A toxicologic and dermatologic assessment of cyclic and non-cyclic terpene alcohols when used as fragrance ingredients

D. Belsito, D. Bickers, M. Bruze, P. Calow, H. Greim, Jon Hanifin, A. E. Rogers, J. H. Saurat, I. G. Sipes, H. Tagami

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

The materials assessed in this report have close structural relationships and similar biochemical and toxicity profiles. They generally participate in the same pathways of metabolic detoxication. The terpene alcohols are dermally absorbed, and a significant amount can be retained briefly within the epidermis, dermis, and subcutaneous tissue. Some have a penetration enhancing effect in vitro. Few data are available from which to characterize the oral bioavailability of the terpene alcohols. For the assessment of potential oral exposures, bioavailability is therefore assumed to be 100%. Based on the data reviewed, the terpene alcohols are expected to undergo extensive conjugation and metabolism by well-characterized pathways, primarily in the liver, to form more polar compounds that are excreted mainly in the urine and to a lesser extent in the feces. They form generally innocuous end products: primary alcohols are metabolized to corresponding aldehydes and acids, and ultimately to CO2, and secondary alcohols are conjugated with glucuronide and excreted. Unsaturated alcohols may undergo further oxidation at the point of unsaturation or be oxidized to the corresponding acid prior to conjugation and excretion in the urine. A few materials, however, may generate α,β-unsaturated metabolites or hydroperoxides. The acute dermal toxicity of the terpene alcohols is very low, with LD50 values in rabbits reported to be greater than 2000 mg/kg body weight. The acute oral toxicity is likewise low with LD50 values generally greater than 1000 mg/kg body weight. Dermal repeated dose toxicity studies have been conducted only with linalool and α-bisabolol and indicated, apart from local effects, a low magnitude of systemic toxicity with NOAELs of 250 and 200 mg/kg body weight/day, respectively. Slight effects on body weight and food consumption were observed at a dose level of 1000 mg/kg body weight/day. The liver and kidneys were the only target organs affected in oral repeated dose toxicity studies. The magnitude of systemic toxicity is considered to be low with NOAELs generally greater than 50 mg/kg body weight/day. Hence, it can be assumed that efficient detoxication mechanisms are in place to prevent significant toxicity. Terpene alcohols have been extensively tested in genotoxicity studies in vitro. Ames and other bacterial mutation data demonstrate no mutagenic activity of this group of compounds. A few positive results have been obtained in chromosome aberration studies in vitro, but these materials showed no evidence of genotoxicity in vivo. The relevance of the positive findings is, therefore, limited. Reproductive and developmental toxicity data are limited but give no indication of a relevant adverse effect on reproductive function or the developing organism. NOAELs for maternal and developmental toxicity are far in excess of current human exposure levels and raise no safety concern. At concentrations likely to be encountered by consumers, these chemicals are considered non-irritating to human skin. Their potential for eye irritation under the present maximum use concentrations is considered minimal. Cases of sensitization, mostly in dermatitis patients, have been reported for many of the assessed terpene alcohols. Due to their sensitizing effects, 6,7-dihydrogeraniol, hydroabietyl alcohol and isopropyl-2-decahydronaphthalenol have been prohibited for use in fragrance materials. Restrictions exist for farnesol, geraniol, citronellol and rhodinol (3,7-dimethyl-7-octen-1-ol). Sclareol and linalool must comply with specific purity criteria if used as fragrance materials. No test results were available for some materials. 2(10)-Pinen-3-ol and 2,6-dimethyloct-3,5-dien-2-ol do not have structural alerts for topical effects (Ford et al., 2000). Based on structural elements that indicate a potential for sensitization, 3,7-dimethyl-4,6-octadien-3-ol, should be regarded as a potential sensitizer until tested. Based on the UV spectra and review of phototoxic/photoallergy data, terpene alcohols would not be expected to elicit phototoxicity or photoallergy under the current conditions of use as a fragrance ingredient.

Original languageEnglish (US)
JournalFood and Chemical Toxicology
Volume46
Issue number11 SUPPL.
DOIs
StatePublished - Nov 2008

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Fragrances
Terpenes
terpenoids
Toxicity
ingredients
alcohols
odors
Alcohols
Body Weight
No-Observed-Adverse-Effect Level
no observed adverse effect level
body weight
toxicity
Photoallergic Dermatitis
developmental toxicity
citronellol
Lethal Dose 50
genotoxicity
linalool
Liver

ASJC Scopus subject areas

  • Food Science
  • Toxicology

Cite this

A toxicologic and dermatologic assessment of cyclic and non-cyclic terpene alcohols when used as fragrance ingredients. / Belsito, D.; Bickers, D.; Bruze, M.; Calow, P.; Greim, H.; Hanifin, Jon; Rogers, A. E.; Saurat, J. H.; Sipes, I. G.; Tagami, H.

In: Food and Chemical Toxicology, Vol. 46, No. 11 SUPPL., 11.2008.

Research output: Contribution to journalArticle

Belsito, D, Bickers, D, Bruze, M, Calow, P, Greim, H, Hanifin, J, Rogers, AE, Saurat, JH, Sipes, IG & Tagami, H 2008, 'A toxicologic and dermatologic assessment of cyclic and non-cyclic terpene alcohols when used as fragrance ingredients', Food and Chemical Toxicology, vol. 46, no. 11 SUPPL.. https://doi.org/10.1016/j.fct.2008.06.085
Belsito, D. ; Bickers, D. ; Bruze, M. ; Calow, P. ; Greim, H. ; Hanifin, Jon ; 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. In: Food and Chemical Toxicology. 2008 ; Vol. 46, No. 11 SUPPL.
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T1 - A toxicologic and dermatologic assessment of cyclic and non-cyclic terpene alcohols when used as fragrance ingredients

AU - Belsito, D.

AU - Bickers, D.

AU - Bruze, M.

AU - Calow, P.

AU - Greim, H.

AU - Hanifin, Jon

AU - Rogers, A. E.

AU - Saurat, J. H.

AU - Sipes, I. G.

AU - Tagami, H.

PY - 2008/11

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N2 - The materials assessed in this report have close structural relationships and similar biochemical and toxicity profiles. They generally participate in the same pathways of metabolic detoxication. The terpene alcohols are dermally absorbed, and a significant amount can be retained briefly within the epidermis, dermis, and subcutaneous tissue. Some have a penetration enhancing effect in vitro. Few data are available from which to characterize the oral bioavailability of the terpene alcohols. For the assessment of potential oral exposures, bioavailability is therefore assumed to be 100%. Based on the data reviewed, the terpene alcohols are expected to undergo extensive conjugation and metabolism by well-characterized pathways, primarily in the liver, to form more polar compounds that are excreted mainly in the urine and to a lesser extent in the feces. They form generally innocuous end products: primary alcohols are metabolized to corresponding aldehydes and acids, and ultimately to CO2, and secondary alcohols are conjugated with glucuronide and excreted. Unsaturated alcohols may undergo further oxidation at the point of unsaturation or be oxidized to the corresponding acid prior to conjugation and excretion in the urine. A few materials, however, may generate α,β-unsaturated metabolites or hydroperoxides. The acute dermal toxicity of the terpene alcohols is very low, with LD50 values in rabbits reported to be greater than 2000 mg/kg body weight. The acute oral toxicity is likewise low with LD50 values generally greater than 1000 mg/kg body weight. Dermal repeated dose toxicity studies have been conducted only with linalool and α-bisabolol and indicated, apart from local effects, a low magnitude of systemic toxicity with NOAELs of 250 and 200 mg/kg body weight/day, respectively. Slight effects on body weight and food consumption were observed at a dose level of 1000 mg/kg body weight/day. The liver and kidneys were the only target organs affected in oral repeated dose toxicity studies. The magnitude of systemic toxicity is considered to be low with NOAELs generally greater than 50 mg/kg body weight/day. Hence, it can be assumed that efficient detoxication mechanisms are in place to prevent significant toxicity. Terpene alcohols have been extensively tested in genotoxicity studies in vitro. Ames and other bacterial mutation data demonstrate no mutagenic activity of this group of compounds. A few positive results have been obtained in chromosome aberration studies in vitro, but these materials showed no evidence of genotoxicity in vivo. The relevance of the positive findings is, therefore, limited. Reproductive and developmental toxicity data are limited but give no indication of a relevant adverse effect on reproductive function or the developing organism. NOAELs for maternal and developmental toxicity are far in excess of current human exposure levels and raise no safety concern. At concentrations likely to be encountered by consumers, these chemicals are considered non-irritating to human skin. Their potential for eye irritation under the present maximum use concentrations is considered minimal. Cases of sensitization, mostly in dermatitis patients, have been reported for many of the assessed terpene alcohols. Due to their sensitizing effects, 6,7-dihydrogeraniol, hydroabietyl alcohol and isopropyl-2-decahydronaphthalenol have been prohibited for use in fragrance materials. Restrictions exist for farnesol, geraniol, citronellol and rhodinol (3,7-dimethyl-7-octen-1-ol). Sclareol and linalool must comply with specific purity criteria if used as fragrance materials. No test results were available for some materials. 2(10)-Pinen-3-ol and 2,6-dimethyloct-3,5-dien-2-ol do not have structural alerts for topical effects (Ford et al., 2000). Based on structural elements that indicate a potential for sensitization, 3,7-dimethyl-4,6-octadien-3-ol, should be regarded as a potential sensitizer until tested. Based on the UV spectra and review of phototoxic/photoallergy data, terpene alcohols would not be expected to elicit phototoxicity or photoallergy under the current conditions of use as a fragrance ingredient.

AB - The materials assessed in this report have close structural relationships and similar biochemical and toxicity profiles. They generally participate in the same pathways of metabolic detoxication. The terpene alcohols are dermally absorbed, and a significant amount can be retained briefly within the epidermis, dermis, and subcutaneous tissue. Some have a penetration enhancing effect in vitro. Few data are available from which to characterize the oral bioavailability of the terpene alcohols. For the assessment of potential oral exposures, bioavailability is therefore assumed to be 100%. Based on the data reviewed, the terpene alcohols are expected to undergo extensive conjugation and metabolism by well-characterized pathways, primarily in the liver, to form more polar compounds that are excreted mainly in the urine and to a lesser extent in the feces. They form generally innocuous end products: primary alcohols are metabolized to corresponding aldehydes and acids, and ultimately to CO2, and secondary alcohols are conjugated with glucuronide and excreted. Unsaturated alcohols may undergo further oxidation at the point of unsaturation or be oxidized to the corresponding acid prior to conjugation and excretion in the urine. A few materials, however, may generate α,β-unsaturated metabolites or hydroperoxides. The acute dermal toxicity of the terpene alcohols is very low, with LD50 values in rabbits reported to be greater than 2000 mg/kg body weight. The acute oral toxicity is likewise low with LD50 values generally greater than 1000 mg/kg body weight. Dermal repeated dose toxicity studies have been conducted only with linalool and α-bisabolol and indicated, apart from local effects, a low magnitude of systemic toxicity with NOAELs of 250 and 200 mg/kg body weight/day, respectively. Slight effects on body weight and food consumption were observed at a dose level of 1000 mg/kg body weight/day. The liver and kidneys were the only target organs affected in oral repeated dose toxicity studies. The magnitude of systemic toxicity is considered to be low with NOAELs generally greater than 50 mg/kg body weight/day. Hence, it can be assumed that efficient detoxication mechanisms are in place to prevent significant toxicity. Terpene alcohols have been extensively tested in genotoxicity studies in vitro. Ames and other bacterial mutation data demonstrate no mutagenic activity of this group of compounds. A few positive results have been obtained in chromosome aberration studies in vitro, but these materials showed no evidence of genotoxicity in vivo. The relevance of the positive findings is, therefore, limited. Reproductive and developmental toxicity data are limited but give no indication of a relevant adverse effect on reproductive function or the developing organism. NOAELs for maternal and developmental toxicity are far in excess of current human exposure levels and raise no safety concern. At concentrations likely to be encountered by consumers, these chemicals are considered non-irritating to human skin. Their potential for eye irritation under the present maximum use concentrations is considered minimal. Cases of sensitization, mostly in dermatitis patients, have been reported for many of the assessed terpene alcohols. Due to their sensitizing effects, 6,7-dihydrogeraniol, hydroabietyl alcohol and isopropyl-2-decahydronaphthalenol have been prohibited for use in fragrance materials. Restrictions exist for farnesol, geraniol, citronellol and rhodinol (3,7-dimethyl-7-octen-1-ol). Sclareol and linalool must comply with specific purity criteria if used as fragrance materials. No test results were available for some materials. 2(10)-Pinen-3-ol and 2,6-dimethyloct-3,5-dien-2-ol do not have structural alerts for topical effects (Ford et al., 2000). Based on structural elements that indicate a potential for sensitization, 3,7-dimethyl-4,6-octadien-3-ol, should be regarded as a potential sensitizer until tested. Based on the UV spectra and review of phototoxic/photoallergy data, terpene alcohols would not be expected to elicit phototoxicity or photoallergy under the current conditions of use as a fragrance ingredient.

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