Hexachlorophene

Hexachlorophene, also known as Nabac, is an organochlorine compound that was once widely used as a disinfectant. The compound occurs as a white odorless solid, although commercial samples can be off-white and possess a slightly phenolic odor. It is insoluble in water but dissolves in acetone, ethanol, diethyl ether, and chloroform. In medicine, hexachlorophene is useful as a topical anti-infective, anti-bacterial agent, often used in soaps and toothpaste. It is also used in agriculture as a soil fungicide, plant bactericide, and acaricide.[1]

Hexachlorophene

Clinical data
Trade names	pHisoHex, Gamophen, Septisol, Turgex, Germa-Medica, Hexachlorophane, Almederm
ATC code	D08AE01 (WHO) QP52AG02 (WHO)
Legal status
Legal status	US: ℞-only for human use Rx-only for human use
Identifiers
IUPAC name 2,2'-methylenebis(3,4,6-trichlorophenol)-3,4,6-trichloro-2-[(2,3,5-trichloro-6-hydroxyphenyl)methyl]phenol
CAS Number	70-30-4
PubChem CID	3598
DrugBank	DB00756
ChemSpider	3472
UNII	IWW5FV6NK2
KEGG	D00859
ChEBI	CHEBI:5693
ChEMBL	ChEMBL496
CompTox Dashboard (EPA)	DTXSID6020690
ECHA InfoCard	100.000.667
Chemical and physical data
Formula	C13H6Cl6O2
Molar mass	406.89 g·mol^−1
3D model (JSmol)	Interactive image
Density	1.71 g/cm^3
Melting point	163 to 165 °C (325 to 329 °F)
Boiling point	471 °C (880 °F)
SMILES C1=C(C(=C(C(=C1Cl)Cl)CC2=C(C(=CC(=C2Cl)Cl)Cl)O)O)Cl
InChI InChI=1S/C13H6Cl6O2/c14-6-2-8(16)12(20)4(10(6)18)1-5-11(19)7(15)3-9(17)13(5)21/h2-3,20-21H,1H2 Key:ACGUYXCXAPNIKK-UHFFFAOYSA-N

Removal from market

French deaths

In 1972, the "Bébé" brand of baby powder in France killed 39 babies. It also did great damage to the central nervous systems of several hundred other babies. The batch of toxic "Bébé" brand of powder was manufactured with 6% hexachlorophene. This industrial accident directly led to the removal of hexachlorophene from consumer products across the world.[2][3]

United States

In 1972, the U.S. Food and Drug Administration (FDA) halted the production and distribution of products containing more than 1% of hexachlorophene.[4] After that point, most products that contain hexachlorophene were available only with a doctor's prescription.[5] The restrictions were enacted after 15 deaths in the United States and 39 deaths in France were reported following brain damage caused by hexachlorophene.[6]

Several companies manufactured over-the-counter preparations which utilised hexachlorophene in their formulations. One product, Baby Magic Bath by The Mennen Company, was recalled in 1971, and removed from retail distribution.

Two commercial preparations using hexachlorophene, pHisoDerm and pHisoHex, were widely used as antibacterial skin cleansers in the treatment of acne, (with pHisoDerm developed for those allergic to the active ingredients in pHisoHex). During the 1960s, both were available over the counter in the US. After the ban, pHisoDerm was reformulated without hexachlorophene, and continued to be sold over-the-counter, while pHisoHex, (which contained 3% hexachlorophene - 3 times the legal limit imposed in 1972),[6] became available as a prescription body wash. In the European Community countries during the 1970s and 1980s, pHisoHex remained available over the counter. A related product, pHisoAc, was used as a skin mask to dry and peel away acne lesions whilst pHiso-Scrub, a hexachlorophene-impregnated sponge for scrubbing, has since been discontinued. Several substitute products (including triclosan) were developed, but none had the germ-killing capability of hexachlorophene. (Sanofi-Aventis was the sole manufacturer of pHisoHex, while The Mentholatum Company owns the pHisoDerm brand today. Sanofi-Aventis discontinued production of several forms of pHisoHex in August 2009 and discontinued all production of pHisoHex in September 2013).[7]

The formula for Dial soap was modified to remove hexachlorophene after the FDA put an end to over-the-counter availability in 1972.[5]

Bristol-Myers' discontinued Ipana toothpaste brand at one time contained hexachlorophene. [8]

Another company involved in the production of products with hexachlorophene was cosmetic company, J.R. Watkins Company of Winona, Minnesota. They had previously produced "Watkins Cologne for Men".

Germany

In Germany, cosmetics containing hexachlorophene have been forbidden since 1985.

Austria

In Austria, sale of drugs containing the substance has been forbidden since 1990.[9]

Production

Hexacholorophene is produced by alkylation of 2,4,5-trichlorophenol with formaldehyde. Related antiseptics are prepared similarly, e.g., bromochlorophene and dichlorophene.[1]

Safety

The LD50 (oral, rat) is 59 mg/kg, indicating that the compound is relatively toxic. It is not mutagenic nor teratogenic according to Ullmann's Encyclopedia,[1] but "embryotoxic and produces some teratogenic effects" according to the International Agency for Research on Cancer.[10] 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) is always a contaminant in this compound's production. Several accidents releasing many kilograms of TCDD have been reported. The reaction between 2,4,5-trichlorophenol and formaldehyde is exothermic. If the reaction occurs without adequate cooling, TCDD is produced in significant quantities as a byproduct and contaminant. The Seveso disaster and the Times Beach, Missouri contamination incident exemplify the industrial hazards of hexachlorophene production.

Trade names

Trade names for hexachlorophene include: Acigena, Almederm, AT7, AT17, Bilevon, Exofene, Fostril, Gamophen, G-11, Germa-Medica, Hexosan, K-34, Septisol, Surofene, M3.[11][12]

References

1. Fiege H, Voges HM, Hamamoto T, Umemura S, Iwata T, Miki H, et al. (2000). "Phenol Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a19_313. ISBN 3-527-30673-0.
2. "Talcum Suspected in Deaths of 21 French Babies" (29 August 1972). New York Times. p. 10. Retrieved 18 March 2020.
3. "FDA CURBS USE OF GERMICIDE TIED TO INFANT DESTHS" (23 September 1972). New York Times. p. 1. Retrieved 18 March 2020.
4. Germicide Limit Stirs Confusion, New York Times, September 24, 1972, pg. 53.
5. The Milwaukee Sentinel: "US Order Curbs Hexachlorophene" (UPI), September 23, 1972. From Google News.
6. Ocala Star Banner, "15 Deaths Cited In Use of Germ Killer, Hexachlorophene" (AP), March 21, 1973. From Google News.
7. "Drug Shortages". American Society of Health-System Pharmacists. Archived from the original on 10 September 2014.
8. "1959 Ipana Toothpaste Ad". YouTube.
9. Rechtsinformationssystem des österreichischen Bundeskanzleramtes (in German)
10. "Hexachlorophene". International Agency for Research on Cancer (IARC) - Summaries & Evaluations. IPCS Inchem. 20: 241. 1998 [1979].
11. "Hexachlorophene". PharmGKB. Retrieved 2012-12-28.
12. Dept. of Health, Education, and Welfare (1972). "Consumer news". Office of Consumer Affairs. 2 (21): 10.CS1 maint: multiple names: authors list (link)