Technology  Review Series

Triclosan and Its Impurities

By: J. Menoutis, Ph.D., F.A.I.C., C.P.C. and A. I. Parisi

Copyright (c) 1998-2006 Quantex Laboratories. All rights reserved

Triclosan  is a broad-spectrum antibacterial/anti-microbial agent. It is manufactured by Ciba Specialty Chemicals, under their trade names Irgasan or Irgacare, and by several other manufacturers outside of the U.S.. As a result of its bacteriostatic activity against a wide range of both gram-negative and gram-positive bacteria it has found increasing and recent popular use in personal care products, i.e.- toothpaste, deodorant soaps, deodorants, antiperspirants and body washes, detergents, dish washing liquids, cosmetics and anti-microbial creams, lotions and hand soaps. It is also used as an additive in plastics, polymers and textiles to give these materials antibacterial properties. 

Triclosan is a diphenyl ether (bis-phenyl) derivative, known as either 2,4,4'-Trichloro-2'-hydroxy diphenyl ether or 5-Chloro-2-(2,4-dichlorophenoxy) phenol.  It is related in structure to a number of bis-phenyl  polychlorinated and bis-phenyl chlorophenol compounds. Due principally to the synthesis chemistry of polychloro diphenyl ethers and phenoxy phenols there is the potential for the formation of small amounts of unwanted trace by-products which are of concern. Beginning in  the early 1970's  and into the mid 1980's  research revealed that phenoxy herbicides such as 2,4-D and 2,4,5-T (1,2,3), the major components of Agent Orange, the bactericide Hexachlorophene (4,5), various chlorophenols, i.e.- pentatchlorophenol, used in wood treatment (6), certain polychloro phenoxy phenols (7) and polychloro diphenyl ethers (8) and diphenyl ether herbicides (9) contained various low levels of  polychlorinated dioxins and polychlorinated furans

Consequently, since triclosan  is by its chemical structure a polychloro phenoxy phenol it is possible that several polychlorodibenzo-p-dioxins (dioxins) polychloro-dibenzofurans (dibenzofurans) can be found in varying low level amounts, as synthesis impurities in triclosan. Their presence or absences is dependent upon the type and  purity of the starting materials used to synthesize triclosan as well as reaction conditions such as temperature, pressure and the like.  If present, their relative concentrations as impurities can vary from batch to batch. This raises concerns because of the toxicity of dioxins and dibenzofurans.

The toxicity of dioxins and dibenzofurans varies with the position and number of chlorine atoms attached to the aromatic rings. In general, their toxicity increases with increasing chlorine substitution. Those dioxins and dibenzofurans that have chlorine atoms at the 2,3 and 7 positions are particularly toxic. Tetrachlorodibenzo-p-dioxin and tetrachlorodibenzo-furan, which have chlorine atoms at the 2,3,7, and 8 positions, are considered the most toxic of the dioxins and dibenzofurans (4), with 2,3,7,8-tetrachlorodibenzo-p-dioxin referred to as one of the most toxic substances known

As a result of the potential for the formation of dioxins and dibenzofurans as unwanted low level trace by-products the USP, in Pharmacopeial Form, Volume 22, Number 3, Pharmacopeial Reviews and subsequently in Pharmacopeial Form, Volume 23, Number 5, In-Process Revision,  proposed  a new monograph for the specific testing of triclosan. The monograph for Triclosn was officially issued in USP24. It details the assay and testing of USP triclosan. In addition to setting product specification standards and procedures to assay the purity and physical identity of USP triclosan, it also defines the limits and methods of testing for unwanted trace by-products which may be present. The tests for these unwanted by-products are (1) Limit of  Monochlorophenol and 2,4-Dichlorophenol, (2) Limit of 1,3,7-trichlorodibenzo-p-dioxin, 2,8-dichlorodibenzo-p-dioxin, 2,8-Dichlorodibenzofuran, and 2,4,8-Trichlorodibenzofuran, and (3) Limit of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,3,7,8-Tertrachlorodibenzofuran

Quantex Laboratories is currently the only contract analytical laboratories in the U.S. capable of analyzing triclosan for dioxins and dibenzofurans employing isotope dilution high resolution gas chromatography/mass spectrometry (HRGC/MS), as required by the USP monograph. For those requiring the testing and certification of triclosan as meeting the proposed USP limits for unwanted trace by-products Quantex Laboratories can perform the three limit tests (1) Limit of  Monochlorophenol and 2,4-Dichlorophenol, (2) Limit of 1,3,7-trichloro-dibenzo-p-dioxin,  2,8-dichlorodibenzo-p-dioxin, 2,8-Dichlorodibenzofuran, and 2,4,8-Trichlorodibenzofuran, and (3) Limit of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,3,7,8-tertrachlorodibenzofuran. We can also provide the complete testing and assay of triclosan as required by the USP, for those requiring the certification of triclosan to USP, which includes the three limit tests, the assay of triclosan for purity, the testing for heavy metals, physical identification and residue on ignition. All analytical testing is conducted in conformance to cGMP (Good Manufacturing Practices).

References

Gribble, G. W., Chemistry, Vol. 47, No. 2,  15-18.
 USEPA, Health Assessment Document for Polychlorodibenzo-p-dioxins,  EPA-600/8-84-014A.
 Courtney, K.D., Moore,J.A., Toxicology and Applied Pharmacology, Vol. 20, 396.
Menoutis, J., A Current Overview of the Occurrence, Toxicity and Disposal of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 11/84, internal Givaudan research monogram.
Kulkarni, S., V., Kowalski, J., A., Waste Streams From Hexachlorophene Manufacturing  Processes, Final Draft, USEPA, March 1984.
Rappe, C., Bauser, H., R.,Bassharrdt, H., P., Annuls of the New York Academy of    Science, 1979, No. 1, 320.

 Nilsson, C., A., Anderson, K., Rappe, C., et. al., Journal of Chromatography, Vol.    96, 137-147.
 Norstrom, A., Anderson, K., Rappe, C., Chemosphere, Vol. 1 (1976), 21-24.
Yamagiaki, T., Miyazaki, T., Akilyana, K., et. al., Chemosphere, Vol. 10 ( 1981),    1137.
 USP, Pharmacopeial Form, Volume 22, Number 3, Pharmacopeial Reviews,    2287-2291.
 USP, Pharmacopeial Form, Volume 23, Number 5, In-Process Revision, 4827-4831.

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