0.020 0.012 0.015 0.005
0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02
0.0001 0.0000 0.0002 0.0002 0.0000 0.0000 0.0000 0.0000 0.0000 0.0000 0.0005
a b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products. Based on a 60-kg adult.
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A. Lapczynski et al. / Food and Chemical Toxicology 46 (2008) S286–S288
Table 4 Summary of animal irritation studies Methods
Dose (%)
Species
Results
References
Irritation as part of a phototoxicity test Primary irritation LD50 irritation
5, 10, 30 or 50% in acetone 5% in DEP or 100% (undiluted) 100% (undiluted)
Guinea pigs Rabbits Rabbits
No irritation observed at up to 30%. Irritation observed at 50% Irritation observed Irritation observed
RIFM (1999) RIFM (1967) RIFM (1976a)
moderate to well define discharge and slight corneal opacity. At 5% only very slight conjunctival reaction was observed (RIFM, 1967).
4.7. Repeated dose toxicity No data available on this material.
4.4. Skin sensitization 4.8. Reproductive and developmental toxicity 4.4.1. Human studies 4.4.1.1. A maximization test (Kligman, 1966; Kligman and Epstein, 1975) was carried out with 4% (2760 lg/cm2) tetrahydrolinalool in petrolatum on 32 healthy volunteers. Tetrahydrolinalool was applied under occlusion to the same sites on the volar forearms of all the subjects for five alternate-days 48 h periods. Patch sites were pretreated for 24 h with 5% aqueous Sodium lauryl sulfate (SLS) for the initial patch only. Following a 10–14 day rest period challenge patches of the test material were applied for 48 h under occlusion to fresh sites. The challenge applications were preceded by 30 minutes application with 5% aqueous SLS under occlusion. Additional SLS controls were placed on the left and the petrolatum on the right. T he challenge sites were read at patch removal and 48 and 72 h thereafter. No (0/32) sensitization reactions were observed (RIFM, 1976b). 4.4.2. Animal studies 4.4.2.1. The skin contact sensitization potential of tetrahydrolinalool was evaluated in guinea pig maximization study using female albino guinea pigs (5/group). For the intradermal induction, animals were injected with 10% tetrahydrolinalool in Complete Adjuvant and 10% tetrahydrolinalool in a mixture of Freund’s Complete Adjuvant Test (FCAT) plus physiological saline (1:1). During topical induction a patch containing 10% tetrahydrolinalool in Complete Adjuvant was applied to each animal. All animals were challenged with topical application of 5, 10, 20 or 40% test material in acetone. Reactions were observed at 48 h. No sensitization was observed at 5, 10 and 20% tetrahydrolinalool in acetone. At 40% reactions were observed in 3/5 animals (RIFM, 1999).
No data available on this material. 4.9. Mutagenicity and genotoxicity 4.9.1. Bacterial studies 4.9.1.1. In an Ames test using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 no mutagenic effects were observed with tetrahydrolinalool at doses up to 3600 lg/plate with and without S9 activation (Wild et al., 1983). 4.10. Carcinogenicity No data available on this material. This individual Fragrance Material Review is not intended as a stand alone document. Please refer to A safety Assessment of Cyclic and Non-Cyclic Terpene Alcohols When Used as Fragrance Ingredients (Belsito et al., 2008) for an overall assessment of this material.
Conflict of interest statement This research was supported by the Research Institute for Fragrance Materials, an independent research institute that is funded by the manufacturers of fragrances and consumer products containing fragrances. The authors are all employees of the Research Institute for Fragrance Materials.
References 4.5. Phototoxicity and photoallergy 4.5.1. Animal studies 4.5.1.1. Tetrahydrolinalool was evaluated for phototoxicity in female Hartley strain albino guinea pigs (5/group). Tetrahydrolinalool at concentration of 5, 10, 30 or 50% in acetone was applied on a 1.5 cm diameter circle. Each circle containing one concentration was applied on the right and the left sides. Eight applications were made in total. Immediately after application, one side was covered with aluminum foil. The other side was irradiated with a bank of six ultra-violet lights (model FL-40 BLB lamps 40 W tubes; emission: 320–400 nm) that had been equipped with window glass filter to eliminate radiation below 320 nm. The distance from the light source to the skin was 10 cm. Irradiation was continued for 70 minute. Reactions were assessed at 24 and 48 h after irradiation. No reaction was observed at 5, 10 and 30%. At 50% phototoxicity could not be determined as there were no differences in the reactions between the UV-radiated sites and the non-radiated sites (RIFM, 1999). 4.6. Absorption, distribution and metabolism No data available on this material.
Belsito, Bickers, D., Bruze, Calow, P.M., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H.. A toxicologic and dermatologic assessment of cyclic and non cyclic terpene alcohols when used as fragrance ingredients. Food and Chemical Toxicology 46 (11S), S1–S71. Kligman, A.M., 1966. The identification of contact allergens by human assay. III. The maximization test. A procedure for screening and rating contact sensitizers. Journal of Investigative Dermatology 47, 393–409. Kligman, A.M., Epstein, W.L., 1975. Updating the maximization test for identifying contact allergens. Contact Dermatitis 1, 231–239. RIFM (Research Institute for Fragrance Materials, Inc.), 1967. Acute toxicity, eye and skin irritation test of fragrance materials. Unpublished report from HoffmannLaRoche. RIFM Report Number 30642, September 20, RIFM, Woodcliff Lake, NJ, USA. RIFM (Research Institute for Fragrance Materials, Inc.), 1976a. Acute toxicity studies in rats, mice, rabbits and guinea pigs. RIFM Report Number 2019, March 13, RIFM, Woodcliff Lake, NJ, USA. RIFM (Research Institute for Fragrance Materials, Inc.), 1976b. Report on human maximization studies. RIFM Report Number 1796, March 23, RIFM, Woodcliff Lake, NJ, USA. RIFM (Research Institute for Fragrance Materials, Inc.), 1999. Toxicology studies of tetrahydrolinalool in the guinea pig. Unpublished report from Takasago Inc. RIFM Report Number 35061, RIFM, Woodcliff Lake, NJ, USA. Takenaka, T., Hasegawa, E., Takenaka, U., Saito, F., Odaka, T., 1986. Fundamental studies of safe compound perfumes for cosmetics. Part 1: the primary irritation of compound materials to the skin. Unknown Journal, 313–329 (in Japanese). Wild, D., King, M.T., Gocke, E., Eckhardt, K., 1983. Study of artificial flavouring substances for mutagenicity in the Salmonella/microsome, basic and micronucleus tests. Food and Chemical Toxicology 21, 707–719.
Contents lists available at ScienceDirect
Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox
Fragrance material review on tetrahydrolinalool A. Lapczynski *, R.J. Foxenberg, S.P. Bhatia, C.S. Letizia, A.M. Api Research Institute for Fragrance Materials Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
a r t i c l e
i n f o
Keywords: Review Fragrance Tetrahydrolinalool
a b s t r a c t A toxicologic and dermatologic review of tetrahydrolinalool when used as a fragrance ingredient is presented. Ó 2008 Published by Elsevier Ltd.
Introduction In 2006, a complete literature search was conducted on tetrahydrolinalool. Online databases that were surveyed included Chemical Abstract Services and the National Library of Medicine. In addition, fragrance companies were asked to submit pertinent test data. All relevant references are included in this document. More details have been provided for unpublished data. Any papers in which the vehicles and/or the doses are not given have not been included in this review. The number of animals, sex and strain are always provided unless they are not given in the original report or paper. This individual Fragrance Material Review is not intended as a stand alone document. Please refer to A Safety Assessment of Cyclic and Non-Cyclic Terpene Alcohols When Used as Fragrance Ingredients (Belsito et al., 2008) for an overall assessment of this material. 1. Identification (Fig. 1) 1.1 Synonyms: 2,6-dimethyl-6-octanol; 3,7-dimethyloctan-3ol; 3-octanol, 3,7-dimethyl. 1.2 CAS Registry number: 78-69-3. 1.3 EINECS number: 201-133-9. 1.4 Formula: C10H22O. 1.5 Molecular weight: 158.29. 1.6 Council of Europe: Tetrahydrolinalool was included by the Council of Europe in the list of substances granted B-information requires 28 day oral study (COE No. 77) 1.7 Food and Drug Association (FDA): Tetrahydrolinalool was approved by the FDA as a flavor (21 CFR 172.515).
* Corresponding author. Tel.: +1 201 689 8089; fax: +1 201 689 8090. E-mail address: [email protected] (A. Lapczynski). 0278-6915/$ - see front matter Ó 2008 Published by Elsevier Ltd. doi:10.1016/j.fct.2008.06.076
1.8 FEMA: Flavor and Extract Manufacturers’ Association states: Generally Recognized as Safe as a flavor ingredient – GRAS3 (3060). 1.9 JECFA: The Joint FAO/WHO Expert Committee on Food Additives (JECFA No. 357) concluded that the substance does not present a safety concern at current levels of intake when used as a flavoring agent. 2. Physical properties 2.1 Physical form: A colorless, oily liquid with a sweet, oily, delicately floral odor, less green-woody than linalool, more floral and powdery sweet-dry odor. 2.2 Boiling point: 311 °C. 2.3 Melting point: 11.77 °C. 2.4 Flash point: 185 °F; CC. 2.5 Log Kow (calculated): 3.6. 2.6 Henry’s law (calculated): 0. 0000547 atm m3/mol 25 °C. 2.7 Specific gravity: 0.83 g/ml. 2.8 Vapor pressure (calculated): 0.4 mm Hg at 20 °C. 2.9 Water solubility (calculated): 188.9 mg/l at 25 °C. 3. Usage (Table 1) Tetrahydrolinalool is a fragrance ingredient used in many fragrance compounds. It may be found in fragrances used in decorative cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non-cosmetic products such as household cleaners and detergents. Its use worldwide is in the region greater than 1000 metric tonnes per annum. The maximum skin level that results from the use of tetrahydrolinalool in formulae that go into fine fragrances has not been reported. A default value of 0.02% is used, assuming use of the fragrance oil at levels up to 20% in the final product. The 97.5 percentile use level in formulae for use in cosmetics in general has not
S287
A. Lapczynski et al. / Food and Chemical Toxicology 46 (2008) S286–S288 Table 2 Summary of acute toxicity studies
HO Fig. 1. Tetrahydrolinalool.
been reported. As such the default value of 0.02% is used to calculate the maximum daily exposure on the skin of 0.0005 mg/ kg for high end users of these products. 4. Toxicology data 4.1. Acute toxicity (Table 2) 4.1.1. Oral studies 4.1.1.1. Ten rats received a single oral dose of tetrahydrolinalool at 5.0 g/kg. The animals were observed for 14 days. The clinical signs included lethargy. The LD50 exceeded 5.0 g/kg based on 0/10 deaths on that dose (RIFM, 1976a). 4.1.1.2. Ten male and female CF-1 mice, weighing 17–25 g received a single oral dose of undiluted tetrahydrolinalool. The animals were observed for 72 h. The calculated LD50 was 6.233 g/ kg ± 0.498 g/kg (RIFM, 1967). 4.1.2. Dermal studies 4.1.2.1. The acute dermal LD50 in rabbits exceeded 5.0 g/kg based on 0/10 deaths at that dose. Ten rabbits received a single dermal application of neat tetrahydrolinalool at 5.0 g/kg. The rabbits were observed for 14 days. No clinical effects were observed (RIFM, 1976a).
Route
Species
Number of animals/dose group
LD50
References
Oral Oral Dermal
Rats Mice Rabbits
10 10 10
>5.0 g/kg 6.233 g/kg >5.0 g/kg
RIFM (1976a) RIFM (1967) RIFM (1976a)
Table 3 Summary of human irritation studies Method
Dose (%)
Results
References
48 h closed patch test 24–48 h closed patch test
4% in petrolatum
0/5
RIFM (1976b)
0.05–0.5% in base cream or 99% ethanol
0/46
Takenaka et al. (1986)
guinea pigs (5/group). Applications of tetrahydrolinalool at concentrations of 5, 10, 30 or 50% in acetone were made on the right and the left side of all the animals. Immediately after application, one side was covered with aluminum foil, while the other side was subject to irradiation. Reactions were assessed at 24 and 48 h after irradiation using the Draize scale. No reactions were observed at concentrations up to 30%. At 50% slight irritation reaction was observed in 1/5 animals (RIFM, 1999). 4.2.2.2. A primary dermal irritation study was conducted using three rabbits per dose group. Each animal received a single dermal application of 5% in diethyl phthalate or neat tetrahydrolinalool on intact and abraded skin sites. Observations were made at 24 and 72 h after application. A dose of 5% produced very slight erythema, in 1/3 rabbits at 24 h. Neat test material produced very slight erythema in 2/3 rabbits at 72 h (RIFM, 1967).
4.2. Skin irritation (Table 3) 4.2.1. Human studies 4.2.1.1. In a pre-test for a maximization study, no reactions were observed to 4% tetrahydrolinalool in petrolatum when applied for 48 h under occlusion on the backs of 32 healthy volunteers (RIFM, 1976b). 4.2.1.2. Tetrahydrolinalool at 0.05–0.5% was utilized in a closed patch test on the back or forearm of 46 subjects for 24–48 h. No irritation was observed (Takenaka et al., 1986). 4.2.2. Animal studies (Table 4) 4.2.2.1. As part of an associated phototoxicity study, tetrahydrolinalool was evaluated for primary irritation in female Hartley albino
4.2.2.3. As part of the associated LD50 study, irritation to neat tetrahydrolinalool was evaluated in ten rabbits. Moderate (9/10) to slight erythema (1/10) and moderate (9/10) to slight edema (1/ 10) was observed (RIFM, 1976a). 4.3. Mucous membrane (eye) irritation 4.3.1.1. The eye irritation potential of tetrahydrolinalool was evaluated in 3 rabbits using the Draize procedure. A 0.1 ml aliquot of tetrahydrolinalool at 5% in DEP or 100% was instilled into conjunctival sac of all the animals with no further treatment. Fluorescein was injected to check for corneal damage. Reactions were assessed at 0–4 h and 1–3 days after the instillation. Tetrahydrolinalool at 100% produced well defined to moderate conjunctival redness,
Table 1 Calculation of the total human skin exposure from the use of multiple cosmetic products containing tetrahydrolinalool Type of cosmetic product
Grams applied
Applications per day
Retention factor
Mixture/Product
Ingredient/Mixturea
Ingredient mg/kg/dayb
Body lotion Face cream Eau de toilette Fragrance cream Antiperspirant Shampoo Bath products Shower gel Toilet soap Hair spray Total
8.00 0.80 0.75 5.00 0.50 8.00 17.00 5.00 0.80 5.00
0.71 2.00 1.00 0.29 1.00 1.00 0.29 1.07 6.00 2.00
1.000 1.000 1.000 1.000 1.000 0.010 0.001 0.010 0.010 0.010
0.004 0.003 0.080 0.040 0.010 0.005 0.020 0.012 0.015 0.005
0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02
0.0001 0.0000 0.0002 0.0002 0.0000 0.0000 0.0000 0.0000 0.0000 0.0000 0.0005
a b
Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products. Based on a 60-kg adult.
S288
A. Lapczynski et al. / Food and Chemical Toxicology 46 (2008) S286–S288
Table 4 Summary of animal irritation studies Methods
Dose (%)
Species
Results
References
Irritation as part of a phototoxicity test Primary irritation LD50 irritation
5, 10, 30 or 50% in acetone 5% in DEP or 100% (undiluted) 100% (undiluted)
Guinea pigs Rabbits Rabbits
No irritation observed at up to 30%. Irritation observed at 50% Irritation observed Irritation observed
RIFM (1999) RIFM (1967) RIFM (1976a)
moderate to well define discharge and slight corneal opacity. At 5% only very slight conjunctival reaction was observed (RIFM, 1967).
4.7. Repeated dose toxicity No data available on this material.
4.4. Skin sensitization 4.8. Reproductive and developmental toxicity 4.4.1. Human studies 4.4.1.1. A maximization test (Kligman, 1966; Kligman and Epstein, 1975) was carried out with 4% (2760 lg/cm2) tetrahydrolinalool in petrolatum on 32 healthy volunteers. Tetrahydrolinalool was applied under occlusion to the same sites on the volar forearms of all the subjects for five alternate-days 48 h periods. Patch sites were pretreated for 24 h with 5% aqueous Sodium lauryl sulfate (SLS) for the initial patch only. Following a 10–14 day rest period challenge patches of the test material were applied for 48 h under occlusion to fresh sites. The challenge applications were preceded by 30 minutes application with 5% aqueous SLS under occlusion. Additional SLS controls were placed on the left and the petrolatum on the right. T he challenge sites were read at patch removal and 48 and 72 h thereafter. No (0/32) sensitization reactions were observed (RIFM, 1976b). 4.4.2. Animal studies 4.4.2.1. The skin contact sensitization potential of tetrahydrolinalool was evaluated in guinea pig maximization study using female albino guinea pigs (5/group). For the intradermal induction, animals were injected with 10% tetrahydrolinalool in Complete Adjuvant and 10% tetrahydrolinalool in a mixture of Freund’s Complete Adjuvant Test (FCAT) plus physiological saline (1:1). During topical induction a patch containing 10% tetrahydrolinalool in Complete Adjuvant was applied to each animal. All animals were challenged with topical application of 5, 10, 20 or 40% test material in acetone. Reactions were observed at 48 h. No sensitization was observed at 5, 10 and 20% tetrahydrolinalool in acetone. At 40% reactions were observed in 3/5 animals (RIFM, 1999).
No data available on this material. 4.9. Mutagenicity and genotoxicity 4.9.1. Bacterial studies 4.9.1.1. In an Ames test using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 no mutagenic effects were observed with tetrahydrolinalool at doses up to 3600 lg/plate with and without S9 activation (Wild et al., 1983). 4.10. Carcinogenicity No data available on this material. This individual Fragrance Material Review is not intended as a stand alone document. Please refer to A safety Assessment of Cyclic and Non-Cyclic Terpene Alcohols When Used as Fragrance Ingredients (Belsito et al., 2008) for an overall assessment of this material.
Conflict of interest statement This research was supported by the Research Institute for Fragrance Materials, an independent research institute that is funded by the manufacturers of fragrances and consumer products containing fragrances. The authors are all employees of the Research Institute for Fragrance Materials.
References 4.5. Phototoxicity and photoallergy 4.5.1. Animal studies 4.5.1.1. Tetrahydrolinalool was evaluated for phototoxicity in female Hartley strain albino guinea pigs (5/group). Tetrahydrolinalool at concentration of 5, 10, 30 or 50% in acetone was applied on a 1.5 cm diameter circle. Each circle containing one concentration was applied on the right and the left sides. Eight applications were made in total. Immediately after application, one side was covered with aluminum foil. The other side was irradiated with a bank of six ultra-violet lights (model FL-40 BLB lamps 40 W tubes; emission: 320–400 nm) that had been equipped with window glass filter to eliminate radiation below 320 nm. The distance from the light source to the skin was 10 cm. Irradiation was continued for 70 minute. Reactions were assessed at 24 and 48 h after irradiation. No reaction was observed at 5, 10 and 30%. At 50% phototoxicity could not be determined as there were no differences in the reactions between the UV-radiated sites and the non-radiated sites (RIFM, 1999). 4.6. Absorption, distribution and metabolism No data available on this material.
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