Fragrance raw materials monographs 659

Synonym: n-Butylidene phthalide. Structure :

BUTYLIDENE PHTHALIDE

CH • [ C H 2 ] 2 C H 3

o

Description and physical properties: A yellow liquid. Occurrence: Reported to occur in celery and lovage (CIVO-TNO, 1977). Preparation: From sodium valerate, valeric anhydride and phthalic anhydride. Uses: In public use since the 1950s. Use in fragrances in the USA amounts to less than 1000 lb/yr.

Concentrat ion in final product (%):

Soap Detergent Creams, lotions Perfume Usual 0.003 0.0003 0.0015 0.04 Maximum 0.03 0.003 0.01 0.2

Analytical data: Gas chromatogram, R I F M no. 79-29; infra-red curve, R I F M no. 79-29.

Status

Butylidene phthalide was given G R A S status by F E M A (1973) and was included by the Council of Europe (1981) in the list of flavouring substances that have not been fully evaluated. CAS Registry No. 551-08 6.

Biological data*

Acute toxicity. The oral LDs0 value in rats has been reported by Moreno (1980) as 1.85 g/kg (1.37 2.50 g/kg) and in an unpublished report (Posternak, 1965), the oral LDs0 in female rats was reported as 2.42 g/kg. The acute dermal LDs0 value in rabbits has been reported to exceed 5 g/kg (Moreno, 1980).

Irritation. Butylidene phthalide applied full strength to intact or abraded rabbit skin for 24 hr under occlusion was slightly irritating (Moreno, 1980). Tested at 2% in petrolatum, it produced no irritation after a 48-hr closed-patch test on human subjects (Epstein, 1979).

Sensitization. A maximization test (Kligman, 1966; Kligman & Epstein, 1975) was carried out on 29 volunteers, The material (R IFM no. 79-29) was tested at a concentration of 2% in petrolatum and produced no sensitization reactions (Epstein, 1979).

References

CIVO TNO (1977). Volatile Compounds in Food. 4th Ed. Edited by S. Van Straten. Centraal Instituut Voor Voedingsonderzoek TNO, Zeist, The Netherlands.

Council of Europe (1981). Flavouring substances not fully evaluated. No. 10083, p. 10. P-SG (81) 26. July 1981, Strasbourg.

Epstein W. L. (1979). Report to RIFM, 31 August. Flavoring Extract Manufacturers' Association (1973). Survey of flavoring ingredient usage levels. No. 3333. Fd

Technol., Champaign 27 (1), 64. Kligman A. M. (1966). The identification of contact allergens by human assay. III. The maximization test. A

procedure for screening and rating contact sensitizers. J. invest. Derm. 47, 393. Kligman A. M. & Epstein W. (1975). Updating the maximization test for identifying contact allergens. Contact

Dermatitis 1~ 231. Moreno O. M. (1980). Report to RIFM, 11 February. Posternak J. M. (1965). Acute toxicity of the flavoring substance TT-135 (butylidene phthalide). Unpublished

report; cited in Flavor and Extract Manufacturers' Association (1978).

Additional references

Flavor and Extract Manufacturers' Association (1978). Scientific literature review of fused ring aromatic lactones in flavor usage. Food and Drug Administration Report FDA/BF-78/117, Vol. l, pp. 70. National Technical Information Service Report No. PB-283 502.

Pharmacodynamics f

Ko W.-C. (1980). A newly isolated antispasmodic--butylidenephthalide. Jap. J. Pharmac. 30, 85; cited from Chem. Abstr. 1980, 92, 208863.

*Literature searched from 1962 through 1981. tArrangement is based on section headings from Chemical Abstracts.

660 D. L. J. OPDYKE and C. LETIZIA

Ko W., Lin S., Yeh C. & Wang Y. (1977). Alkylphthalides isolated from Ligusticum wallichii Franch and their in vitro inhibitory effect on rat uterine contraction induced by prostaglandin F2alpha. T'ai-wan 1 Hsueh Hui Tsa Chih 76, 669; cited from Chem. Abstr. 1978, 88, 130721.

Occurrence

Fehr D. (1979). Study on the aroma substances of celery (Apium graveolens L.). Part I. Pharmazie 34, 658; cited from Chem. Abstr. 1980, 92, 213657.

Fehr D. (1980). Essential oil of Levisticum officinale. I. Studies on essential oil from fruit, leaves, stems and roots. Planta reed. 1980 (Suppl.), 34; cited from Chem. Abstr. 1981, 94, 127131.

Fehr D. (1981). Study on the aroma substances of celery (Apium graveolens L.). Part 2. Pharmazie 36, 374; cited from Chem. Abstr. 1981, 95, 120964.

Gijbels M. J. M., Schefl'er J. J. C. & Svendsen A. B. (1980). 2-Butylidenephthalide in the essential oil from roots of Levisticum officinale. Planta med. 1980 (Suppl.), 41; cited from Chem. Abstr. 1981, 94, 127132.

Ko W. C., Wang Y. T. & Lin L. C. (1978). Phytochemical studies on spasmolytic constituents of Ligusticum walliehii Franch. Hua Hsueh 1978 (3), 74; cited from Chem. Abstr. 1980, 92, 37764.

Lin M., Zhu C.-D., Sun Q.-M. & Fang Q.-C. (1979). Studies on the chemical constituents of Angelica sinensis. Yao Hsueh Hsueh Pao 14, 529; cited from Chem. Abstr. 1980, 92, 177412.

Mitsuhashi H., Muramatsu T., Nagai U., Nakano T. & Ueno K. (1963). Constituents of Umbelliferae. VIII. Distribution of alkylphthalides in Umbelliferae. Chem. pharm. Bull., Tokyo 11, 1317; cited from Chem. Abstr. 1964, 60, 11044.

Mitsuhashi H., Nagai U. & Saito T. (1968). Constituents of umbelliferous plants. XIV. Constituents of Conioselinum kamtschatieum. Revta Fac. Farm. Bioquim. Univ. S Paulo 6, 237; cited from Chem. Abstr. 1969, 71, 88456.

Stahl E. & Bohrmann H. (1967). Phthalides, chief constituents of the essential oil of Meum athamanticum fruits. Naturwissenschaften 54, 118; cited from Chem. Abstr. 1967, 67, 5641.

Yamagishi T. & Kaneshima H. (1977). Constituents of Onidium officinale Makino. Structure of senkyunolide and gas chromatography-mass spectrometry of the related phthalides. Yakugakuzasshi 97, 237; cited from Chem. Abstr. 1977, 87, 44123.

Yamagishi T., Kaneshima H., Kinoshita Y. & Honma S. (1975). The standardization of crude drugs produced in Hokkaido. VII. The ether soluble components of Angelica radix (Touki). Hokkaidoritsu Eisei Kenkyusho Ho 25, 20; cited from Chem. Abstr. 1976, 84, 132662.

Yamagishi T., Kaneshima H., Kinoshita Y. & Mori M. (1974). Standardization of crude drugs produced in Hokkaido. 5. Existence of ligustilide in Angelicae radix. Hokkaidoritsu Eisei Kenkyusho Ho 24, 47; cited from Chem. Abstr. 1975, 83, 84751.