Author: S.P. Bhatia, L. Jones, C.S. Letizia, A.M. Api
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
ABSTRACT
A toxicologic and dermatologic review of 1,3,3-trimethyl-2-norbornanyl acetate when used as a fragrance ingredient is presented.
Introduction
In 2007, a complete literature search was conducted on 1,3,3-trimethyl-2-norbornanyl acetate. On-line 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. 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 the Toxicologic and Dermatologic Assessment of Cyclic Acetates (Belsito et al., 2008) for an overall assessment of this material.
1. Identification (Fig. 1)
- Synonyms: Bicyclo[2.2.1]heptan-2-ol, 1,3,3-trimethyl-, acetate; 3,3-Dimethyl-8,9-dinorbornan-2-yl acetate; Fenchyl acetate; 1,3,3-Trimethylbicyclo[2.2.1]hept-2-yl acetate. 1.2 CAS Registry Number: 13851-11-1.
- CAS Registry Number: 13851-11-1.
- EINECS Number: 237-588-5.
- Formula: C12H20O2.
- Molecular weight: 196.29.
- FEMA: Flavor and Extract Manufacturers’ Association: Generally Recognized as Safe as a flavor ingredient – GRAS 6. (3390) (FEMA, 1973).
- Joint Expert Committee on Food Additives: The Joint FAO/WHO Expert Committee on Food Additives (JECFA No.1399) concluded that the substance does not present a safety concern at current levels of intake when used as a flavouring agent (JECFA, 2004).
2. Physical properties
- Physical description: Colorless, mobile liquid with a mild, sweet, fir needle oil-type odor.
- Log Kow (calculated): 3.86.
- Vapor pressure (calculated): 0.07 mm Hg at 20℃.
- Water solubility (calculated): 23.23 mg/l at 25℃.
- Specific gravity: 0.967.
| Type of cosmetic product | Grams applied | Applications per day | Retention factor | Mixture/product | Ingredient/mixturea (%) | Ingredient mg/kg/dayb |
|---|---|---|---|---|---|---|
| Anti-perspirant | 0.50 | 1.00 | 1.00 | 0.01 | 0.01 | 0.0000 |
| Bath products | 17.00 | 0.29 | 0.001 | 0.02 | 0.01 | 0.0000 |
| Body lotion | 8.00 | 0.71 | 1.00 | 0.004 | 0.01 | 0.0000 |
| Eau de toliette | 0.75 | 1.00 | 1.00 | 0.08 | 0.01 | 0.0001 |
| Face cream | 0.80 | 2.00 | 1.00 | 0.003 | 0.01 | 0.0000 |
| Fragrance cream | 5.00 | 0.29 | 1.00 | 0.04 | 0.01 | 0.0001 |
| Hair spray | 5.00 | 2.00 | 0.01 | 0.005 | 0.01 | 0.0000 |
| Shampoo | 8.00 | 1.00 | 0.01 | 0.005 | 0.01 | 0.0000 |
| Shower gel | 5.00 | 1.07 | 0.01 | 0.012 | 0.01 | 0.0000 |
| Toilet soap | 0.8 | 6.00 | 0.01 | 0.015 | 0.01 | 0.0000 |
| Total | 0.0003 | |||||
| a Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products. b Based on a 60 kg adult. | ||||||
| Route | Species | Animals/dose group | LD50 | References |
|---|---|---|---|---|
| Oral | Rat | 10 | ＞ 5 g/kg | IRIFM (1975a) |
| Dermal | Rabbit | 10 | ＞ 5 g/kg | IRIFM (1975a) |
3. Usage
1,3,3-Trimethyl-2-norbornanyl acetate 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 of 10–100 metric tonnes per annum.
The maximum skin level that results from the use of 1,3,3-trimethyl-2-norbornanyl acetate in formulae that go into fine fragrances has been reported to be 0.011% 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 been reported to be 0.01% (IFRA, 2007), which would result in a conservative calculated maximum daily exposure on the skin of 0.0003 mg/kg for high end users of these products (see Table 1).
4. Toxicology data
4.1 Acute toxicity
See Table 2.
Oral studies
- The acute oral LD50 was reported to exceed 5.0 g/kg. Ten rats received single oral doses of 5.0 g/kg test material each. Animals were observed for 14 days. Two animals died (2/10). No adverse clinical signs were observed (RIFM, 1975a).
Dermal studies
- The acute dermal LD50 in rabbits exceeded 5 g/kg based on no (0/10) deaths at that dose. Ten rabbits each received a single dermal application of neat test material. Animals were observed for 14 days. No clinical signs were observed (RIFM, 1975a).
- Acute dermal toxicity was evaluated during a skin absorption study. Two mice were each administered a single 4-hour dermal application of neat 1,3,3-trimethyl-2-norbornanyl acetate on the shaved abdominal skin. Observations were made after 4 hours. No deaths (0/2) or adverse clinical signs (Meyer and Meyer, 1959).
4.2 Skin Irritation
Human studies
- In a pre-test for a maximization study, a 48 h occluded patch test was conducted on 5 healthy volunteers. No irritation was produced by 1,3,3-trimethyl-2-norbornanyl acetate at 5% in petrolatum (RIFM, 1975b).
Animal studies
- Irritation was evaluated as a part of an acute dermal LD50 study conducted on 10 rabbits. A single 24 h occluded dermal application of neat (5 g/kg) test material produced moderate erythema (10/10) and slight (1/10) to moderate (7/10) edema, observed after patch removal (RIFM, 1975a).
4.3 Mucous membrane (eye) irritation
No data available on this material.
4.4 Skin sensitization
Human studies
- A human maximization (Kligman, 1966) study was carried out with 5% (3450 lg/cm2) 1,3,3-trimethyl-2-norbornanyl acetate in petrolatum on 25 (10 male:15 female) healthy volunteers. Application was under occlusion to the same site on the forearms of all subjects for five alternate-day 48-hour periods. Patch sites were pretreated for 24 h with 5% aqueous sodium lauryl sulfate (SLS) under occlusion. Following a 10 day rest period, challenge patches were applied under occlusion to fresh sites for 48 h. Challenge applications were preceded by 1-hour applications of 10% aqueous SLS under occlusion. Challenge sites were read on removal of the patch and 24 h thereafter. No sensitization reactions (0/25) were observed (RIFM, 1975b).
Animal studies
No data available on this material.
4.5 Phototoxicity and photoallergy
UV spectra revealed that 1,3,3-trimethyl-2-norbornanyl acetate peaked in the 200–220 nm range, with slight absorption in the 240 to 300 nm range.
4.6 Absorption, distribution and metabolism
In vivo animal studies
- Meyer and Meyer (1959) studied the skin absorption of 1,3,3-trimethyl-2-norbornanyl acetate in 5 male mice. An area of 2.2 cm2 on the shaved abdominal skin was used. Eserine (0.23%) was used as an indicator and the test material was used as a carrier for eserine. The latency period between application to the skin and the appearance of the eserine effect in the periodically stimulated masticatory muscles was used as a measure of the absorption rate. Absorption for 1,3,3-trimethyl-2-norbornanyl was 54 min.
4.7 Repeated dose toxicity
No data available on this material.
4.8 Reproductive and developmental toxicity
No data available on this material.
4.9 Mutagenicity and genotoxicity
No data available on this material.
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 the Toxicologic and Dermatologic Assessment of Cyclic Acetates (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
- Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.H., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H., 2008. A Toxicologic and Dermatologic Assessment of Cyclic Acetates When Used as Fragrance Ingredients. Food and Chemical Toxicology 46(12S), S1–S27.
- FEMA Flavor and Extract Manufacturers Association, 1973. Recent progress in the consideration of flavoring ingredients under the food additives amendment 4.GRAS substances. Food Technology 27 (1), 64–67.
- IFRA (International Fragrance Association), 2007. Use Level Survey, September 2007. Joint Expert Committee on Food Additives, 2004. Safety Evaluation Of Certain Food Additives. Who Food Additives Series: 54 Prepared by the Sixty-third Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). World Health Organization, Geneva 2004.
- Kligman, A.M., 1966. The identification of contact allergens by human. III. The maximization test. A procedure for screening and rating contact sensitizers. Journal of Investigative Dermatology 47, 393–409.
- Meyer, F., Meyer, E., 1959. Absorption of ethereal oils and substances contained in them through the skin. Arzneimittel-Forsch 9, 516–519.
- RIFM (Research Institute for Fragrance Materials, Inc.), 1975a. Acute Toxicity Studies on Rats, Rabbits and Guinea Pigs. RIFM Report Number 2020, May 22, RIFM, Woodcliff Lake, NJ, USA.
- RIFM (Research Institute for Fragrance Materials, Inc.), 1975b. Report on Human Maximization Studies. RIFM Report Number 1799, May 19, RIFM, Woodcliff Lake, NJ, USA.
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