Butylcarbamate Rr

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RE-RE

Safety Assessment of

Iodopropynyl Butylcarbamate

as Used in Cosmetics

Status: Re-Review for Panel Review

Release Date: August 16, 2013Panel Meeting Date: September 9-10, 2013

The 2013 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D.,

Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Ronald A Hill, Ph.D.

Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph

Director is Lillian J Gill D P A This report was prepared by Wilbur Johnson Jr M S Senior Scie


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Commitment & Credi

Memorandum

To: CIR Expert Panel Members and Liaisons

From: Wilbur Johnson, Jr.

Senior Scientific Analyst

Date: August 16, 2013

Subject: Re-review Document on Iodopropynyl Butylcarbamate

At the June 3-4, 1996 Expert Panel meeting, the Panel issued a final report on the safety assessme

Butylcarbamate with the following conclusion: On the basis of the data presented in this report, th

concludes that Iodopropynyl Butylcarbamate is safe as a cosmetic ingredient at concentrations 0

butylcarbamate should not be used in products intended to be aerosolized. The final report was publishe

The lengthy discussion on which the Panels conclusion is based occurred at the December 11-12, 1

during which the European Unions 0.1% concentration limit on iodopropynyl butylcarbamate in co

Currently, the following 3 maximum authorized concentrations of this ingredient in cosmetics are in eff

Union, each of which is lower than the 0.1% limit previously determined: (1) rinse-off products (0

products (0.01%, except deodorants/antiperspirants), and (3) deodorants/antiperspirants (0.0075%)

ingredient is not to be used in oral hygiene and lip care products, and the following warning must be di

of rinse-off and leave-on cosmetic products that contain iodopropynyl butylcarbamate: Not to be used f

years of age. These restrictions deserve the Panels consideration.

Included for your review is a copy of the Re-review document, the CIR report history, Literature search

Data profile, 2013 FDA VCRP data, Minutes from the December 11-12, 1995 (58 th) and June 3-4

meetings, a copy of the published final report, and use concentration data from the Council (data1 pdf fil

After reviewing the available data, the Panel needs to determine whether the final report on Iodopropy

should be re-opened.


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Distrbuted for comment only -- do not cite or quote


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CIR History of:


At the June 3-4, 1996 Expert Panel meeting, the Panel issued a final report on the safety assessment

butylcarbamate with the following conclusion: On the basis of the data presented in this report,

Panel concludes that iodopropynyl butylcarbamate is safe as a cosmetic ingredient at concent

Iodopropynyl butylcarbamate should not be used in products intended to be aerosolized. The

published in 1998.

1stRe-review, Belsito and Marks Teams/Panel: September 9-10, 2013



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December 11-12, 1995 (57th)CIR Expert Panel Meeting (Full Panel) D


Dr. Belsito noted that his Team had concluded that Iodopropynyl Butylcarbamas used.

Dr. Schroeter indicated that his Team had restricted the final concentration ofIodopropynyl Butylcarbamate to 1%. This is based on human repeated insult patchFurthermore, his Team determined that because of the danger of this compound (binhalation toxicity data) and the fact that it is used in an aerosolized product, that thdiscussion should contain a caution statement.

Dr. Bailey said that most of the tests were conducted at concentrations much(0.125%) than the 1% limitation proposed by the Schroeter Team. He also noted thas established a concentration limit of 0.1%, and that a limitation of 1% would be

Dr. Shank wanted to know the basis for the EU's concentration limit.

Dr. Bailey said that he did not know the basis for this limitation. However, he that most of the testing was done at a concentration of 0.125% in the data supplied

Dr. Schroeter stated that the real risks with respect to safety are irritancy andand, with this in mind, 1% is an acceptable limitation.

Dr. McEwen said that he did not see a problem with establishing a concentrabased on the available data or a conclusion of safe as used.

Dr. Belsito noted that comedogenicity had not been tested at concentrations

1%. He said that a variety of data had been submitted, and that one does not knowIodopropynyl Butylcarbamate is toxic at concentrations greater than 1%, unless it isthese concentrations.

Dr. Belsito asked why the sensitization potential of Iodopropynyl Butylcarbambelieved to be the only risk that this ingredient has.

Dr. Shank said that the other studies that were submitted give no indication tingredient poses a health hazard.

Dr. Belsito noted that comedogenicity was tested only at a concentration of 0said that one does not know if Iodopropynyl Butylcarbamate is going to be comedoconcentration of 1%. He also said that comedogenicity is a major issue for those ucosmetics.

Dr McEwen said that the comedogenicity data involve concentrations that ar



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Dr. Andersen said that the data represent approximately 40 formulations, andhighest value was 0.0125%.

Dr. Shank asked if the Panel could rely on the concentration of use data as thconcentration range in industry today.

Dr. Andersen noted that the concentration of use data are 1995 data.

Dr. Shank recalled that these data were received from one company and wanif Iodopropynyl Butylcarbamate is used by one company only.

Dr. McEwen said that the concentration of use data submitted are the only da

area that CIR has, and that they were submitted in response to the Panel's request

Dr. Shank confirmed with Dr. McEwen that these data don't necessarily repremarket.

Dr. Shank also noted that many studies on Iodopropynyl Butylcarbamate havavailable to the Panel, none of which suggests any problems. He said that the highconcentration (1%) that was tested well was tested in the human repeated insult pathat the results were negative at this concentration.

Dr. Belsito said that any concentration limit should be established based oncomedogenicity data. Therefore, the concentration limit should be set at 0.1%, theconcentration for comedogenicity. He mentioned that the argument relative to the Iodopropynyl Butycarbamate was initiated because of a Hawaiian lawsuit over acnelesions of the back.

Dr. Shank reiterated that there is an excellent database on the toxicity of thisand that there are no data suggesting that Iodopropynyl Butylcarbamate is comedo

Dr. Belsito said that the data do not suggest comedogenicity at concentrationthe highest concentration that was tested.

Dr. Shank wanted to know why comedogenicity is a major concern.

Dr. Belsito said that comedogenicity is an issue that has been raised in assocIodopropynyl Butylcarbamate, and that this is the weakest link with respect to settinconcentration limit. He noted that this ingredient is a halogenated compound, and medical conditions that are known as iododerma and bromoderma.

Dr. McEwen suggested that the Panel consider setting a 0.1% concentration on the comedogenicity data, and that any interested parties can respond to this limthe 90-day comment period to the Tentative Report.

The Panel voted in favor of issuing a Tentative Report with a conclusion indic



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Dr. Shank noted that his Team deleted one of the acute inhalation toxicity stubecause of the number of animals used and the fact that the particle size was not i

Dr. Schroeter noted that the case studies do not contribute to the safety asseIodopropynyl Butylcarbamate and should be deleted from the report.

Dr. Andersen confirmed with Dr. Schroeter that the concern about aerosol usraised in the report discussion.

Referring to the carcinogenicity study included in the CIR report on IodopropyButylcarbamate, Dr. Slaga noted that a marked reduction in body weight was obsethe Schroeter Team had suggested that this be mentioned in the report discussion The two highest doses used in the carcinogenicity study suggest a toxic effect becawas a marked reduction in body weight.

Dr. Klaassen noted that the observation on weight loss is not important to thethis should be noted in the report discussion.

Dr. McEwen said that the marked reduction in body weight suggests that the exceeded.

On the subject of skin penetration, Dr. Schroeter said that the study using frocadaverous skin was less than adequate.

Dr. Jeffrey Yourick, with FDA, said that cadaverous skin probably gives a reaestimate of dermal absorption. He said that the use of cadaverous skin may be anfact if the Panel considers the metabolism of Iodopropynyl Butylcarbamate to be imsuch a case, it would probably be essential to use viable skin.

Dr. Schroeter said that he was concerned about the use of viable skin becauIodopropynyl Butylcarbamate were metabolized in any way, this might alter skin pe

Dr. Slaga said that, ideally, one would rather use live skin in any skin penetraHe acknowledged that skin penetration studies involving frozen cadaverous skin hadone for years. Furthermore, if Iodopropynyl Butylcarbamate is going to be modifiewould be no indication of this when using cadaverous skin.

Dr. Belsito said that, in this situation, one is looking for absorption in an unmIf the concern is modification in terms of carcinogenicity or end organ toxicity, such available. He did not see the basis for rejecting the skin penetration data involving skin (absorption, unmodified, through frozen cadaverous skin).

Dr. Schroeter said that he had not proposed deleting the in vitroskin penetrareiterated that skin penetration studies on viable skin would have been preferable.

D B f ld id th t th f t th t th P l h d di i i bl


Di b d f l d i


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June 3-4, 1996 (59th)CIR Expert Panel Meeting (Full Panel) Day 2


Dr. Belsito noted that at the December 11-12, 1995 Panel meeting, the Panefavor of issuing a Tentative Report with the following conclusion: On the basis of thpresented in this report, the CIR Expert Panel concludes that Iodopropynyl Butylca

(IPBC) is safe as a cosmetic ingredient at concentrations of 0.1%. IPBC should nin products intended to be aerosolized.

Dr. Belsito also noted that information on methods of manufacture and a UV analysis were received after the Tentative Report was announced, and that these dwarrant substantively changing the Panels conclusion.

The Expert Panel voted unanimously in favor of issuing a Final Report on IodButylcarbamate with the conclusion stated above.


Distrb ted for comment onl do not cite or q ote


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Iodopropynyl Butylcarbamate Check List for September, 2013. Analyst Wilb

Acute toxicityRepeated dose

toxicityIrritation Sensitiza

Skin

Penetration

AD

ME

Oral

Parenteral

Dermal

Inh

ale

Oral

Parenteral

Dermal

Inh

ale

Ocular

Irri

tation

DermalIrr.

Animal

DermalIrr

Hu

man

Sensitization

Animal

Hu

man

Iodopropynyl

Butylcarbamate

X X X X X X X X X X X



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Safety Assessment ofIodopropynyl Butylcarbamate

as Used in Cosmetics

Status: Re-Review for Panel Review

Release Date: August 16, 2013Panel Meeting Date: September 9-10, 2013

Distrbuted for comment only do not cite or quote



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Table of Contents

INTRODUCTION .................................................................................................................................

CHEMISTRY ........................................................................................................................................

DEFINITION AND STRUCTURE ..................................................................................................................

METHOD OF PRODUCTION ......................................................................................................................

USE .........................................................................................................................................................

COSMETIC ...............................................................................................................................................

NONCOSMETIC ........................................................................................................................................

TOXICOLOGY .....................................................................................................................................

REPEATED DOSE TOXICITY .....................................................................................................................SKIN SENSITIZATION ...............................................................................................................................

CASE REPORTS .......................................................................................................................................

GENOTOXICITY .................................................................................................................................

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY ...............................................................

DISCUSSION SECTION FROM CIR FINAL REPORT ON IODOPROPYNYL BUTYLCARBAM

y q



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INTRODUCTION

A Cosmetic Ingredient Review (CIR) Final Report with the following conclusion was published

basis of the data presented in this report, the CIR Expert Panel concludes that iodopropynyl butylcarbama

cosmetic ingredient at concentrations 0.1%.1Iodopropynyl butylcarbamate should not be used in produ

aerosolized. The discussion from this final safety assessment is included at the end of this report. This r

contains the results of pertinent studies that became available after the final safety assessment was issued

CHEMISTRYDefinition and Structure

Iodopropynyl butylcarbamate (CAS No. 55406-53-6) is the organic compound2 that conforms t

formula in Figure 1. It is a solid with a melting point of 64.72 - 66.34 oC and a low vapor pressure of 0.0

logKowof this chemical is 2.81, at 25 C, and a water solubility of 223 mg/L is also reported.

N

H

O

OH3

C

Ibutyl carbamate

iodopropynyl

Figure 1. Iodopropynyl Butylcarbamate

Method of Production

The synthesis of iodopropynyl butylcarbamate can be achieved in two steps.1.4 The first of whphosgene with butylamine and propargyl alcohol. The product of this first step, propynyl butylcarbamate

with iodine monochloride.

USE

Cosmetic

Iodopropynyl butylcarbamate reportedly functions as a pesticide and preservative in cosmetic pr

to information supplied to the Food and Drug Administration (FDA) by industry as part of the Voluntary

Registration Program (VCRP) in 2013, iodopropynyl butylcarbamate was being used in 942 cosmetic pro

are summarized in Table 1. Results from a survey of ingredient use concentrations provided by the Perso

Council (also included in Table 1) in 2013 indicate that iodopropynyl butylcarbamate was being used at c6



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rinse-off products, iodopropynyl butylcarbamate is not to be used in mixtures for children under 3 years o

products/shower gels and shampoo. Regarding leave-on products, iodopropynyl butylcarbamate is not to

lotion and body cream, and is not to be used in mixtures for children under 3 years of age. Furthermore,

butylcarbamate is not to be used in oral hygiene and lip care products. The following warning must be d

of rinse-off and leave-on cosmetic products that contain iodopropynyl butylcarbamate: Not to be used fo

years of age.7

Noncosmetic

Iodopropynyl butylcarbamate, as an antifungal preservative, has been approved by FDA for use

adhesives that may be safely used as components of articles intended for use in packaging, transporting, o

TOXICOLOGY

Repeated Dose Toxicity

Troysan polyphase p100 (98.7% pure iodopropynyl butylcarbamate) was evaluated in a repeated

involving groups of 10 New Zealand white rabbits (~ 4 months old; 5 males, 5 females per group). 3 Thre

dietary concentrations of 500 ppm, 2,000 ppm, and 4,000 ppm, respectively, daily for 13 weeks. The con

the same diet without the test substance. There were no treatment-related deaths in the study. Adverse e

observed in the 2 lower dose groups. In the 4,000 ppm group, the animals ate less and gained less weigh

weeks of the study. Feeding with 4,000 ppm and 2,000 ppm resulted in the hepatic changes defined as sGGT enzyme levels (at 4,000 ppm) and increased liver weights (at 2,000 ppm and 4,000 ppm, only in fem

changes in females in these 2 groups consisted of centrilobular hepatocellular enlargement (cell swelling)

in the cytoplasm of hepatocytes, and sinusoidal macrophages. The no-observed-effect-level (NOEL) in t

ppm (~13 mg/kg/day).

Skin Sensitization

Iodopropynyl butylcarbamate, a biocide, was originally used for wood or paint preservation, but

as a preservative in cosmetics. The use of iodopropynyl butylcarbamate in cosmetic products has caused

and allergic contact dermatitis. Although the risk of sensitization appears to be quite low, at concentratio

cosmetic products, continued surveillance for iodopropynyl butylcarbamate allergy is necessary, as incid

allergy may increase with increasing availability of iodopropynyl butylcarbamate-containing cosmetic pr

Iodopropynyl butylcarbamate (0.1%) in petrolatum) was tested on 4,883 consecutive patients for

between January of 1998 and June of 1999.10 Regarding the MOAHLFA index (percentage of male, oc

dermatritis, hand dermatitis, leg dermatitis, face dermatitis, age > 40), the study comprised the following

with occupational dermatitis, 19% with atopic dermatitis, 31% with hand dermatitis, 10% with leg derma

dermatitis, and 61% were 40 years old. Patches were applied for 1 or 2 days, and reactions were score

International Contact Dermatitis Research Group (ICDRG) and German Contact Dermatitis Research Gr

recommendations, with obligatory readings at day 3 or day 4. At the day 3 reading, 0.3% were allergic t

butylcarbamate (14 + reactions; 2 ++ reactions). Doubtful or irritant reactions occurred twice as frequent

tested for 24 h (n = 1814) reacted less frequently (0.1%) than the remaining patients patch tested for 48 h

patients). The reaction pattern was subsequently evaluated, after considering the possibility that a certain

reactions could have been false positives. More than 80% of the positive reactions displayed a crescendo

pattern Eighteen of 43 do btf l reactions (?) appeared as late as da 3; these reactions co ld ha e been



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(17%). Of the 251 metal workers, 206 were patch tested with the current MWF series, which included io

butylcarbamate. Monoethanolamine ranked number 1 (11.6% positive reactions) among the current MW

Iodopropynyl butylcarbamate caused positive reactions in 0.5% of the patients.

To determine the concentration of iodopropynyl butylcarbamate that should be used in screening

analysis was performed on data filed by 26 centers of dermatology (cooperating in the IVDK and the GerDermatitis Research Group [DKG]) on patch tests performed with 1 or 2 concentrations of iodopropynyl

(0.1%, 0.2%, 0.3%, or 0.5%) in 8106 unselected patients.12 Most centers used small Finn chambers on S

remained in place for 1 or 2 days. The criteria used to determine the best test concentration of iodopropy

were: the reaction index, the positivity ratio, the rate of crescendo reactions, and the relationship between

butylcarbamate reactions and the MOAHLFA index irritant reactions to sodium lauryl sulfate (SLS), and

other contact allergens, including preservatives. Iodopropynyl butylcarbamate test concentrations of 0.1

0.5% yielded 0.5%, 0.8%, 1.3%, and 1.7% positive reactions, respectively. However, this increase was a

even greater increase in doubtful and irritant reactions. Based on these figures and other criteria examine

that the range of suitable test concentrations of iodopropynyl butylcarbamate should lie between 0.2% ananalysis of MOAHLFA indices and of associations between reactions to iodopropynyl butylcarbamate an

allergens and to SLS showed that most of the positive reactions to 0.2% iodopropynyl butylcarbamate ca

allergic reactions. This analysis also showed that, with 0.2% iodopropynyl butylcarbamate, fewer false p

be expected when compared to 0.3% iodopropynyl butylcarbamate. The authors concluded that patch tes

iodopropynyl butylcarbamate is suggested for patients with eczema, possibly related to preservatives.

The North American Contact Dermatitis Group (NACDG) tested iodopropynyl butylcarbamate

in petrolatum) between 1998 and 2008.13 Patch tests were performed using Finn chambers on Scanpore t

remained in place for 48 h; reactions were scored initially at 48 h to 72 h, and, subsequently, between 72

initial placement. Two patient groups of interest were defined, based on patch test reactions to iodopropy

namely, weak (+) reactors and strong (++ or +++) reactors. Of the 25,321 patients tested, there were 226

reactors and 67 (0.3%) strong reactors. For iodopropynyl butylcarbamate-positive patients, the most freq

dermatitis were scattered generalized distribution, hands, and arms. Most (> 50%) of the currently releva

personal care products, and most reactions (> 90%) were not related to occupation. Only 4 of the strong

clinical relevance, i.e., a positive use-test reaction or a positive patch-test reaction to a product containing

butylcarbamate. The frequency of positive reactions increased (0.25 vs. 1.5%) when the higher concentra

iodopropynyl butylcarbamate was used; however, most were weak reactions, of which some were likely i

A study was performed to estimate the risk of sensitization to selected preservatives.14 The occupreservatives in 3541 leave-on products, based on the labeling of the ingredients, was documented. Freq

sensitization to preservatives was analyzed on the basis of IVDK data for 2006-2009. As an estimate of

the sensitization exposure quotient (SEQ) was calculated as the quotient of the relative frequency of sens

relative frequency of use. An SEQ of 3.4 was reported for iodopropynyl butylcarbamate. This SEQ may

the value for phenoxyethanol (SEQ = 0.06, lowest SEQ reported in study) and the value for 2-bromo-2-

diol (SEQ = 13, highest SEQ reported in study).

The thin-layer rapid user epicutaneous test (TRUE TestTM) was investigated for its effectiveness

contact dermatitis.15

This standard method for diagnosing allergic contact dermatitis in the United Statescontaining 20 individual allergens and 8 allergen mixes. In this study, a retrospective analysis of 2088 p

underwent patch testing between 1995 and 2010 was performed. Study groups were analyzed to determi

reactions were to allergens and/or mixes present in the TRUE TestTM panels. All patients were tested us

Chambers technique. The patch panels were applied to the back, and reactions were scored on days 2 a

the NACDG scoring system. A score of 1, 2, or 3 was classified as positive. Iodopropynyl butylcarbama

the top 25 allergens and/or mixes, not contained in the TRUE TestTMseries, that elicited positive reaction



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significant increase (P < 0.05) in the positive reaction rate was reported for the following 4 allergens: iod

butylcarbamate (tested at 0.5% in petrolatum), fragrance mix II (tested at 14% in petrolatum), propylene

30% aqueous), and benzocaine (tested at 5% in petrolatum).

Case Reports

A 63-year-old male developed severe perianal and palmar contact dermatitis that was caused by

iodopropynyl butylcarbamate in moist sanitary wipes.17

A 58-year-old male worker in window-frame manufacturing company developed itch, scale, and

hands over a 2-year period.18 The wood (pine) used for window frame assembly had been treated with a

the following composition: propiconazole (0.25%), tebuconazole (0.25%), and 3-iodo-2-propynyl butylc

dissolved in white spirit. Patch testing with 0.1% 3-iodo-2-propynyl butylcarbamate yielded a ++ reacti

A 20-year-old female presented with a 9-month history of recurrent, itchy facial dermatitis with

periorbital swelling.19 The patient had been using a cleansing wipe that contained iodopropynyl butylcar

oil. The facial dermatitis resolved after use of the cosmetic cleansing wipe was discontinued. In patch te

chamber containing either ingredient was applied to the back using Scanpor tape. A 3+ reaction to 0

butylcarbamate was observed at days 2 and 4. A 2+ reaction to tea tree oil was also observed on days 2 a

GENOTOXICITY

The genotoxicity of Troysan polyphase p100 (98.7% pure iodopropynyl butylcarbamate) was ev

test using the following Salmonella typhimuriumstrains: TA98, TA100, TA1535, TA1537, and TA1538

metabolic activation, the test substance was evaluated at doses up to 1,000 g/plate. Except for strain TA

1,000 g/plate), the test substance was evaluated at doses up to 333 g/plate in the absence of metabolic

negative control was dimethylsulfoxide (DMSO), and the following positive controls were used: 2-amin

azide, 9-aminoacridine, and 2-nitrofluorene. The test substance was not genotoxic with or without metab

Positive and negative control values were within normal ranges.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

The developmental toxicity/teratogenicity of Troysan polyphase p100 (98.7% pure iodopropyn

was evaluated using groups of 20 female New Zealand White rabbits (weight range: 3 to 4 kg). 3 The 3 g

doses (in corn oil; dose volume = 0.5 ml/kg) of 2, 20, and 50 mg/kg/day on gestation days 6 through 18.

comprised the vehicle (corn oil) control group. Substantial toxicity was noted after dosing with 50 mg/kg

and 1 (moribund) was killed between gestation days 21 and 23. Additional observations of maternal toxi

mg/kg/day dose level included adverse clinical signs, body weight loss, and reduced food consumption.

toxicity at 50 mg/kg/day were: few feces, no feces, and soft stools. There were no adverse maternal effelower dose groups. One female in the 50 mg/kg/day dose group aborted on gestation day 24. There wer

significant differences in cesarean section parameters among the dose groups. However, at the 50 mg/kg

there was a slight increase in mean post-implantation loss and a corresponding decrease in the mean num

These differences occurred in the presence of substantial maternal toxicity. In all dose groups, there wer

related fetal malformations or developmental variations during the study. The NOEL for maternal toxici

be 20/mg/kg/day, and the NOEL for teratogenicity was determined to be 50 mg/kg/day.



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DISCUSSION SECTION FROM CIR FINAL REPORT ON IODOPROPYNYL BUTYLCA

The Cosmetic Ingredient Review (CIR) Expert Panel was concerned about the acute inhalation t

animal studies with Iodopropynyl Butylcarbamate. The Panel thereby concluded that IPBC should not b

cosmetic products meant to be aerosolized.

The Panel stated that skin penetration studies using viable skin are preferable to those using cad

using cadaver skin measure penetration of unmodified compounds only, and do not provide information o

other factors such as skin metabolism. Therefore, studies using viable skin are more useful in assessing t

cosmetic ingredients.

The Panel noted that dose-related reductions in body weight gain were observed in a long-term c

study using Sprague-Dawley rats, although no evidence of carcinogenic potential was found. Although n

of sensitization observed in animal studies and in human repeated insult patch tests, the Panel acknowledirritation potential of this ingredient. Because the highest concentration tested for comedogenicity was 0

considered that concentration to be the highest for which the available data would support safety.



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Table 1. Frequency and Concentration of Use

According to Duration and Type of Exposure.5,6

Iodopropynyl

Butylcarbamate

# of Uses Conc. (%)Exposure Type

Eye Area 45 0.009-0.023

Incidental Ingestion NR NR

Incidental Inhalation Sprays 48 0.001-0.02

Incidental Inhalation - Powders 1 0.02

Dermal Contact 548 0.002-0.05

Deodorant (underarm) NR 0.0075-0.02

Hair - Non-Coloring 374 0.00012-0.05

Hair-Coloring 14 0.0078-0.011Nail 1 0.03

Mucous Membrane 102 0.015-0.05

Baby Products 14 NR

Duration of Use

Leave-On 564 0.001-0.05

Rinse off 364 0.00012-0.05

Diluted for (bath) Use 14 0.015

Totals***/Conc. Range 942 0.00012-0.05

NR = Not Reported; Totals = Rinse-off + Leave-on Product UsesNOTE: Because each ingredient may be used in cosmetics with multiple exposure

types, the sum of all exposure type uses may not be equal to sum total uses.



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References

1. Andersen, F. A. Final report on the safety assessment of iodopropynyl butylcarbam

International Journal of Toxicology. 1998;17(5):1-37.

2. Gottschalck, T. E. and Breslawec, H. P. International Cosmetic Ingredient Diction

Handbook. 14ed. Washington, DC: Personal Care Products Council, 2012

3. Environmental Protection Agency (EPA). High Production Volume Information SMammalian health effects SIDS. Genetic toxicity and developmental toxic

data on iodopropynyl butylcarbamate.http://www.epa.gov/hpvis.Date Ac

4. Xu, S. Synthesis of 3-iodo-2-propynyl butylcarbamate.Jingxi Huagong Zhongjian2010;40(5):58-60.

5. Food and Drug Administration (FDA). Information supplied to FDA by industry a

VCRP FDA database. 2013. Washington, D.C.: FDA.

6. Personal Care Products Council. Concentration of use by FDA product category.

butylcarbamate. Unpublished data submitted by the Personal Care Produc

29-2013. 2013.

7. European Union. Consolidated version of Cosmetic Directive 76/768/EEC, as am

through IX.http://eur-

lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1976L0768:20

Date Accessed 7-4-2013.

8. Food and Drug Administration (FDA). Substances for use only as components of

CFR 175.105. 2013.

9. Badreshia, S. and Marks, J. G., Jr. Iodopropynyl butylcarbamate.Am J Contact D

2002;13(2):77-79.

10. Schnuch, A., Geier, J., Brasch, J., and Uter, W. The preservative iodopropynyl bu

frequency of allergic reactions and diagnostic considerations. Contact Der

2002;46(3):153-156.

11. Geier, J., Lessmann, H., Dickel, H., Frosch, P. J., Koch, P., Becker, D., Jappe, U.,

Schnuch, A., and Uter, W. Patch test results with the metalworking fluid sGerman Contact Dermatitis Research Group (DKG). Contact Dermatitis.

130.

http://www.epa.gov/hpvishttp://www.epa.gov/hpvishttp://www.epa.gov/hpvishttp://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1976L0768:20100301:en:PDFhttp://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1976L0768:20100301:en:PDFhttp://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1976L0768:20100301:en:PDFhttp://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1976L0768:20100301:en:PDFhttp://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1976L0768:20100301:en:PDFhttp://www.epa.gov/hpvis


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butylcarbamate: Retrospective analysis of North American Contact Dermafrom 1998 to 2008.Dermatitis. 2010;21(6):303-310.

14. Schnuch, A., Mildau, G., Kratz, E. M., and Uter, W. Risk of sensitization to prese

estimated on the basis of patch test data and exposure, according to a sampon products. Contact Dermatitis. 2011;65(3):167-174.

15. Patel, D. and Belsito D. V. The detection of clinically relevant contact allergens w

screening tray of 28 allergens. Contact Dermatitis. 2013;66:154-158.

16. Warshaw, E. M. Belsito D. V. Taylor J. S. Sasseville D. DeKoven J. G. Zirwas M

F. Mathias T. Zug K. A. DeLeo V. A. Fowler Jr. J. F. Marks J. G. Pratt M.

and Maibach H. I. North American Contact Dermatitis Group patch test re2010.Dermatitis. 2013;24(2):50-59.

17. Schllnast, R., Krnke, B., and Aberer, W. [Anal and palmar contact dermatitis ca

iodopropynyl butylcarbamate in moist sanitary wipes].Hautarzt. 2003;54

18. Davis, R. F. and Johnston, G. A. Iodopropynyl butylcarbamate contact allergy fro

preservative. Contact Dermatitis. 2007;56(2):112.

19. Natkunarajah, J., Osborne, V., and Holden, C. Allergic contact dermatitis to iodopbutylcarbamate found in a cosmetic cleansing wipe. Contact Dermatitis. 2

317.

20. Noda, T. Yamano T. and Shimizu M. Developmental toxicity of antimicrobial age

propynyl butylcarbamate, in rats. Seikatsu Eisei. 1999;43(1):21-26.



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2013 FDA VCRP Data


01A - Baby Shampoos 1

01B - Baby Lotions, Oils, Powders, and Creams 1

01C - Other Baby Products 12

02B - Bubble Baths 14

03B - Eyeliner 10

03C - Eye Shadow 1

03D - Eye Lotion 14

03E - Eye Makeup Remover 8

03F - Mascara 5

03G - Other Eye Makeup Preparations 7

04A - Cologne and Toilet waters 8

04B - Perfumes 4

04E - Other Fragrance Preparation 8

05A - Hair Conditioner 87

05B - Hair Spray (aerosol fixatives) 5

05C - Hair Straighteners 2

05E - Rinses (non-coloring) 105F - Shampoos (non-coloring) 80

05G - Tonics, Dressings, and Other Hair Grooming Aids 142

05H - Wave Sets 4

05I - Other Hair Preparations 52

06A - Hair Dyes and Colors (all types requiring caution statements

and patch tests) 12

06C - Hair Rinses (coloring) 1

06D - Hair Shampoos (coloring) 107C - Foundations 6

07F - Makeup Bases 1

08A - Basecoats and Undercoats 1

10A - Bath Soaps and Detergents 22

10E - Other Personal Cleanliness Products 66

11A - Aftershave Lotion 7

11D - Preshave Lotions (all types) 211E - Shaving Cream 3

11G - Other Shaving Preparation Products 2

12A - Cleansing 62

12C - Face and Neck (exc shave) 38

12D - Body and Hand (exc shave) 49



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F I N A L R E P O R T O N T H E S A F E T Y A S S E S S M E NO F I O D O P R O P Y N Y L B U T Y L C A R B A M A T E I P B C

lodopropynyl Butylcarbamate (IPBC) functions as a preservative in ariety of cosmetic formulations. Although concentrations as high as 0been reported, most applications appear to require this preservative at O. 0125 . IPBC readily penetrates through the skin. The average acute oin rats is 1.47 g]kg. Rats fed 1PBC for 4 weeks had increased liver weidecreased plasma cholinesterase activity, and rats fed 1PBC for 13 wtransient behavior alteration, increased liver weights, hepatocyte enlastomach lesions, and decreased weight gain. Rats administered IPBCand liquid aerosols had labored breathing--lung edema, emphysema, dened lungs were observed after exposure. Dermal irritation, but no of skin sensitization, was seen in animal studies. At concentrations IPBC caused iritis and conjunctival irritation in rabbit eyes, but exconcentrations up to 0.015 produced only slight conjunctival rednewas not genotoxic, with or without metabolic activation. No evidenccinogenic potential was found in a 104-week chronic oral toxicity sturats. Reductions in weight gain were observed, along with inflammatinonglandular stomach and lesions in the submaxillary salivary glanproductive an d developmental toxicity stud&s using rats and mice, Ino significant effect on fertility, reproductive performance, or on the incfetal malformation,~ IPBC was found to be mildly irritating, but not sein clinical testing. At concentrations up to 0.1 , 1PBC was not comedclinical tests. Given the acute inhalation toxicity observed in animalstential for mild irritation, and the absence o f any data on comedegeconcentrations higher than 0.1 in clinical tests, the Expert Panel cthat IPBC is safe as a cosmetic ingredient at concentrations


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2 COSMETIC NGO

I - - C ~ C - - C H 2 - O - - C - - N H C H2)3C H 3F i g u r e 1 . Ch em ica l fo rm ula fo r Iodopropy l B u ty lc a rba m ate ( I

H E M I S T R YD e f i n i t i o n a n d S t r u c t u r eI P B C ( C A S N o . 5 5 40 6 -5 3 -6 ) c o n f o r m s to t h e f o r m u l a s h o w( W e n n i n g e r a n d M c E w e n 1 99 3). O t h e r t e c h n ic a l n a m e sc l u d e : B u t y l - 3 - I o d o - 2 - P r o p y n y l c a r b a m a t e ; C a r b a m i c AI o d o - P ro p y n y l E s t e r ( W e n n i n g e r a n d M c E w e n 1 99 3); 3 - IoB u t y l c a r b a m a t e ( H a n s e n 1 98 4; R e g i s t ry o f T ox ic E f f ec tS u b s t a n c e s , 1 99 5); B u t y l - c a r b a m i c a c id 3 - Io d o - P ro p - 2 -y n yt if ic a n d T e c h n i c a l I n f o r m a t i o n N e t w o r k 1 9 80 a ); 3 - I o d o -B u t y l - c a r b a m a t e ; a n d I P B C ( Sc ie n ti f ic a n d T e c h n i ca l I n fw o r k 1 98 0 b). I P B C h a s s e v e r a l c o m m e r c i a l n a m e s , i n c l u( W e n n i n g e r a n d M c E w e n 1 99 3) a n d T r o y s a n P o l y p h a s e (T e c h n i c a l In f o r m a t i o n N e t w o r k 1 9 80 b ).P h y s i c a l a n d h e m i c a l P r o p e r t ie sI P B C i s a w h i t e o r s l i g h t l y o ff -w h i t e c r y s t a l l i n e p o w d e rw e i g h t 2 8 1 , d e n s i t y 1 .5 7 5 g / c m 3, a n d v a p o r p r e s s u r e 2 x 12 6 C . I P B C m e l t s a t 6 5 - 6 6 C ( H a n s e n 1 98 4; H e n d e r s o n c o m p o s e s a t 1 0 0 C ( H a n s e n 1 9 84 ) t o f o r m c a r b o n m o n o x i d ei de , n i t r o g e n d io x id e , d i n i tr o g e n o x id e , a n d h y d r o g e n i o d id1 9 92 ). A t 5 4 C , t h e c o m p o u n d i s s t a b l e ( H e n d e r s o n 1 99 2)m o d e r a t e l y s o l u b l e i n w a t e r , b u t i s h i g h l y s o l u b le i n a c e t oa l co h o l , a s w e ll a s o t h e r a r o m a t i c a n d p o l a r s o l v e n t s (



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IPBC

Table 1 Physical and chemical properties ofIodepropynyl Buty]carb' Reference

Molecular formula CsH12INO2

PhysicalpropertiesMolecular weightMelting point

Boiling pointDensityOctanol/WaterVapor pressureSolubility

White or off-whitecrystalline solid28165--66C

Decomposes at 100C1.575 g/cm36462 10 -6 mm Hg (26C)Soluble in water; lowsolubility n aliphaticsolvents and

hydrocarbon resins; mediumsolubility n alkyd resins;high solubility n aromaticand polar solventsWater: 188 ppm at 25C156 mg/L at 20-30C0.016 g/100 gMineral oil: 3.5 g/100gIsopropanol: 19.2 g/100gPEG monolaurate: 20.1 g/100gDipropylene glycol: 20.5 g/100g

Hansen 198WenningMcEwen Hansen 198HendersoHansen 198Hansen 198HendersoHorn andMarutzkyHansen 198

Henderson Henderson Hansen 198HendersoHansen 198

Hansen 98Henderson G + G Inte rnInc. 1995



25/61

COSMETIC IN

4 0 0 h o u r s o f e x p o s u r e . A t 1 0 8 h o u r s , t h e d e c o m p o s i t i o na p p e a r e d , a n d t h i s p r o d u c t d i s a p p e a r e d a f t e r 4 0 0 h o u r s A s e c o n d a r y d e c o m p o s i ti o n p ro d u c t b e c a m e p r e s e n t a t 2T s u n o d a , a n d T a k a h a s h i 1 9 91 a) . W h e n i r ra d i a t e d , t h eb o n d o f I P B C i s t h o u g h t to b e p h o t o l y ti c a l l y c l e a v e d i o di ne h o m o l y ti c a ll y fr o m t h e p r i m a r y d e c o m p o s i t io nt h e i o d in e w a s t h e n s u b s t i t u t e d f o r b y h y d r o g e n (L e e, T a k a h a s h i 1 9 91 b) .M e t h o d o f M a n u f a c t u r eI P B C i s p r e p a r e d b y t h e i o d i n a t i o n o f t e r m i n a l a c e t y l e nn e s) . C o m m e r ci a ll y , I P B C is p r im a r i l y m a n u f a c t u r e d u si o d in e i n a c o ld , a q u e o u s h y d r o x i d e s o l u t i o n o r b y a d d i n gc h l o ri te t o a n a l k a l i i o d id e s o l u t i o n . R e f i n e m e n t s i n t hy i e ld s o f 9 0 - 9 6 a n d m a k e it p o s s i b l e t o r e a c h p u r i t i e s w( R a o a n d P e r i a s a m y 1 9 9 5 ; G + G I n t e r n a t i o n a l , I nc . 1 9 96

n a l y tic a l M e t h o d sI P B C c a n b e d e t e r m i n e d b y g a s c h r o m a t o g r a p h y ( G C ) (a n d T a k a h a s h i 1 99 1a ), G C / m a s s s p e c t r o m e t r y (L ee , T a k a h a s h i 1 99 1 b; H o r n a n d M a r u t z k y 1 99 4; G + G I n t e1 9 9 6) , i n f r a r e d s p e c t r o m e t r y ( G + G I n t e r n a t i o n a l , I n c. 1 9c h r o m a t o g r a p h y ( T LC ) , a n d e l ec t ro n c a p t u r e G C ( G a b r i e le1 98 4). I P B C i n e f f l u e n t s a n d s e d i m e n t s c a n b e e x t r a c t e d wc h lo r id e , fi lt e re d , a n d d r ie d . T h e r e s i d u e i s t h e n d i s s o l v ea n d a n a l y z e d b y h i g h p e r fo r m a n c e l iq u id c h r o m a t o g rH P L C h a s a ls o b e e n u s e d to d e t e rm i n e I P B C i n w( H e n d e r s o n 1 99 2). I P B C i n s a m p l e s o f w o o d p r e s e r v a t i v eb e m e a s u r e d a f t e r c o m b u s t i o n i n a P a r r o x y g e n bo m b . A n a



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IPSC

and water solvent is 190 nm, with extinction coefficients of 6570cm (pH 5) and approximately 6000 L/mol-cm (pHs 7 and 9). A peak occurs at 227 nm (500 L/mol-cm at pHs 5, 7, and 9). Nwavelength maxima were observed between 190 and 800 nm (RInc. 1994). UV spectroanalysis of IPBC in methanol had two peasmaller peak was located at 230.5 nm and a larger shoulder at with a valley at 218.5 nm. A peak at approximate ly 195 nm was idas being solvent related (G + G Inte rnat ional, Inc. 1996).Impur i t i esTechnical grade IPBC is 97-99% pure (Henderson 1992; G + G Itional 1995). Primary impurities are sodium chloride (0.9% maand t riiodoallylbutylcarbamate (


27/61

6 COSMETIC ING

T a b l e 2. Cosmetic formulation data on Iodopropynyl ButylcaFDA 1996)TotTotal no. formula- latProduct category tions in category

Other fragrance preparations 195Hair conditioners noncoloring) 715Shampoos noncoloring) 972Tonics, dressings, and other hairgrooming aids 604Other hai r preparations 395noncoloring)Hair dyes and colors 1612Hair shampoos coloring) 29Other manicuring preparations 83Ai~ershave lotion 268Other shaving preparation 63productsCleansing preparations 820Face and neckpreparations excludingshaving preparations) 300Body and hand preparationsexcluding shaving preparations) 1012Moisturizing preparat ions 942Night preparations 226Paste masks mud packs) 300Other skin care preparations 810Suntan gels, creams, and liquids 196Indoor tann ing preparations 67Other suntan preparations 68



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IPBC

(Machemer 1979; Henderson 1992), metalworking fluids, canvcordage (Henderson 1992). IPBC applied to wood or timber wi thtreatment at 0.75% (w/w) or by vacuum/soak impregnation pagainst the fungi Co rio lus vers ico lor, Tyrom yces pa lus t r i s , and Sl a c r y m a n s (Lee, Tsunoda, and Takahashi 1990a, 1992). IPBC hadergistic effect when a surface-active agent was also applied to theand protected against every w o o d - d e c a y i n g fungus tested (HanseLee, Tsunoda, and Takahashi 1990b). Approximately 50 ppm (0.IPBC controlled fungal growth and 250-1000 ppm provided badal protection (G+G Interriational, Inc. 1995). Bacteria controIPBC included Bac i l l u s sub t i l i s , Escher i ch ia co l i , S taphy lococcr e u s, K l e b s ie l la p n e u m o n i a e , and Ps eud om on as aerog inosa. Thmum inhibitory concentrations (MIC) ofIPBC (agar inhibition tea variety of microorganisms were submi tted by industry. The MIPBC for common molds, mildews, yeasts, and fungi ranged from 0Aspergi l lus n iger) to 10 ppm Tr i choderm a v i ri de ). For algae, thwere below 50 ppm (G + G In ternational, Inc. 1996).G E N E R A L B I O L O G YA b s o r p t i o n D i s t ri b u t io n M e t a b o l is m a n d E x c r e tio nIn rats, 14C-IPBC was quickly absorbed from the intest inal tracbloodstream when adminis tered orally as a suspension in 0.5% cmethylcellulose. The compound was then rapidly eliminated. Peama concentrations occurred at 2 hours postdose, and 23-36%parent dose was bound to plasma proteins. Radioactivity in the likidney decreased steadily up to 240 hours postdose, but in skeletacle, lungs, and hear t, the decrease was slower. From 12 to 240 houadministration, radioactivity in fat tis sue and sk in remained relconstant. At 1 hou r after intravenous adminis trat ion (dissolvedethanol : water), very little IPBC was detected in the plasma (Hen



29/61

CO SM ETIC IN

other unidentified polar compounds; 32.3-50.9 of the IPBC was excreted in urine and 38.2-56.7 in the exhaamount s were also eliminated in the feces and/or re taine(Hazleton Laboratories, Deutschland 1987; Henderson 193- Iodo- 2-[14C]- propyny l-N- [1-14C]-butylcarbamate-tskin samples (400-800 ltm diameter, epidermis and papwere evaluated to determine the potential for systemic eIPBC. A dose of 5 Izl of 0.1 radioactive IPBC in acetonto six previously frozen skin samples (epidermis and pap400-800 tzm thick, from each of four cadavers. Each skiexposed to a dose of 6 ttg/cm2 so that approximately 0.5plied to each. The contact area size was 0.8 cm2. At 1, 212, 16, 20, and 24 hour s after treatment , the amount oin the receptor fluid was measured. At the time of the ment (24 hours), excess radioactivity on the epidermal skremoved and the amount remaining in the epidermis andsured. Also, the evaporating radioactivity was t rapped asepidermal surface, and was quantitated. Skin penetrationtotal radioactivity in the receptor fluid and dermis, was percent of the applied dose. In this study, 53 14 of tdioactivity penet rated the skin within 24 hours, and the tion occurred wi thin 8 hour s of the application of IPBC. Aevaporated from the skin surface during the course of the smately 87 10 of the applied radioactivity was recovertest (Reifenrath Consulting and Research 1995).

Pharmacologic ffectsCarbama te compounds other tha n IPBC have been implichibition of blood acetylcholinesterase activities. This inhin the accumulation of the n eurotr ansmit ter acetylcholin



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IPBC

N I M L T O X IC O L O G Yc u t e T o x i c it yral

Technical grade (in thi s case, 97 pure) IPBC has an average acLD50 of 1470 mg/kg in rats (Hazleton Laboratories America, IncHenderson 1992). The LDs0 after a 14-day observation period wmg/kg and 1795 mg/kg in female and male ra ts, respectively (HLaboratories America, Inc. 1984; Henderson 1992), to give a rat ing of 3 (moderately toxic) to the compound. Another source rthat technical grade IPBC has an acute oral LDs0 of 1580 mg/kgbut no experimental details were given (Hansen 1984).Adult albino Sprague-Dawley rats weighing 200-250 g each wlotted into g roups of five males and five females per sex, per dosra t received a 10 ml/kg suspension of IPBC in Duke's pure by gavage. Doses were 250, 500, 1000, 1500, or 2000 mg/kg. Ragroups had rough coats. All groups except for the 1000 mg/kg doswere observed to have soft feces and urine stains, as well as slpression. The rats that were administered 1500 mg/kg had redon the nose and /or eyes (Hazleton Laboratories America, Inc. 1

Male and female Sprague-Dawley rat s received by gavage singof undiluted cosmetic formulations containing various concentraIPBC from 0.0100-0.0150 w/v and were killed for necropsy oor 8 of the studies, summarized below.Moisturizing gel, sunscreen lotion, moisturizing cream, and mzing gel conta ining 0.01 IPBC each caused no unscheduled mor changes in body weight in 10 rats tested per preparation. Thoral LDso of each formulation was > 10,000 mg/kg with 95 con(Springborn Laboratories, Inc. 1992a, 1993a, 1993b). Administrthe moisturizing gel resulted in dark material around the fac



31/61

1 COSMETIC ING

other clinical signs were reported (Inte rnat iona l Researchment Corp. 1990a).ermal

Adult male New Zealand white rabbits, each weighing 2.3divided into two groups of five rabbits each. The first grouskin, and the second nonabraded skin. IPBC at 2 g/kg wwith physiologic saline prior to dermal application. All raberved for 14 days after the 24-hour exposure period. Noreported in either group during the study. Erythema andobserved at the t rea tme nt sites in all rabbits during the sure period (Bioassay Systems Corp. 1984a). The LD50 wa2000 mg/kg in male rabbits (Hansen 1984; Bioassay S1984a; Henderson 1992) to give a corresponding toxici(Henderson 1992).InhalationVarious concentrations of IPBC were adminis tered as duaerosols to seven groups of five Sprague-Dawley ra ts per each rat weighing 199-322 g. The first four groups inhaldust (average ma ss median aerodynamic diame ter 0f4.3 ,amometric st andard deviation of 2.9; average of 82 of partireceiving gravimetric concentrations of 1.7, 0.38, or 0.72 tively. The remaining four groups received 3.4, 1.8, 0.45, respectively, as a liquid aerosol (average mass med ian aeromete r 0f2.4 ~m; average geometric standar d deviation of 294 of particles


32/61

IPBC

effects occurred in rats fed 125 mg/kg/day. In the low dose groua slight increase in relative liver weight was observed (Hen1992).In a range-finding reproduction study, mated female ra ts that r80 mg/kg/day IPBC by gavage for 20 days of gestation had no lnecropsy. In a related study, males fed 700 ppm IPBC for 28 dno signs of toxicity (Henderson 1992).

ubchronic Toxici tySprague-Dawley rats (number not given) received 20, 50, or 125IPBC in corn oil five times per week as part of a 13-week feedinRats administered 125 mg/kg had transient behavior alteraticreased liver weights, and hepatocyte enlargement. Males of thgroup had decreased weight gain and gastric lesions. Transi entioral alterations and increased relative and absolute liver weigwere recorded in both sexes at 50 mg/kg. The no-observed-aeffect level (NOAEL) was 20 mg/kg. After a 4-week recovery petreatment-re lated pathologic changes were observed, indicating tlesions were reversible. IPBC and/or the t est vehicle were only irrit ating to the ra t when administe red orally (Henderson 1992)Groups of 28-day-old Sprague-Dawley rats were administerein corn oil by gavage for 13 weeks in a 90-day subchronic oral test. Ten males and 10 females, weighing 217-280 g and 140-1initiat ion, respectively, made up each of five groups. IPBC (0, 425 mg/ml) in corn oil, with a dose volume of 5 ml/kg, were testedof 20, 50, and 125 mg/kg were adminis tered five times per weeweeks. No deaths were repor ted dur ing the study. No toxic effecseen in females administered 125 mg/kg or males given 50 mgchanges in either hematology or clinical chemistry para meters (bistry and urinalysis) or gross lesions were observed. Male ra ts gi



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2 C O S M E T I C I N G

unscheduled deaths occurred, and no differences in meanand body weight gain were found between test and controbits (5/10) had slight to moderate erythema that appearday 6 and cleared by day 48. One rabb it had sporadic ery thout the study. Rabbits (2/10) had slight to moderate edemby day 52. In a few rabbits, desquamation, fissuring, aareas were occasionally observed. No differences in hemawere present. At necropsy, 2/10 rabbits had mild erythemcoloration of the application site. Nei ther gross lesions nordifferences were noted. Microscopic changes that were athe application of the test material were acanthosis and hof the epidermis and chronic inflammation of the dermis (Research and Development Corp. 1994a).In a simi lar study, moisturizer containing either 0.0125IPBC in a n oil/water emulsion caused no signs of systemicapplied to 10 New Zealand white rabbits (International Development Corp. 1994b).

hron ic Tox ic i tyMale and female 4-week-old Sprague-Dawley rats, 200 used in a 104-week chronic oral toxicity study. Fifty rat s ofin each group, including the control. At study initiation, mapproximately 85 4- 5 g and females 60 -4- 5 g. IPBC wasin the diet, which was offered ad libitum, at 20, 40, or 8IPBC concentration was adjusted weekly for the first 13study, then once every 4 weeks to ensure th at the dose wathe duration of the experiment. All rats were necropsiedthe study. Deaths included 22 males and 17 females in group; 20 males and 21 females of Group 2 (20 mg/kg); 10 females of Group 3 (40 mg/kg); and 14 rats of each se



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IP B C

salivary gland, submucosal edema, and inflammation (in the ndula r portion) of the stomach. Acanthosis, hyperkeratosis, ulcebasal cell proliferation, and lesions associated with ulcers weobserved in the nonglandular stomach in those two groups (InResearch International 1989a).

e r m a l I r r it a t io nPrimary skin irrit ation and corrosion test s were performed on sNew Zealand white rabbits weighing between 2.0 and 3.5 kg. A0.5 ml IPBC was applied to two 1 x 1 sites, one abraded and obraded for a 4-hour exposure time. Skin s ites (under occlusive pwere observed and rated at 4, 24, 48, and 72 hours after adminisAt the end of the 4-hour period, slight ery thema and severe edemobserved, bu t recovery was complete by 48 hours. The primary irindex was 0.50 and IPBC was noncorrosive (Bioassay System1981a).In a simi lar study, slight to moderate erythema and slight edemnoted in two rabbits (total n umber not given) that had been expIPBC (concentration not given) under a semiocclusive patch for 4The reactions occurred at 24 hours after patch removal. Slight erpersisted until the 72-hour assessment in one of the affected rInvestigators concluded that IPBC is slightly irritating to rabb(Inveresk Research International, Ltd. 1989b).

e r m a l S e n s i t i z a t i o nHenderson (1992) reported that IPBC (concentration not giveduced slight irritat ion when applied to the skin of rabbit s and tcompound was not a dermal sensitizer in guinea pigs. Hansen sta ted that a 40% solution of IPBC was not a skin sensitizer. Ndetails were given.



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4 COSMETIC IN

O c u l a r r r i t a t i o nThe potential for IPBC to produce ocular irritation in yoZealand white rabbi ts was determined by tes ting 0.5 IPand 0.5 in a typical baby shampoo formulation. Twelvdivided into two groups of three males and three femalesreceived 0.1 ml IPBC in corn oil (right eye) and corn oil second group was administe red IPBC in baby shampoo (rshampoo alone (left). The eyes of all rabbits were rinsed application and were evaluated at 1, 24, 48, and 72 hoursIPBC in corn oil and corn oil alone produced no eye irritatconjunctival irritation were produced in rabbits adminisbaby shampoo and baby shampoo alone. This irritation 7 days after exposure. No apparent differences between robserved in Group 2 rabbit s for shampoo plus 0.5 IPBCalone (Hill Top Biolabs 1991).In another study, nine male New Zealand white rab2.0-3.5 kg Were treated with 0.1 g IPBC, six rabbit s withand three with irrigation. The test substance was appliof each rabbit, and the other eye served as control. Sevechemosis, discharge, and corneal opacity were observed inIn five of six rabbits, the iris appeared congested and unreIn rinsed eyes, discharge was slight in two of three rabbone rabbit , which still had corneal opacity, effects subsiafter exposure in rabbits with unrinsed eyes. In the otheffects were no longer observed after 2 days (Bioassay 1981b).

A dose of 0.055 g (0.1 ml) IPBC was instilled into the coof each of nine New Zealand white rabbits. The contralateas the untr eated control. At 30 seconds postinstillation, thrabbit s were rinsed with 50 ml of physiologic saline. All



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IPBC

eyes, but all reactions had resolved by day 21. As a result of thi sinvestigators reported that IPBC was a severe irritant to the erabb its (Spr ingborn Laboratories, Inc. 1990).Undiluted sunscreen lotion, moisturizing cream, and moisturizion were each instilled directly onto the cornea of the right eyes oNew Zealand white rabbits. A 10 1 dose of each formulation dproduce corneal opacity, iritis, or conjunctivitis as evaluated at 24after dosing (Springborn Laboratories, Inc. 1992b, 1993c).In simi lar studies, 10- 1 doses of undiluted facial cleaner, sunlotion, and sunscreen cream, each containing 0.0125% IPBC, wstilled into conjunctival sacs of New Zealand white rabbit s (SpriLaboratories, Inc. 1991c, 1991d, 1991e, 1993d, 1994a). In one stufacial cleaner did not cause ocular irritation (Springborn LaboraInc. 1993d), but in another, 2/3 tested eyes had conjunctivitis at 24after dosing, which cleared at 72 hours (Springborn Laboratorie1994b). Sunscreen lotion produced conjunctival redness in 3/3 teswhich resolved by 48 hours (Springborn Laboratories, Inc. 1994a),an earlier study it did not result in ocular irritation (Springbornratories, Inc. 1991c). In a thi rd study, 1/3 eyes had conjunctival r(Springborn Laboratories, Inc. 1991d). Sunscreen cream did not pocular irri tat ion (Springborn Laboratories, Inc. 1991d, 1991e).Instil lat ion of 10-~l doses of sunscreen lotion and cream (0.IPBC) resulted in slight conjunctival redness in 1/3-2/3 eyes (Itional Research and Development Corp. 1990b). No ocular irritat iobserved in a similar study (International Research and DeveloCorp. 1990c).ho t o sens i t i z a t i o n

Male and female 300-500 g Hartley guinea pigs (37 of each) werlenged with 5% IPBC to determine delayed contact hypersen



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6 C O S M E T I C I N

week (Monday, Wednesday, and Friday) for three consecu30 minutes after removal of the occlusive dressing, 20-wbulbs were used to irradi ate the guinea pigs with UVA afor 2 hours each time. Exposure intensity peaked at 365 nm310 nm for UVA. Application sites were observed and eand 48 hours after the removal of the occlusive dressings ftation. Photosensitization was not produced by 5 IPBC.pigs in the induced group had grade 1 (slight) irritation, wpigs in the untr eated group had grades of after primary to these questionable findings, a rechallenge was performskin reaction grades of were observed in both induced anprimary challenge groups, establ ishing that photosensitioccur (Hill Top Biolabs 1994).R E P R O D U C T IV E N D D E V E L O P M E N T L T O X IC I T YIPBC was administered to Sprague-Dawley rats by diet toeffects on the P and F1 generations, as well as their offsFib. Each of four groups included 50 rats , 25 male and 25 feand females weighed 175-235 g and 140-85 g, respectivfed diet conta ining 120, 300, or 750 ppm IPBC for 293 daystrol diets were available to the ra ts ad libitum. At the codosing period, the rats were killed for necropsy. No treaeffects were observed in clinical condition, necropsy findmat ing performance, postnatal viability, or postna tal groand functional development were similar to controls. The msumption of 750 ppm-dosed P and F1 males decreased sthe rats ' prema ting period. During the same period, P ma750 ppm and F1 males at 750 ppm had reduced body weeffects were observed in either males or females adminisIPBC (Inveresk Research Internat iona l, Ltd. 1987). Mate



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I P C

6-10, but no other effects were noted. Doses of 20 and 50 mg /kgcause reproduct ive toxicity Henders on 1992).Diet ary admi ni str at ion of 120, 300, and 750 ppm IPBC to gr25 mal e and femal e ra ts per gene rat ion P and F1) had no effectilit y or general reproductive performance in eith er generationa 14-week premat ing treat men t period, the pa rental ra ts wereand the offspring kept unti l weaned. Slight toxicity was obseP males in the int erme dia te and high-dose groups, which had rbody wei ght gain and reduced feed consumptio n before matin g. Fgiven 750 ppm also had simi lar signs duri ng the pre mat ing perevidence of toxicity was observed in ra ts fed 120 ppm. Pos tna taopment of offspring was not affected duri ng the lactati on period,live birth index was slightly lower in both generations at the dose Hender son 1992).

Groups of 35 pr egnant Crl: NMRI Br mice were ad mi nis ter edor 125 mg /kg doses of IPBC by gavage. Mice were dosed once da2.0, 5.0, or 12.5 mg/k g IPBC i n corn oil on days 6 -15 of ges tagive a dose volume of 10 ml/kg/day. There was no positive contday 18 of gestation, all mice were killed for necropsy. The remat er nal and fetal examin atio ns are summa rize d in Table 3. nificant differences were noted between th e negative control 0and the oth er groups. No treat men t-re lat ed effects on clinical oand necropsy findings were observed. IPBC dosing also had no efma te rna l body weig ht gain or feed consumption, incidence of prepre- or pos timp lant atio n loss, or the number, weight, or sex distrof fetuses. Additionally, the incidence of malf orma tions did notas a resu lt of the study Hazleton Laboratories, Deuts chlan dHenderson 1992).Pre gna nt Spra gue-Dawley rats were teste d in a simi lar study. G28 rats) received 20 mg/ kg IPBC in corn oil, Group 2 33 ra



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8 COSMETIC INab l e 4. Reproductive and developmental toxicity resul ts--ra

Dose level 0 mg/kg 20 mg/kg 50 mgMaternal parametersNo. of corpora lutea 313 331 309No. of implanta tions 240 276 240No. of resorptions 8 14 6

Nc aborting 0 0 0Fetal parametersNo. of live fetuses 232 261 232No. of dead or resorbed fetuses 8 15 8No. of fetal anomalies 1 0 1

admin ist er ed 50 mg/kg, and Group 3 30 rats) 124 mggroups received 2.0, 5.0, or 12.5 mg/ml, respectively, and a dose volume of 10 mg/ml/day. All rats were admin ist ereday on days 6-15 of gestati on, the n sacrificed at day 20Table 4 is a summary of the results of the maternal annations. Incidence of malformati ons and skele tal varia tioneg ati ve control and dosed groups were observed to be coth at received the 125 mg/kg dose had a hi gher incidence oossified crani al bones, but this was th oug ht to be temp oby ma te rn al effects Hazleton Laborat ories, Deut sch landGroups of eight mated female NMRI mice received 20, 50, or 125 mg /kg IPBC by gava ge from ges tat ional and were killed for necropsy on gd 18. No tr eatm ent- rewere noted in mat er na l clinical condition or in necropsy gd 10-15, body weight gain was sligh tly reduced at the hiwere no effects of IPBC tr eat me nt on preg nancy incidencepost impl anta tion loss, or the number, weight, and sex dist



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IPBCof IPBC were tested when compared to five different positive c[dimethylsulfoxide (DMSO), methylnitronitrosoguanidine, 9-acridine, 2-nitrofluorene, and 2-aminoanthracene] . The two highcentrations of IPBC were toxic (Hazleton Biotechnologies Corp. Henderson 1992).In a second study, a micronucleus tes t was performed in Char leCD-1 mice. Groups of 15 males and 15 females received a dose 660, or 2000 mg/kg IPBC in corn oil by oral gavage to give a 1dose quantity. The positive control was cyclophosphamide. Micsacrificed at 30, 48, or 72 hours. Doses of 660 and 2000 mg/kproved toxic. No significant increases in the frequency of micronpolychromatic erythrocyte cells were observed; therefore, IPBC wclastogenic (Hazleton Biotechnologies Corp. 1984b; Henderson 1A third study utilizing an unscheduled DNA synthesis assaytigated IPBC s genotoxic potential on p rimary cultures of hepafrom adult male Fischer 344 rats . Michler s ketone in ethanolas the positive control and DMSO the vehicle control. DNA sywas determined by silver grain counts in photographic emulsionsby the cel lular uptake of [6-3H]-thymidine. Doses of 3, 4.5, 6, 7.5,12, and 13.5/~g/ml of IPBC did not induce unscheduled DNA sybut t reated cultures had decreased viability as the concentration was increased (Inveresk Research International, Ltd. 1988b; Hen1992). Hepatocytes t rea ted with the highes t dose had signs of tbut none of the cultures were positive for genotoxicity (HendersonC R C I N O G E N I C I T YIn one study on the carcinogenicity of IPBC, groups of 50 male anmale Sprague-Dawley rats were given different doses of IPBC diet for 104 weeks. The feed, offered ad libitum, was formulat20, 40, or 80 mg/kg/day. Blood was drawn and blood counts perfo



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2 0 C O S M E T I C I N G

differences were found in organ weights. No evidence opotential was detected, and the NOAEL (major struc turaset at 20 mg/kg /day for both sexes (Henderson 1992).

C L IN IC A L A S S E S S M E N T O F S A F ET YIppen (1993) classified IPBC as hav ing the lowest possiallergy test series (nonexisten t or extremely rare reactioded hu ma n sensitization, eczematic skin reactions, contpotential, cross allergy, and a stati stica l ma rk et eval uatioG+G International, Inc. 1995). However, IPBC when momoderate skin irritation, primarily to areas of soft, s(G + G Int er na ti onal , Inc. 1995).

P r i m a r y S k i n I r r i t a t i o nA 4% concentration of a facial cleanser that contained 0was tested for the potentia l to cause skin irritati on. Of the each received an occlusive patch w ith 0.2 ml of the test mvolar forearm for 24 hours. Test sites were evaluated 28after patch application. The observed responses (eryth emaout edema), all of which c leared by 72 hours, we re suggirrit atio n with some occurrences of moderate irritation. Mhowever, did not experience any adve rse reac tions (Hill Inc. 1994e).

5 Day Cumulat ive Irr i ta t ionUndilu ted sun screen lotion containing 0.0125% IPBC



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IPBC

0.2 ml of the test mater ial was applied daily under an occlusivapplied to the infrascapular region of each subjects' back unleerwise noted. Patches applied on Friday were not replaced unfollowing Monday. The positive control in each case was a 0.2 lauryl sulfate. Moistur izing lotion containing 0.0050 (TKL ReInc. 1993c), 0.0100 (Ivy Laboratories 1992), or 0.0125 IPBCResearch, Inc. 1993d) had no significant irritation relative to thtrol when tested on 26, 49, and 26 subjects, respectively. In the the 0.0125 lotion, min imal or doubtful erythema or definite erywere observed in a few cases, sometimes with a papula r or papulular response and/or dryness (TKL Research, Inc. 1993d). Moistcream containing 0.0100 IPBC produced insignificant or negligimary irr itation when 0.1 ml was applied to the volar forearm unocclusive patch. Additionally, the test product was applied twicto the entire face (including the forehead and excluding the imate periorbital areas) of the same volunteers to assess toleranceformulation. No adverse reactions were reported, including erand scaling. Three subjects, however, experienced the developmnew acne lesions (inflammatory papules). Upon examination, it wtermined that the outbreak could not be attributed to the test p(Ivy Laborator ies 1992). Sunscreen lotion (0.0125 IPBC) did nosignificant irri tation relative to a 0.1 sodium lauryl sulfate pcontrol when applied to the infrascapular region of 27 subjectResearch, Inc. 1994h, 1994i), but one subject had definite erythethroughout the first 16 readings tha t was accompanied by a pappapulovesicular response and/or dryness from applications 11-the following application, the subject also had severe damage to dermis (oozing, crusting, superficial erosions), and treatment wcontinued. One other subject had definite erythema (+) on appli12-21 (TKL Research, Inc. 1994i). In simi lar studies , no significatation resulted from the application of the lotion to the forearm



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C O S M E T I C I N

stu dy (3 on face, 3 on shoulder s, 1 on chest, 1 on back, anThe cumula tiv e score for irr it ati on was 82 for week 1 andOne child reported small, white, pinhead-sized spots onlegs and was diagnosed as having here ditary glan dular ha product experience quest ionnai re completed by the pa reof the 4-week trial, nine subjects reported irr itati on experiing, stinging, itching, peeling, redness, and/ or sk in conditamined by a dermatologist, however, these findings wereor were diagnosed as being un rel ate d to the product. Recluded that, because the derm al ir rita tion noted and scburn erythema and not product related, the sunscreen wint end ed use in chi ldren (Hazleton Florida 1991).

um an Repeated Insu lt Patch TestIn a hum an repeated insult patch test th at was an adaShel ansk i and Shela nski method, 170 voluntee rs aged 18trea ted with a concentration of IPBC dete rmine d by thehu ma n skin irri tatio n screens. During th e first screen, 1IPBC in corn oil produced sli ght to moder ate concentratir ri ta ti on after a 24-hour occlusion period. In the seconto 1.0% solutions of the test subst ance failed to cause ithree repeate d applications over 5 days, when each applilowed by 24 hou rs of a semiocclusive patch (Hill Top 1994a; Consumer Product Testing Co., Inc. 1995a, 1995duction test, 0.2 ml of 1.0% IPBC in corn oil was admitimes a week (Monday, Wednesday, and Friday) for threweeks, then once on the Monday of the 4th week. The chatration and amount applied were the same, but were onlyonce. The applicat ion site was a 1 x 1 nonabra ded areaback bet ween t he scapulae , and was covered by a semioc



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IP B C

T a b l e 5 . Hu ma n rep eated insult patch tests (All tests gave negative rNo. ofFormulation subjects Test site References

Sunscre en lotion 106Sunscre en lotion 106Moisturizing cre am 106Moisturizing cre am 95Moisturizing cre am 100Moisturizing lotion 106Moisturizing lotion 96

Moisturizing lotion 109Moisturizing lotion 109

Facial cleanse r 231Moisturizing cre am 100Moistur izing lotion 105Moisturizing lotion 101Sunscreen cream 95Sunscreen cream 107Sunscre en cre am 102Sunscre en cream 102Sunscre en cre am 102

0.0100 I P B CInfrascapularInfrascapularInfrascapularUpper armInfrascapularInfrascapularUpper arm0 . 0 1 2 0 I P B CInfrascapularInfrascapular0 . 0 1 2 5 I P B CUpper armInfrasca )ularInfrasca )ularInfrasca mlarInfrasca )ularInfrasca mlarInfrasca )ularInfrasca mlarInfrasca mlar

HillTop ResearchInc. 1994bHillTop ResearchInc. 1994cTKLR esear ch, IncHillTop ResearchInc. 1994dTKLR esea rch , IncTKLR esea rch , IncHarrison ResearchLabora tories, In

TKLR esea rch , IncTKL Re sea rc h, Inc

Harrison ResearchLabora tories, InTKLResearch IncTKLResearch IncTKLResearch IncTKLResearch IncTKLResearch IncTKLResearch IncTKLResearch IncTKLResearch Inc



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Table 5 Human repeated insult patch tests (All tests gave neresults) Continued.)

No. ofFormulation subjects Test site RefSunscreen lotion 105 Infrascapular TKL Rese

0 .0 3 7 5 I P B CMoisturizing lotion 99 Infrascapular TKL Rese

0 .0 2 00 I P B CMoisturizer 97 Upper arm Harris La(oil/water emulsion) 1990bMoisturizer 95 Upper arm Hill Top R(oil/water emulsion) Inc. 199

0 .1 2 5 0 I P B CMoisturizing lotion 104 Infrascapular TKL Rese

for a 14-day non tre at men t period. Challenge applicatioduring the 6th we ek of the study, and the test sites wer24, 48, 72, and 96 hours (patches were agai n removed aWith each test formulation, a few paneli sts had erythe ma,a pa pula r response, but overall, the r esult s were negativH u m a n r os s S e n s i t i z a ti o nHuman subjects (numbering 10 in all) with demonstrattivity to Thiu ram Mix, a skin contact skin sen sitiza tiontion containing structur ally related dithiocarbama te comtest ed with a topical application of 0.2 ml of 0.1 IPBC



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IPBC

an occlusive patch, and IPBC was administered three times a w4 weeks. The positive control was acetulan. At the end of the experiod, a follicular biopsy sample was taken and examined. Comdensity was determined stereomicroscopically. A dose of 0.1 IPGMS cream was noncomedogenic in humans under the conditthis study. Signs of irritation observed were itching or mild to ately severe erythema. No edema, blistering, discoloration, or swere observed (Hill Top Research, Inc. 1995).Occlusive patches containing 0.2 ml of an undiluted cosmemulation were applied three times per week for 4 weeks to theof panelis ts who had been previously screened for thei r propenform microcomedones. The 4-cm 2 patches (test, positive controltive control) were kept on the application sites for 48 hours, excthose applied on Friday, which remained in place for 72 hoursa 4-week period, a cyanoacrylate follicular biopsy sample was obfrom each test site and evaluated for microcomedone density. Moigel (Hill Top Research, Inc. 1993a), sunscreen lotion (Hill Top ReInc. 1994f), moisturizing cream and lotion (Hill Top Research, Inccontaining 0.0100 IPBC were all noncomedogenic when tested9, and 12 subjects, respectively. In the study testing the moistgel, panelists reported mild to moderately severe itching and mmoderate erythema (Hill Top Research, Inc. 1993a).Facial cleanser (Hill Top Research, Inc. 1993b), sunscreen lotioTop Research, Inc. 1990a, 1994f), moisturizing lotion (Hill Top ReInc. 1993c), and sunscreen cream (Hill Top Research, Inc. 1990taining 0.0125 IPBC were also noncomedogenic when tested oor 11 subjects each. One subject tested with sunscreen lotion enced mild to moderate erythema (Hill Top Research, Inc. 1993slight increases in microcomedone density were observed in patested with mois tur ing lotion (Hill Top Research, Inc. 1993c). In lar study, sunscreen cream (0.00150 IPBC) was noncomedogeni



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twice weekly for 3 weeks, with a 48-hour resp ite bet ween edays after the l ast induction exposure, subjects underwenphase. Patches were applied to untr eat ed skin to the oppolower back for 24 hours, removed, and the sites irr ad ia teUVA. A duplicate set of patches served as an unexposetrol (Ivy Labor atori es 1993a). Suns creen lotion (Ivy Labormoi stu riz ing cream, and moi stu riz ing lotion (TKL Researcon tai ning 0.0100 IPBC possessed no photocontact alltia l when each was te sted on 26 subjects.The following formu lati ons con tain ing 0.0125 IPBClotion (Ivy Labor atori es 1993a), test ed on 25 and 26 subjscreen cream (Ivy Laboratories 1991b, 1994a) tested on 2jects; and sunsc reen lotion tes ted on 26 and 27 subjects (Iv1991b, 1994b), did not possess de tectable photocontact altial. When a dose of 10 ~l/cm2 of moisturiz ing lotion (Iv1990a), suns creen cream, or suns cree n lotion (Ivy Laborcon tai ning 0.0125 IPBC was applied to 26 subjects, thwere observed. Similarly, whe n 25 subjects each were tescreen lotion (Ivy Labor atori es 1990b) or suns creen creamries 1990c) cont aini ng 0.0150 IPBC, or mois tur izi ng lot0.1250 IPBC (Ivy Labora tor ies 1990d), no evidence oalle rgen icit y was found.hototoxic i ty

Undilu ted moi sturi zing lotion (containing IPBC at a co0.0125 ) was applied (0.2 ml of te st ma te ri al unde r occlthe lower midbac k regions of previ ously screened subjecmedical or dermatologic illness or were sensitive to ei thtopical preparatio ns and cosmetics. The irra dia ted controState s Pharmac opeia hydrophilic ointment. Twenty-four plication of the patches, the te st sites were uncovered and

IPBC



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1990h, 1991d, 1993c). Sunscreen creams (0.0125-0.0150 IPBthe same results (Ivy Laboratories 1990f, 1991c, 1994d).S U M M R YIodopropynylbu tylcarbamate functions as a preservat ive in cosmemulations. In 1996, it was reported to the Food and Drug Administh at IPBC was used in 122 cosmetic formulations. It is approvedin the European Union.14C-IPBC was quickly absorbed from the intestinal tract to thest ream when administered orally to rats. 14C was detected in thkidneys, skeletal muscle, lungs, hear t, skin, and fat tissues afterment; radioactivity was rapidly eliminated in the urine and exhaand was also detected in the feces. In skin penetration studies usman cadaver skin, 53 14 of applied 14C-IPBC (0.1 ) penetraepidermis and papillary dermis and 14 5 evaporated from thsurface.The average acute LD50 of IPBC in ra ts is 1470 mg/kg and reseaassigned a toxicity rating of 3 (moderately toxic) to the compoanother study, Sprague-Dawley rat s given 1000-1500 mg/kg IPBsoft feces, urine stains, rough coats, and/or slight depression astains on the nose and eye areas. Cosmetic formulations con0.01-0.0125 IPBC each had an acute oral LD5o > 10,000 mg/kg 0.0150 IPBC had an acute oral LD5o > 20,000 mg/kg. In 24-homal application studies, IPBC caused erythema and edema of tr easites in New Zealand white rabbits; the LD50 was >2000 mg/kg.Sprague-Dawley rat s administered IPBC as dus ts and liquid ahad decreased activity, eye closure, and excessive lacrimation. Suhad labored breathing, gasping, and secretory discharges aftersure. At necropsy, edema, emphysema, and reddened lungs weserved. The average LCso of IPBC was 680 mg/m3 (dust) or 780

8 COSMETIC IN



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Several investigators reported that IPBC produces slritation in rabbits. IBPC, however, was not a skin sensipigs. Photosensitization also did not occur in guinea pig5 IPBC.Cosmetic formulat ions containing 0.5 IPBC caused junctival irritation in the eyes of rabbits. Treatment wiresul ted in severe hyperemia, chemosis, discharge, corneconjunctivitis. The iris appeared congested and unreaWhen 0.055 g IPBC was instilled, corneal opacity associatlial sloughing, iritis, and conjunctivitis were observed. Clations containing 0.1-0.015 IPBC produced only slighredness.In reproductive and developmental toxicity studies mice, IPBC had no significant effect on fertility, repromance, or incidence of fetal malformations. Slight ma(reduced weight gain) was observed at the highest dosstudy using Sprague- Dawley rats. In ano ther study also uDawley rats, a higher incidence of incompletely ossifiedwas noted in fetuses in the highest dose level group, but wrelated to mate rnal effects. Reduced maternal weight gaserved in studies using mice, but no embryotoxic or terawere seen. The NOAEL was 50 mg/kg/day in mice.IPBC was not mutagenic with or without metabolic acSalmonella typhimurium mammalian microsome plateassay. A micronucleus tes t using Charles River CD-1 micto be nonclastogenic. IPBC also did not induce unschedulesis when primary cultures of Fischer 344 ra t hepatocyteNo evidence of carcinogenic potential was found in a 10oral toxicity study using Sprague-Dawley rats. The NOAE20 mg/kg/day. Dose-related reductions in weight gain whowever, along with inflammation of the nonglandula

IPBC



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Cosmetic formulations containing IPBC at concentrations rfrom 0.0015% to 0.1% were tested on human subjects and wercomedogenic. No dat a, however, were availa ble on the comedogof higher IPBC concentrati ons.

D I S U S S I O N

The Cosmetic Ingredient Review (CIR) Expert Panel was concabout the acute inha latio n toxicity observed in animal studieIodopropynyl Butylc arbama te. The Panel there by concluded th atshould not be included in cosmetic products me an t to be aerosoliThe Panel stated tha t skin penetration studies using viable skpreferable to those usi ng cadaver skin. Studies usi ng cadaver skisure penetra tion of unmodified compounds only, and do not provformation on the influence of other factors such as skin metabTherefore, studies us ing viable skin are more useful in as sessisafety of cosmetic ingredient s.The Panel noted t ha t dose-related reductions in body weight gaiobserved in a long-term carcinogenicity study usin g Sprague-Drats, althou gh no evidence of carcinogenic potent ial was found. Altnoting the low degree of sensit izati on observed in ani mal studiin huma n repeated in sult patch tests, the Panel acknowledged thdermal i rrita tion pote ntial of this ingredient. Because the high ecent rati on tested for comedogenicity was 0.1%, the Panel constha t concentration to be the hig hest for which the availab le dat a support safety.

O N L U S I O NOn the basis of the dat a presente d in this report, the CIR Expert

3 C O S M E T I C I



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B i o a s s a y S y s t e m s C o r p. 1 98 1 b. P r / m a r y e y e ir r i t a t i o n t e s t ( Fo n W - 14 5 p o l y p h as e . (T r o y C h e m i c a l C o rp .) U n p u b l i s h e d dTR S (T ab 5) , A ug. 11 , 1995. (1 pa ge . ) 1B i o a s s a y S y s t e m s C o r p. 1 9 8 4a . A c u t e d e r m a l t o x i c it y s t u d y p ep o l y p h a s e . ( T r o y C h e m i c a l C o r p . ) U n p u b l i s h e d d a t a s u(Tab 2), Aug . 11 , 19 95. (1 pag e . ) 1B i o a s s a y S y s t e m s C o rp . 1 9 8 4b . 9 0 - D a y s u b c h r o n i c o r a l t o xt e s t m a t e r i a l : T r o y s a n p o l y p h a s e . (T r oy C h e m i c a l C o rp .) Usu b m i t t e d by TR S ( T a b 15 ), Au g . 11 , 1995. (1 pa ge . ) 1B i o d y n a m i c s , I n c. 1 9 9 0 . ( T r o y s a n P o l y p h a s e P 1 0 0 ) a c u t e i ns t u d y i n t h e r a t . ( T r oy C h e m i c a l C o rp .) U n p u b l i s h e d d a t a s(Tab 3), Aug. 11 , 1995 . (1 pag e . ) 1C o n s u m e r P r o d u c t T e s t i n g C o., I n c. 1 9 9 5 a. O n e w e e k s k i n w i t h 3 - I o d o- 2 -P r o p yn y l B u t y l C a r b a m a t e ( IP B C ) i n H u m aU n p u b l i s h e d d a t a s u b m i t t e d b y T R S ( T a b 1 1), A u g . 1 1, 1 9 9

C o n s u m e r P r o d u c t T e s t i n g C o., In c . 19 95 b. R e p e a t e d i n s u l t pI o d o -2 - P ro p y n y l B u t y l C a r b a m a t e ( IP B C ) i n h u m a n s . ( L ol i s h e d d a t a s u b m i t t e d b y T R S ( T a b 1 1 ), A u g . 1 1 , 1 99 5 . (2 pC o s m e t i c, T o i le t ry , a n d F r a g r a n c e A s s o c i a t i o n (C TF A ). 1 9 9 5c o n c e n t r a t i o n o f u s e o f I P B C w i t h c o v e r l e t t e r d a t e d O c t . 6D u p u i s , J. 1 99 4. E E C C o s m e t i c D i r e c t i v e . P r o p o s a l f o r a c o ut h e a p p r o x i m a t i o n of t h e l a w s o f t h e m e m b e r s t a t e s r e lp r o d u c t s . Official journal of the European CommunitiesA nn e x VI /2 , p. 8 .E P L B i o - A n a l y t i c a l S e r v i c e s, In c . 1 9 9 0 . A q u e o u s H y d r o l y s iC h e m i c a l C o rp . ) U n p u b l i s h e d d a t a s u b m i t t e d b y T R S ( T a b 2( 2 pa ge s . ) 1

F o o d a n d D r u g A d m i n i s t r a t i o n (F D A). 1 9 88 . P e t i t i o n t o a m er e g u l a t i o n s t o p r o v i d e f or t h e s a fe u s e o f 3 - io d o -2 - p ro p y n y li n c o n t a c t w i t h f oo d. Fed Register 5 3 : 4 3 0 4 2 - 4 3 0 4 3 .F D A . 1 9 92 . M o d i c a t io n i n v o l u n t a r y f i l i n g o f c o s m e t ic p r o d u cc o s m e t i c r a w c o m p o s i t io n s t a t e m e n t s . F i n a l r u le . Fed R3 1 3 0 .

I P B C



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Harris Laboratories, Inc. 1990c. Human sensitization test. Unpublishesubmitted by CTFA ( 079), Sept. 6, 1995. (58 pages.) 1Harrison Research Laboratories, Inc. 1993. Human repeat insult patcUnpublishe

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