August 27, 2003

Dockets Management Branch

Food and Drug Administration (HFA-305)

5630 Fishers Lane, Room 1061

Rockville, MD 20852

> **Re: Proposed Rule; Reopening of the Administrative Record for
> Topical Antimicrobial Drug Products for Over-the-Counter Human Use;
> Health-Care Antiseptic Drug Products. 68 Fed. Reg. 32003. (May 29,
> 2003). \[Docket No. 75N-183H\]**

Dear Sir/Madam:

GOJO Industries, Inc. hereby submits these comments in response to the
Food and Drug Administration's (FDA's) reopening of the administrative
record regarding the tentative final monograph for Over-the-Counter
(OTC) Health-Care Antiseptic Drug Products, 59 Fed. Reg. 31402 (June 17,
1994) (1994 TFM). **These comments address the safety and efficacy of
benzalkonium chloride and benzethonium chloride as active antimicrobial
agents in leave-on products (products used without water and that are
not rinsed off the skin).**

**SUMMARY:**

The anticipated finalization of the 1994 TFM will be accompanied by a
review of the safety and efficacy of the quaternary ammonium compounds
(quats), benzalkonium chloride and benzethonium chloride. These active
ingredients are listed as Category III drugs (available data are
insufficient to classify as safe and effective, and further testing is
required) in the 1994 TFM. We submit that benzalkonium chloride and
benzethonium chloride lack sufficient data to be classified as safe and
effective when specifically used in leave-on (no rinse) products
according to the 1994 TFM.

We assert that:

-   **Insufficient scientific evidence exists to approve either**
    **benzalkonium chloride or** **benzethonium chloride as Category I
    active ingredients** **for use in leave-on (non** **rinse)**
    **products** **in the 1994** **TFM** **hand** **antiseptic
    categories.**

-   **FDA should limit the use of benzalkonium chloride and benzethonium
    chloride for hand** **antiseptic use to only** **those** **products
    that are rinsed off the skin** **until such time as** **an extensive
    body of long term scientific evidence exists to demonstrate safety
    and effectiveness in non rinse,** **leave-on products.**

The potential for development of bacterial resistance, sensitization,
irritation and other untoward effects due to the use of benzalkonium
chloride and benzethonium chloride in leave-on products has been
insufficiently addressed. The cumulative safety of these actives for
leave-on antiseptic products requires additional scrutiny due to a use
pattern that allows unlimited daily use for the lifetime of a user at
home, at work and in the health care setting. An important point of
reference is topical First Aid products. A survey conducted by Voss and
Widmer (1997) suggested that nurses should wash 200 to 300 times per
week. Based upon this use frequency, we estimate that nurses using quat
containing, no rinse products would be exposed to 100 to 600 grams of
quat per week, whereas a first aid antiseptic user would be exposed to
approximately 10 to 40 grams of quat per week. In addition, leave-on
products may expose the user to a higher initial concentration of the
active and for an extended time. Finally, the potential for unchecked
use and proliferation of these actives in leave-on products in the
consumer market (as is already occurring) further multiplies the
potential safety risks. The cumulative exposure to these actives across
all applications and use patterns requires in-depth consideration by
FDA.

#### BACKGROUND:

FDA has previously recognized limitations for the use of benzalkonium
chloride and benzethonium chloride. Although quats have been briefly
mentioned in several proposed monographs, the use of benzalkonium
chloride and benzethonium chloride has not been granted Category I
(generally recognized as safe and effective) status in any final OTC
rule. Both have been proposed for Category I status in the tentative
First Aid Antiseptic Monograph (FR 56(140):33644-33680, July 22, 1991)
(1991 TFM). However, FDA mandated critical limits on the duration of use
(i.e. 7 days), the frequency of use (e.g. one to three times per day),
and the size of the treatment area (i.e. small cuts and scrapes). These
limitations are not required by the 1994 TFM. The use range of 0.1% to
0.13% benzalkonium chloride and 0.1% to 0.2% benzethonium chloride has
been drawn from this 1991 TFM, although the 1994 TFM does not clearly
specify a range. Due to the aforementioned controlled use of quats in
First Aid products, FDA should not rely upon the historical experience
of First Aid products, as it clearly does not adequately simulate the
dose or usage patterns of the 1994 TFM. This approved use pattern
represents but a fraction of the exposure that could come from
unrestricted, repeated daily use of a quat-based leave-on antiseptic.

FDA has previously recognized the paucity of data on file for
benzalkonium chloride and benzethonium chloride, and in fact, recently
requested additional absorption and systemic toxicity data in rodent and
non-rodent species, skin wound repair comparison, contact dermatitis,
and skin sensitization studies. Furthermore, there are insufficient data
in the public domain to support the use of these actives in an
unlimited, high-frequency use pattern which involves a direct leave-on
application. .

**IRRITATION / SENSITIZATION:**

The attached references reveal the potential for irritation,
sensitization and allergic response resulting from the use of
benzalkonium chloride and other quaternary ammonium chlorides. A
five-year study of healthcare workers showed a significant difference in
dermatitis resulting from exposure to benzalkonium chloride compared to
non-healthcare workers (p=0.046) (Shaffer et al. 2000). In addition,
quaternary ammonium chlorides have demonstrated potential for inhibition
of wound healing and tissue injury when used as antiseptics (Branemark,
1966, 1967). Prolonged exposure to these actives due to direct
"leave-on" application may increase exposure, and thus health effects,
as much as ten-fold.

The 2002 Cosmetic Ingredient Review (CIR) Compendium considers
benzalkonium chloride "cosmetic" formulations above 0.1% to be unsafe;
thus the 1994 TFM formulation ranges are inconsistent with more recent
national safety guidelines. Although less safety and efficacy
information exists for benzethonium chloride, the 2002 CIR Compendium
lists benzethonium chloride formulations as safe for use in cosmetics at
or below 0.5%. Based upon the CIR, benzethonium chloride formulations
above 0.5% would not be safe for use on human skin. However, the
Cosmetic Ingredient Review has listed the benzethonium chloride group as
requiring re-evaluation due to the age of the submitted studies (early
1980s). As the CIR review was based upon the application of cosmetics,
1994 TFM use patterns would most likely necessitate further reductions
in the CIR cut-off values. **Benzalkonium chloride and benzethonium
chloride have not been proven safe and effective for use in leave-on
products under the extensive use scenario covered by the 1994 TFM.
Current 1994 TFM concentration ranges for benzalkonium chloride are
[unsafe]{.underline} according to the 2002 CIR Compendium.**

**ANTIMICROBIAL EFFECTIVENESS:**

The efficacy of quaternary ammonium compounds may be severely
compromised during formulation and use. Benzalkonium chloride and
benzethonium chloride may be neutralized by anionic or nonionic
surfactants, hard water, proteins and other moieties. Special expertise
is required when formulating to avoid neutralization of these active
ingredients and to carefully balance the need for fast, broad spectrum
antimicrobial activity with low irritation. Little published data exist
to demonstrate the effectiveness, according to 1994 TFM testing
standards, of leave-on formulations based on benzalkonium and
benzethonium chloride across the proposed concentration range. **Thus,
we conclude that benzalkonium and benzethonium chloride have not been
proven to be generally recognized as effective for use** **in**
**leave-on products in the future monograph.**

**MICROBIAL SKIN FLORA**

Published scientific studies have identified concerns for the selection
and proliferation of quat-resistant bacteria and accompanying antibiotic
cross-resistance (Adair, 1969, 1971; Gilbert, 2003; Joynson, 2002;
Loughlin, 2002). Although these studies are mainly laboratory
evaluations, many key thought leaders have begun to express concern over
these findings. A.D. Russell, the lead academician in this field, stated
as early as 1998, "Extensive use of cationic biocides \[benzalkonium
chloride and benzethonium chloride\] could lead to the selection of
staphylococcal strains showing resistance to both antibiotics and
biocides..." (Russell, 1998). No studies have been published to date
exploring the short or long term impact of the use of benzalkonium
chloride and benzethonium chloride on the ecology of the skin flora and
the resistance profiles of its members. Horn's and Larson's elucidations
of the changes in the ecology of the skin flora of healthcare workers
further emphasize the concern that increased use of benzalkonium
chloride and benzethonium chloride may contribute to a shift in resident
skin flora, specifically selecting for Gram negative strains due to the
unique innate resistance of these strains to quat compounds or
biocide/antibiotic resistant *Staphylococci* (Horn, 1988; Larson, 1998).
**Benzalkonium and benzethonium chloride should not be approved as
Category I active ingredients for unlimited, high-frequency use in
leave-on products until further investigation elucidates their potential
to alter the ecology as well as** **the biocide and antibiotic
resistance profiles of human skin flora.**

**In summary,** **FDA should not approve benzalkonium chloride and
benzethonium chloride** **as** **Category I active ingredients for use
in** **leave-on products in the future antiseptic monograph**.
Benzalkonium and benzethonium chloride have not been proven safe and
effective for use in leave-on products. FDA should limit the use of
benzalkonium and benzethonium chloride for antiseptic use to rinse-off
products until an extensive body of long term scientific evidence exists
to demonstrate safety and effectiveness for leave-on products.

> Respectfully Submitted,
>
> GOJO INDUSTRIES, INC.
>
> Michael J. Dolan
>
> Research and Development Vice President

**REFERENCES**

2002 CIR Compendium. Cosmetic Ingredient Review. 2002; Washington, D.C.

Adair FW, Geftic SG, Gelzer J. Resistance of *Pseudomonas* to Quaternary
Ammonium Compounds: I. Growth in Benzalkonium Chloride Solution. Applied
Microbiology. 1969; 18: 299-302.

Adair FW, Geftic SG, Gelzer J. Resistance of *Pseudomonas* to Quaternary
Ammonium Compounds: II. Cross-Resistance Characteristics of a Mutant of
*Pseudomonas aeruginosa*. Applied Microbiology. 1971; 21: 1058-1063.

Aetna InteliHealth. Skin and Chemical Allergies. Available at
<http://www.intelihealth.com/IH/ihtIH/WSIHW000/7945/8215/20816.html?d=dmtJHE>.
Accessed July 14, 2003.

Branemark P-I, Albrektsson B, Lindstrom J, Lundborg G. Local Tissue
Effects of Wound Disinfectants. Acta Chir Scand Suppl. 1966; 357:
166-76.

Branemark P-I, Ekholm R, Albrektson B, Lindstrom J, Lundborg G, Lundskog
J. Tissue Injury Caused by Wound Disinfectants. The Journal of Bone and
Joint Surgery. 1967; 49: 48-62.

Burdon DW, Whitby JL. Contamination of Hospital Disinfectants with
*Pseudomonas* Species. Brit. Med. J. 1967; 2: 153-155.

Cosmetic Ingredient Review. Ingredient Review Priorities. Available at
<http://www.cir-safety.org/priorities.shtml>. Accessed August 20, 2003.

The Cosmetic, Toiletry, and Fragrance Association. Compilation of Safety
Data and Activities of Active Ingredient Suppliers. 2001.

De Groot AC, Conemans J, Liem DH. Contact allergy to benzoxonium
chloride (Bradophen®). Contact Dermatitis. 1984; 11: 324-325.

Díaz-Ramón L, Aguirre A, Ratón-Nieto JA, de Miguel M. Contact dermatitis
from benzoxonium chloride. Contact Dermatitis. 1999; 41: 53-54.

Fisher AA, Stillman MA. Allergic Contact Sensitivity to Benzalkonium
Chloride. Arch Derm. 1972; 106: 169-171.

The Food and Drug Administration. Topical Antimicrobial Drug Products
for Over-the-Counter Human Use; Tentative Final Monograph for First Aid
Antiseptic Drug Products; Notice of Proposed Rulemaking. Federal
Register. July 22, 1991. 56(140):33644-33680.

The Food and Drug Administration. Topical Antimicrobial Drug Products
for Over-the-Counter Human Use; Tentative Final Monograph for
Health-Care Antiseptic Drug Products; Notice of Proposed Rulemaking.
Federal Register. June 17, 1994. 59(116):31402-31452.

Fraki JE, Kalimo K, Tuohimaa P, Aantaa E. Contact Allergy to Various
Components of Topical Preparations for Treatment of External Otitis.
Acta Otolaryngol (Stockh). 1985; 100: 414-418.

Gilbert P, McBain AJ. Potential Impact of Increased Use of Biocides in
Consumer Products on Prevalence of Antibiotic Resistance. Clinical
Microbiology Reviews. 2003; 16: 189-208.

Henderson ND. A Review of the Environmental Impact and Toxic Effects of
DDAC. June, 1992.

Horn WA, Larson EL, McGinley KJ, Leyden JJ. Microbial Flora on the Hands
of Health Care Personnel: Differences in Composition and Antibacterial
Resistance. Infection Control and Hospital Epidemiology. 1988; 9:
189-193.

Huriez C, Agache P, Martin P, Vandamme G, Mennecier J. L'Allergie Aux
Sels D'Ammonium Quaternaire. Sem Hop. 1965; 41: 2301-2304.

Huriez C, Agache P, Martin P, Vandamme G, Mennecier J. Un Groupe
D'Allergènes Chimiques Fréquemment en Cause: Les Sels D'ammonium
Quaternaire. Rev Fr Allergol. 1965; 5: 134-142.

Jones MV, Herd TM, Christie HJ. Resistance of *Pseudomonas aeruginosa*
to amphoteric and quaternary ammonium biocides. Microbios. 1989; 58:
49-61.

Joynson JA, Forbes B, Lambert RJW. Adaptive resistance to benzalkonium
chloride, amikacin and tobramycin: the effect on susceptibility to other
antimicrobials. Journal of Applied Microbiology. 2002; 93: 96-107.

Kaslow RA, Mackel DC, Mallison GF. Nosocomial Pseudobacteremia: Positive
Blood Cultures Due to Contaminated Benzalkonium Antiseptic. JAMA. 1976;
236: 2407-2409.

Kanerva L, Jolanki R, Estlander T. Occupational allergic contact
dermatitis from benzalkonium chloride. Contact Dermatitis. 2000; 42:
357-358.

Larson EL, Norton Hughes CA, Pyrek JD, Sparks SM, Cagatay EU, Bartkus
JM. Changes in bacterial flora associated with skin damage on hands of
health care personnel. American Journal of Infection Control. 1998; 26:
513-521.

Lee JC, Fialkow PJ. Benzalkonium Chloride -- Source of Hospital
Infection with Gram-Negative Bacteria. JAMA. 1961; 177: 144-146.

Lee JY-Y, Wang B-J. Contact dermatitis caused by cetrimide in
antiseptics. Contact Dermatitis. 1995; 33: 168-171.

Loughlin MF, Jones MV, Lambert PA. *Pseudomonas aeruginosa* cells
adapted to benzalkonium chloride show resistance to other
membrane-active agents but not to clinically relevant antibiotics.
Journal of Antimicrobial Chemotherapy. 2002; 49: 631-639.

Maibach HI, Mathias CT. Vulvar dermatitis and fissures -- irritant
dermatitis from methyl benzethonium chloride. Contact Dermatitis. 1985;
13): 340.

Placucci F, Benini A, Guerra L, Tosti A. Occupational allergic contact
dermatitis from disinfectant wipes used in dentistry. Contact
Dermatitis. 1996; 35: 306.

Russell AD. Possible link between bacterial resistance and use of
antibiotic and biocides. Antimicrobial

Agents and Chemotherapy. 1998; 42:2151.

Russell AD. Biocides and pharmacologically active drugs as residues and
in the environment: Is there a correlation with antibiotic resistance?
AJIC. 2002; 30: 495-498.

Russell AD. Mechanisms of Antimicrobial Action of Antiseptics and
Disinfectants: An Increasingly Important Area of Investigation. Journal
of Antimicrobial Chemotherapy. 2002; 49: 597-599.

Schnuch A, Geier J, Uter W, Frosch PJ. Patch testing with preservatives,
antimicrobials and industrial biocides. Results from a multicentre
study. British Journal of Dermatology. 1998; 138: 467-476.

Scientific Committee on Cosmetic Products and Non-Food Products. Opinion
of the Scientific Committee on Cosmetic Products and Non-Food Products
Intended for Consumers concerning Benzethonium Chloride. 2002.

Shaffer MP, Belsito DV. ACD to Glutaraldehyde in Health Care Workers.
Presented at the 11^th^ Annual Meeting of the American Dermatitis
Society. March 9, 2000. San Francisco, CA.

Shmunes E, Levy EJ. Quaternary Ammonium Compound Contact Dermatitis From
a Deodorant. Arch Derm. 1972; 105: 91-93.

Toxicology / Regulatory Services. Overview and Summary of the ADBAC Data
Development Program. April 30, 1995.

Voss A, Widmer F. No Time for Handwashing!? Handwashing Versus Alcoholic
Rub: Can We Afford 100% Compliance? Infection Control and Hospital
Epidemiology. 1997; 18: 205-208.