-

_ ~nq~`li

July 24, 1985

Page 2 July 24, 1985

requirement in New Drugs .

A 2-year study with TCC (triclocarban) -was reviewed, by the Antimicrobial I Panel, while i~_ was In progress . Later this study in rats was a basis Cor FDA action against IBT who had performed the study . Somf-~ possibly ser.ious er -FeLts were seen then, and -later regarded as quest ~ilnable in this studIv .

Mosanto, in order to remove the cloud about Lf1e -initial study, performed a second 2-ye~r feeding study to resolve questions about 'the first one . This second study was cieUno Neither the Pane! nor FDA --equested this second 2-year study . The first one was extant when the Panel was meeting ; the second was a voluntary effort to put to -rest the questions r<aised by r he first study at IB'I`~ With the triclosan 2-year siuuy . similar situaLion e=_isted . This 2-year stud = also was done at IBT (also nut requested b9 the, Panel j � When questions were raised about this studyy, attempts were made to validate the original Ii3T sr.udv, However, these failed, and again, in order to clear up any doubts or questions remaining, but noi, as a response to any previously idlentified -Larger organ, a -2--year study was 'repeated . As I pointed out on June, ;.9th, a 90-day study normally identifies the Larget organ .

The spectre of hexachlorophene has pervaded .~~~1 aspects of the Antimicrobial Panel's review . However,, it is clear 3n a11 the published data- befcsr :_ ~i_nd LO _ i: er_ the Antimierobiai T review, that HCP is _z toxic molecule . The toxicity of HC;P for the central n,~rvous system showed in animals -"-r, only days after i~e;ir~ni-r<~; administration of i cw doses in rats ~ One crit:lcal , 90-day bathin_- study in neonatal mortkeys shoved the same tOxociLy . < I am pointing Ou L the hisf-cr i caJ_ context in which the Antimicrabia1. Panel produced their Toxicity Testing Guidelines to recall how iiite~~twi.ned [:he testing procedures became with the hexac:hlJreph.(-~,rte issue a--ad the use of chemicals in bar soaps . The Panel's concern was the potential for unrestricted use of these soaps over , the entire body for a lifetime .

Page 3 July 24, 1985

Please keep in mind that c'noroxylenol (PCM-Y-) Ls

a 50-year old antimicrQbial ingredietit - aun old,

drug - not a new drug entity: Bil1, :I reaJ_-ly

don't mean to unnecessarily belabor the paint ., ,

but Z think it is clear `that I do just --not.

believe further tests should neither be required

nor will be helpful in describing the toxicity

profile of PCMX .

Again, thank you :for your cooperation and attention

to our feedbacts meel.Lng of June l'9, 1985 .

Best Regards,

DEXIDE, INC . :

----~.,

Mary Brueh . Vice. President- Liir- Sciences

Quality Assurance u Regulatory Affairs

th

Presentation by Mary K. Bruch ,

June 19, 1985

Feedback Meeting on Chloraxylenal

We are pleased to have an opportunity to respond to

FDA's feedback Iee:ter of March 23, 1985 .

The statements in this letter are concerned with the, safety

of chloroxylenol as follows :

"The available data are not aclequaLe to s>>gpqrL the

safety of chloraxyJ_erol for long-timo use as a

surgical hand scrub or a health-care personnel

handwash . Because the ingredient is intended far

repeated daily use, &tta from- a 2-year rat feeding

study are essential to assess the ch,"onic effects

of ch2aroxylencl, . . .~"ne of the Panel's ,.ind agency's

, continuing concern is the absorption o-f topically

applied antzmicrobi:als, particularly when used

repeatedly overmany years ."

This recent letter' concerning the safety of PCMX- has

stimulated Ferro and Dexide's concern, and focusad us to

do another review and anag isis of the data on hanct, and

to then piece togeLher ne~:aer published data and data

extracted from previous studies .

There were few details in your letter about the specific

concerns or the data 'dec::cted in the toYic .~_ty resri_ng

already executed that 1_ec: to your request to," a 2--year

study . We would, Ii k.e to know your spec ific~ cor~c.erns .

Presentation by Ma.ry K . ;;ruch

June 19; 1985

Page 2

We have requested this meeting to discuss these concerns

and to present some information from comput:er modeling

of metabolic data from studies with PCMX .

We are pausing in the Ion- history of 'the use of chloroxylenol

to review official'concer .zs rather than to try to guess what

needs to be done, an,;,-,:hin--, to assure the safe use of

PCMX .

We would like to ask :

"What is your speci-fic c ;: acexn about the toxicity of PCMX?

Now let me proceed with the haw and why we are all here .

In late 1971 the intent i or an OTC review tJa ~;i~~ published and

it was initiated in February, 1972, The OTC 'Panels were

conv,Fned in 1972, the OTC Antzmi:crabial :'afzel_ started

June 29, 1972 . The decision to sepera;t~= Li:c Antimierobiai

Panels was not made unti_:i after June, i~-72 .

PCMX - a call for : data for antimzcrobzai iayredien~--s was

published in the Federal Register in 19-71- Lu response to

this published requcst, ,he data subuitLecl by Ottawa Chemical

Company was sparse, consJ.sting of references and the company

brochure . When thc r an.e]_ first reviewed FC:1-'K, the toxicity

of hexachlorphene had bL+~n -established and i-ec.or.irueneiats.ons

made by the Panel with ~ctiuza by FDA following .

. Presentation by Mary K. l:ruch

June 19, 1985

Page 3

The era of the systemic tonic effects of topic-4111y applied

products had begun at FDA . The AntiTni.crabial T Panel

placed I'CMX .in Category III based. znainiv on its iong

history of use and some published papers, and the familiarity

of the Panel members witl: this antimicrvbial_ ., In response

to the publication of the Antimicrobial 'T- Panel Report and

as a submission to the Ant rmicrobial II (Anui,rungai) Panel,

many more studies, articles and reports or- cbIcro-r.,,,Ienol

-were submitted . Al1 of these submission made to ,the

Antifungal Panel were available to all. the parties involved

in the resolution of the categorization of ingredi;-~nts- in

the Antimicrobial I Panel . The toxicity data submitted are

mainly from three sources : ;

1 . - Ottawa Chemical ; Company (division of Ferro),, manufacturers

of PCMX .

2, Pennwalt, Inc., rci~~.rketed a jock-itch remedy, Cruex,

containing 3% r Ch~ and investigated a hand t,~,ashing

product with 3 .75i: PCMX .

3 . Reckitt and Col-mart manufactures !,ad Det. tol containing -

4.5% PCMX, r_crpiueo1 (distill-ate) and alcohol . Dettol

has been marketed since , 1933 .

The Ant-ifungal Panel reviewed a large . portion of t1he available

data . A brief summary of the toxicity stud-Les was prepared by

Dr . Ann Tucker who was ~: ri:ember of the Panel . A very lengthy

outline of planned ~:tudi~-s was presented to the Panel by

Pennwalt . They were attempting to respond I,--o the -review of

the Antimicrobial I Pane'- with this list of intendod work .

Presentation by Mary K . Bruch ,June 19, 1985

Page 4

Some studies were compleLed, and with other, interim reports have been submit-Led by Pennw~-It . No final report, of the longer-term studie :i has been submitted. It appears that Pennwalt ceased their interest in testing and marketing PCMX . '

Chronic dosing has most o;Cten been applied to the administration of oral drugs over long pe- ;°iods or a lifc~t~time ~ The intent of this oral dosing is to produce a systemic eff~~ct o The most advantageous dosing is usually selected to produce the desired . effect .

Topical products are .app i ied most often to treat conditions _ ..a.° an the skin . However, ~~~da~, there are situat~c~~~s in which

topical application is designed to product sYstemic effects with the transdermr, .21_ application of drugs .,

However, the investigation of the systemic effects of -topical drugs is fairly recent . The use of topical steroids and the toxic effects from pesticides accidentally placed on the skin have stimulated attent~ian to these effncts .

Certainly the surprising 'coxicity of top4cai7e- appLied

hexachlorophene emphasize :; it even mare for antir~icrortaial compounds . The focusing of attention on systemic and CNS effects of very low doses of hexach:ioroph~:,ne occurred as

Presentation by Mary K. T3ruch

June 19, 1985

Page 5

the Antimierobial Panel began its- review in 1972 . Na

more dramatic episbde co ; :"d 'exist than the accidental

clinical demonstration or the effects than when infants

were accidentally intoxicated in France in July, 1372 .

The entire OTC Antimierobial I review was powerfully

influenced and re-rii.reett:cl by this incident and the

prior mounting evidence of hexachlorophene toNieity .

The cosmetic ingredient faview has completed their final

report . Two different toxicologists on thaL Panel have

reviewed the same data as the FDA and OTC Panel's have .

These authors; conclude, �an 'the basis of the information

presented in this report, the CIIt Expert Panel r_onz2,zdes

that chloroxylenol is saf Q as a cosmetic ingz ed :.enL in the

present practices of use", (P .10)' .

The authors of the GIR Report recognized ;_hat in the present

practices o¬ use "many of thcse products can be applied as

infrequently, as once a week to as often as several times a

day . These formulations also have the po,-,eatial to remain .

in contact with body 5uri;-ces for several djys, and to be

applied repeatedly over n he course of several `ears"', Q-6) .

Presentation by Mary K. Bxuch

June 19; 19$5

Page 6

The concentrations of chloraxyIenol in : wide variety of

products range from 0 .1 to 5 percent . Furthermore many

of these products ar2 left on the skiz in use, -(P-5) .

The EPA has recently published caxic:i_ty testing guidelines -

specifically for ethylhexanoic acid on May _7, 1985 .

EPA's requirements are for detection of the Larget organ

in a 90-day study nn,3 Lo discuss long--tarm, 2-year studies

only to characterize car-i_nogcnc.it_v and teratGgencity

- , potential. These issues have already beer rus,olved with '

reference to chloroxylenalo

INDEX

le Acute Oral Administration of Ottasept (F'CMX) to rats - Ottawa

Chemical Co .

2 . Studies on the acute toxici49 o£ Dettol and Dcttol substitutes .

Reckitt & Colman .

3, 30-day sub--acute toxicity in rats . PC`X . Pennwalt .

4 . 30-day sub-acute toxicity in rats . Dettol (RBA666) . Oral

week, Huntingdon Research Center .

56 days - Oral tcxicityin Beagle dog: . Dettal (RBy666)~ RECkitt

& Golman~

6 . 90-day sub--acute toxicity in rats . FCMX . Oral . Pennwalt .

7 . Oral toxicity in Beagle dogs . 13 weeks . RBAK6, Reckitt &

Colman . Huntingdon Research Center .

$ . 360-day study (8-month interim report only) in Beagles . Topical .

PCMX and Product . Pennwalt .

9> Summary Material - 8-month , report . Topical study in Beagles .

Pennwalt . PCM,X >

0, Summary of OTC review of the Pennwalt submission. Dr . Ann Tucker .

11 . Reproductive study in rats . Pennwalt . (4 generation study -

2 generation study completed)

lZ, 2-week application of Dettol (RBA666) to vaginal n:ucosa in rabbits .

F:ecki.tt & Colmar. . Huntingdon Research Center .

13 . Met=abolism o£ PCMX in Sprague-Dawley and GuriraTraistax rats .

Reckitt & Colman .

14 . Metabolism studies of PCMX . Dogs . Reckitt & C:olmar .

15 . Tlettol_ Bathing Product . A preliminary volunteer study . Human .

Keckitt & Calman .

16 . Dettcl Bathing Product . Human volunteer study . Reckitt & f:olnian .

17 . Zondek, Slzapiro and Hastr :iD< 1943 . Application of the Millon

reaction to the determination of chlorophenals in body fluids

and tissues,

18, Zondek and Shapiroe 1943 . Fate of halogenated phenols in the

organism.

,. 19 . Zcndek and Finkel.stein . Blood concentration P-Chlv?-o <iy7_enol

in man following pdrenteraI ., percutaneous and rectal application .

20 . Zandek . 1942 . The excretion of hayogenatecl phenols and their

use in the treatment of urogenital infections .

21 . DE:tto1 and Related Antiseptics/disinfectants--Emergency calls to

New Cross Hospital Poisons Unit . 196Q-1976 .

22 . Summary of adverse reactions to Dettol . Recl<itt & Colman .

23 . Meek, Piercy and Gabriel, 1977 . Fatal self-poisoning with Dettol .

24 . Letter to Dr . William Gilbextson. . Dated June 10, 1985 .

25 . Final report of the safety assessment or chioroxylencl . Nov,

1984 . Cosmetic Ingredient Review .