Studies of the Toxicological Potential of Capsinoids: IX. Teratology Studies of Dihydrocapsiate in Rats and Rabbits

Abstract

In order to determine the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS no. 205687-03-2), teratology studies were conducted in pregnant Sprague-Dawley rats (18 to 20 animals per group) and pregnant New Zealand white rabbits (20 to 21 animals per group). The test substance was administered by gavage for 11 days, from days 7 to 17 of gestation in rats, and for 13 days from days 6 to 18 of gestation in rabbits, at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. In the rat study, no deaths occurred in any group and there were no test substance–related changes or abnormalities in clinical signs, body weight, food consumption, or gross pathological findings. There were no test substance–related changes in the number of corpora lutea, number of implantations, index of implantations, index of embryofetal deaths, and number, sex ratio, or body weight of live fetuses at the end of the gestation period and there were no abnormalities in the placentae of live fetuses. There were no test substance–related abnormalities or variations in the external, skeletal, or visceral examinations of live fetuses. There were no abnormalities in ossification. En toto, it was concluded there were no teratogenic effects in the rat study. In the rabbit study, there were no test substance–related effects on clinical signs, body weight, food consumption, or necropsy findings in any group. There were neither test substance–related abortions nor test substance–related effects on the number of corpora lutea, number of implantations, or implantation index in any group. There were no test substance–related effects on the number of dead embryos/fetuses, the number, sex ratio, or body weight of live fetuses, or gross pathological finding of placentae. There were no test substance–related external abnormalities, or incidence of visceral or skeletal abnormalities or variations, and there were no test substance–related effects on the progress of ossification in any group. Based upon these data, the no observed adverse effect level (NOAEL) of dihydrocapsiate for general toxicity in dams, reproductive functions of dams, and embryofetal development was judged to be 1000 mg/kg/day both in rats and rabbits.

Keywords

Capsiate Capsinoids Dihydrocapsiate Teratogenicity

References

Akagi

, Sano

, Uehara

, Minami

, Otsuka

, and Izumi

1998. Non-carcinogenicity of capsaicinoids in B6C3F1 mice. Food Chem. Toxicol. 36: 1065–1067; 1069–1071.

Bernard

B. K.

, Watanabe

, Kodama

, Tsubuku

, Otabe

, Kalsumata

, Matsuoka

, and Masuyama

2008. Studies of the toxicological potential of capsinoids: IV. Teratology studies of CH-19 Sweet extract in rats and rabbits. Int. J. Toxicol. 27: this supplement.

Chanda

, Sharper

, Hoberman

, and Bley

2006. Developmental toxicity study of pure trans-capsaicin in rats and rabbits. Int. J. Toxicol. 25: 205–217.

Dawson

A. B.

1926. A note on staining of the skeleton of cleared specimens with alizarin red S. Stain Technol. 1: 123–124.

Dunnett

C. W.

1964. New tables for multiple comparisons with a control. Biometrics 20: 482–91.

Guidelines for Designation of Food Additives and for Revision of Standards for Use of Food Additives. Notification No. 29 of the Environmental Health Bureau, Ministry of Health and Welfare. Japan. March 22, 1996.

Hollander

, and Wolf

D. A.

1973. Nonparametric statistical methods. 120–123. New York: John Wiley and Sons.

Kobata

, Kawaguchi

, and Watanabe

2002. Enzymatic synthesis of a capsinoid by acylation of vanillyl alcohol with fatty acid derivatives catalyzed by lipase. Biosci, Biotechnol. Biochem. 66: 319–327.

Kobata

, Sutoh

, Todo

, Yazawa

, Iwai

, and Watanabe

1999. Nordihydrocapsiate, a new capsinoids from the fruits of nonpungent pepper. Capsicum annuum. J. Nat. Prod. 62: 335–336.

10.

Kobata

, Todo

, Yazawa

, Iwai

, and Watanabe

1998. Novel capsaicinoid-like substances, capsiate and dihydrocapsiate, from the fruits of a nonpungent cultivar, CH-19 sweet, of pepper (Capsicum annuum L.). J. Agric. Food Chem. 46: 1696–1697.

11.

Kodama

, Watanabe

, Masuyama

, Tsubuku

, Otabe

, Katsumata

, and Bernard

B. K.

2008a. Studies of the toxicological potential of capsinoids: III. A two-generation reproduction study of CH-19 Sweet extract in rats. Int. J. Toxicol. 27: this supplement.

12.

Kodama

, Watanabe

, Masuyama

, Tsubuku

, Otabe

, Mochizuki

, and Bernard

B. K.

2008b. Studies of the toxicological potential of capsinoids: II. A 26-week daily gavage dosing toxicity study of CH-19 Sweet extract in rats. Int. J. Toxicol. 27: this supplement.

13.

Kodama

, Watanabe

, Tsubuku

, Otabe

, Mochizuki

, Masuyama

, and Bernard

B. K.

2008c. Studies of the toxicological potential of capsinoids: VII. A 13-week toxicity study of dihydrocapsiate in rats. Int. J. Toxicol. 27: this supplement.

14.

Monsereenusorn

1983. Subchronic toxicity studies of capsaicin and capsicum in rats. Res. Commun. Chem. Pathol. Pharmacol. 41: 95–110.

15.

Nishimura

1974. Microdissection method for examination of anomalies in the thoracic viscera in mouse and rat fetuses. Congenital Anomalies 14: 23–40.

16.

OECD Guidelines for the Testing of Chemicals. Section 4: Health Effects Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Original Guideline, adopted 22nd March 1996).

17.

Sokal

R. R.

, and Rohlf

F. J.

1969. Bartlett's test of homogeneity of variances. In Biometry, 370–371, San Francisco: W. H. Freeman and Co.

18.

Watanabe

, Kodama

, Masuyama

, Tsubuku

, Otabe

, Mochizuki

, Nakajima

, Masumori

, and Bernard

B. K.

2008. Studies of the toxicological potential of capsinoids: I. Single-dose toxicity study and genotoxicity studies of CH-19 Sweet extract. Int. J. Toxicol. 27: this supplement.

19.

Wilson

J. G.

1965. Methods for administering agents and detecting malformation in experimental animals. In Teratology; principles and techniques, ed. Wilson

J. G.

, and Warkany

, 262–277. Chicago: University of Chicago Press.

20.

Yates

1934. Contingency table involving small numbers and the χ² test. J. R. Stat. Soc. (Suppl. 1): 217–235.

21.

Yazawa

, Yoneda

, Hosokawa

, Fushiki

, and Watanabe

2004. Novel capsaicinoid like substances in the fruits of new non-pungent cultivar CH-19 sweet of pepper (Capsicum annuum). Capsicum Eggplant Newslett. 23: 17–20.