In the1996 safety assessment of methyldibromo glutaronitrile, the Cosmetic Ingredient Review Expert Panel stated that this ingredient is safe as used in rinse-off products and safe at <0.025% in leave-on products.1 The Expert Panel reviewed newly available studies since that assessment along with updated frequency and concentration of use information and did not reopen this safety assessment.2–65 The Expert Panel confirmed that methyldibromo glutaronitrile is safe as used in rinse-off products and safe at <0.025% in leave-on products (Table 1).
Historic and Current Uses and Concentrations of Methyldibromo Glutaronitrile.1,37,38
No. of usesa
Maximum concentration of use, %
Methyldibromo glutaronitrile
Data year
1996
2011
1996
2011
Totalsb
35
36
0.0075-0.06c
0.005-0.04
Duration of use
Leave-on
23
22
c
0.012
Rinse-off
12
11
c
0.04
Diluted for (bath) use
NR
3
c
NR
Exposure type
Eye area
5
NR
c
NR
Incidental ingestion
NR
NR
c
NR
Incidental inhalation—sprays
4
NR
c
0.01
Incidental inhalation—powders
5
NR
c
NR
Dermal contact
22
22
c
0.04
Deodorant (underarm)
NR
NR
c
NR
Hair—Noncoloring
12
14
c
0.016
Hair-coloring
NR
NR
c
NR
Nail
1
NR
c
NR
Mucous membrane
NR
9
c
NR
Baby products
NR
NR
c
NR
Abbreviation: NR, not reported.
aBecause each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum of total uses.
bTotals = rinse-off + leave-on product uses.
cBreakdown is not available.
Discussion
Information supplied to the US Food and Drug Administration (FDA) by industry as part of the Voluntary Cosmetic Ingredient Reporting Program indicates that in 1996, methyldibromo glutaronitrile was being used in 35 cosmetic formulations at concentrations up to and including 0.06%. Use of this ingredient in 36 product formulations in specific product categories was reported to FDA in 2011, and an industry survey produced use concentrations up to 0.04%. The European Commission had banned the ingredient from use in both leave-on and rinse-off products due to increased reports of sensitivity. However, the Expert Panel opined that many, if not most, reports of sensitization in patch test studies likely are due to testing at high concentrations such that the reactions observed are actually irritation responses.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The articles in this supplement were sponsored by the Cosmetic Ingredient Review. The Cosmetic Ingredient Review is financially supported by the Personal Care Products Council.
References
1.
AndersenFA, ed. Final Report on the safety assessment of methyldibromo glutaronitrile. JACT. 1996;15(2):140–165.
2.
De GrootAC. Contact allergens—what’s new? Cosmetic Dermatitis. Clin Dermatol. 1997;15(4):485–491.
3.
De GrootACVan GinkelCJWWeijlandJW. Methyldibromoglutaronitrile (Euxyl K 400): an important “new” allergen in cosmetics. JAAD. 1996;35(5):743–747.
4.
FischerLAJohansenJDMenneT. Methyldibromoglutaronitrile allergy: relationship between patch test and repeated open application test thresholds. Br J Dermatol. 2008;159(5):1138–1143.
5.
FischerLAMenneTVoelundAJohansenJD. Can exposure limitations for well-known contact allergens be simplified? An analysis of dose-response patch test data. Contact Dermatitis. 2011;64(6):337–342.
6.
GeierJSchnuchABraschJGefellerO. Patch testing with methyldibromo glutaronitrile. Am J Contact Dermat. 2000;11(4):207–212.
7.
GeierJLessmannHFroschPJ. Patch testing with components of water-based metalworking fluids. Contact Dermatitis. 2003;49(2):85–90.
8.
GruvbergerBAndersenKEBrandaoFM. Patch testing with methyldibromo glutaronitrile, a multicentre study within the EECDRG. Contact Dermatitis. 2005;52(1):14–18.
9.
GruvbergerBAndersenKEBrandaoFM. Repeated open application test with methyldibromo glutaronitrile, a multicentre study within the EECDRG. Contact Dermatitis. 2005;52(1):19–23.
10.
HaldMAgnerTBlandsJRavnHJohansenJD. Allergens associated with severe symptoms of hand eczema and a poor prognosis. Contact Dermatitis. 2009;61(2):101–108.
11.
AakhusAEWarshawEM. Allergy to methyldibromoglutaronitrile/phenoxyethanol (Euxyl K 400): regulatory issues, epidemiology, clinical characteristics, and management. Dermatitis. 2011;22(3):127–140.
12.
BoyvatAAkyolAGurgeyE. Contact sensitivity to preservatives in Turkey. Contact Dermatitis. 2005;52(6):329–332.
BruzeMGruvbergerBGoossensAHindsenMPontenA. Allergic contact dermatitis from methyldibromoglutaronitrile. Dermatitis. 2005;16(2):80–86.
15.
BruzeMGruvbergerBZimersonE. A clinically relevant contact allergy to methyldibromo glutaronitrile at 1% (0.32 mg/cm2) detected by a patch test. Contact Dermatitis. 2006;54(1):14–17.
16.
BruzeMGoossensAGruvbergerB. Recommendation to include methyldibromo glutaronitrile in the European standard patch test series. Contact Dermatitis. 2005;52(1):24–28.
17.
HeratizadehAKilligCWormM. Quantitative repeated open application testing with a rinse-off product in methyldibromo glutaronitrile-sensitive patients: results of the IVDK. Contact Dermatitis. 2010;62(6):330–337.
18.
JappeUSchnuchAUterW. Rosacea and contact allergy to cosmetics and topical medicaments—retrospective analysis of multicentre surveillance data 1995-2002. Contact Dermatitis. 2005;52(2):96–101.
19.
JavvajiSBelsitoDV. Patch testing with methyldibromoglutaronitrile in a localized population in the United States. Dermatitis. 2010;21(6):321–326.
20.
JohansenJDVeienNKLaurbergG. Contact allergy to methyldibromo glutaronitrile—data from a “front line” network. Contact Dermatitis. 2005;52(3):138–141.
21.
JongCTStathamBNGreenCM. Contact sensitivity to preservatives in the UK, 2004-2005: results of multicentre study. Contact Dermatitis. 2007;57(3):165–168.
22.
JowseyIRBasketterDAIrwinA. Proliferative responses in the local lymph node assay associated with concomitant exposure to 1,4-phenylenediamine and methyldibromo glutaronitrile: evidence for synergy?Contact Dermatitis. 2008;59(2):90–95.
23.
KeltererDKaatzMBauerHIThieleJElsnerP. Contact allergy to methyldibromo glutaronitrile in Euxyl K 400 in a cosmetic cream for protection against a permanent wave solution. Contact Dermatitis. 2002;46(4):250.
24.
PoyaiGNemethIHuszS. Contact hypersensitivity to epoxy resin, methyldibromoglutaronitrile, tixocortol pivalate and budesonide in Hungary: a study in 1448 patients. G Ital Dermatol Venereol. 2011;146(1):53–56.
25.
RamloganDBasketterDABeckMH. Methyldibromoglutaronitrile: an increasingly important allergen in the UK. Exog Dermatol. 2003;2(4):184–189.
26.
ZugKAKornikRBelsitoDV. Patch-testing North American lip dermatitis patients: data from the North American Contact Dermatitis Group, 2001 to 2004. Dermatitis. 2008;19(4):202–208.
27.
NguyenSHDangTPMacPhersonCMaibachHMaibachHI. Prevalence or patch test results from 1970-2002 in a multi-center population in North America (NACDG). Contact Dermatitis. 2008;58(2):101–106.
28.
ZugKAWarshawEMFowlerJF. Patch-test results of the North American Contact Dermatitis Group 2005-2006. Dermatitis. 2009;20(3):149–160.
29.
JensenCDJohansenJDMenneTAndersenKE. Methyldibromo glutaronitrile contact allergy: effect of single versus repeated daily exposure. Contact Dermatitis. 2005;52(2):88–92.
30.
PedersenLKHaslundPJohansenJDHeldEVolundAAgnerT. Influence of a detergent on skin response to methyldibromo glutaronitrile in sensitized individuals. Contact Dermatitis. 2004;50(1):1–5.
31.
SauerJMSmithRLBaoJKattnigMJKuesterRKSipesIG. Metabolic and dispositional fate of 1,2-dibromo-2,4-dicyanobutane in the male Fischer 344 rat. Drug Metab Dispos. 1998;26(5):429–436.
32.
SchnuchAKeltererDBauerA. Quantitative patch and repeated open application testing in methyldibromo glutaronitrile-sensitive patients. Contact Dermatitis. 2005;52(4):197–206.
33.
SchnuchAGeierJUterWFroschPJ. Patch testing with preservatives, antimicrobials and industrial biocides. Results from a multicentre study. Br J Dermatol. 1998;138(3):467–476.
34.
TostiAVincenziCTrevisiPGuerraL. Euxyl K 400: incidence of sensitization, patch test concentration and vehicle. Contact Dermatitis. 1995;33(3):193–195.
35.
McFaddenJPRossJSJonesABRycroftRJGSmithHRWhiteIR. Increased rate of patch test reactivity to methyldibromo glutaronitrile. Contact Dermatitis. 2000;42(1):54–54.
36.
JensenCDJohansenJDMenneTAndersenKE. Increased retest reactivity by both patch and use test with methyldibromoglutaronitrile in sensitized individuals. Acta Derm Venereol. 2006;86(1):8–12.
37.
US Food and Drug Administration. Frequency of use of cosmetic ingredients. FDA Database. Washington, DC: FDA; 2011.
38.
Personal Care Products Council. 1-28-2011. Updated Concentration of Use by FDA Product Category: Methyldibromo Glutaronitrile.
39.
Scientific Committee on Consumer Products. Opinion on Methyldibromo glutaronitrile (sensitisation only) Colipa No. P77. European Commission Health & Consumers Directorate C: Public Health and Risk Assessment. 6-20-2006. Report No. SCCP/1013/06. http://ec.europa.eu/health/archive/ph_risk/committees/04_sccp/docs/sccp_o_060.pdf. Accessed October 20, 2011.
40.
National Toxicology Program. NTP technical report on the toxicology and carcinogeneisis studies of 1,2-dibromo-2,4-dicyanobutane (CAS No. 35691-65-7) in F344/N rats and B6C3F1 mice (dermal studies). Report No. NTP TR 555. US Department of Health and Human Services; 2010: 1–173.
41.
WahlkvistHBomanAMonteliusJWahlbergJE. Sensitizing potential in mice, guinea pig and man of the preservative Euxyl K 400 and its ingredient methyldibromo glutaronitrile. Contact Dermatitis. 1999;41(6):330–338.
42.
ZollerLBergmanRWeltfriendS. Preservatives sensitivity in Israel: a 10-year overview (1995-2004). Contact Dermatitis. 2006;55(4):227–229.
43.
BanerjeePMcFaddenJPRossJSRycroftRJGWhiteIR. Increased positive patch test reactivity to methyldibromo glutaronitrile. Contact Dermatitis. 2003;49(2):111–113.
44.
Van GinkelCJWRundervoortGJ. Increasing incidence of contact allergy to the new preservative 1,2-dibromo-2,4-dicyanobutane (methyldibromoglutaronitrile). Br J Dermatol. 1995;132(6):918–920.
45.
GuimaraensDHernandezMIGonzalezMAConde-SalazarL. Contact allergy to Euxyl K 400 in consecutively patch-tested patients. Contact Dermatitis. 2000;43(1):55–56.
46.
JacksonJMFowlerJF. Methyldibromoglutaronitrile (Euxyl K400): a new and important sensitizer in the United States?JAAD. 1998;38(6):934–937.
47.
JensenCDJohansenJDMenneTAndersenKE. Methyldibromoglutaronitrile in rinse-off products causes allergic contact dermatitis: an experimental study. Br J Dermatol. 2004;150(1):90–95.
48.
ZachariaeCJohansenJDRastogiSCMenneT. Allergic contact dermatitis from methyldibromo glutaronitrile—clinical cases from 2003. Contact Dermatitis. 2005;52(1):6–8.
49.
WilkinsonJDShawSAndersenKE. Monitoring levels of preservative sensitivity in Europe—a 10-year overview (1991-2000). Contact Dermatitis. 2002;46(4):207–210.
50.
De GrootACDe CockPAJJMCoenraadsPJ. Methyldibromoglutaronitrile is an important contact allergen in The Netherlands. Contact Dermatitis. 1996;34(2):118–120.
51.
Kynemund PedersenLAgnerTHeldEJohansenJD. Methyldibromoglutaronitrile in leave-on products elicits contact allergy at low concentration. Br J Dermatol. 2004;151(4):817–822.
52.
OkkerseAGeursen-ReitsmaAMVan JoostT. Contact allergy to methyldibromoglutaronitrile and certain other preservatives. Contact Dermatitis. 1996; 34(2):151–152.
53.
Sanchez-PerezJDel RioMJJimenezYDGarcia-DiezA. Allergic contact dermatitis due to methyldibromo glutaronitrile in make-up removal wipes. Contact Dermatitis. 2005;53(6):357–358.
54.
SilvestreJFRodriguez-SernaMMiquelJFGauchiaRAliagaA. Allergic contact dermatitis from Euxyl K 400 in a sunscreen cream. Contact Dermatitis. 1996;35(5):315.
55.
TostiAVincenziCSmithKA. Provocative use testing of methyldibromo glutaronitrile in a cosmetic shampoo. Contact Dermatitis. 2000;42(2):64–67.
56.
WongCSMBeckMH. Occupational contact allergy to methyldibromo glutaronitrile in abrasive cleansers and work creams. Contact Dermatitis. 2001;44(5):311–312.
57.
YoungHSBeckMH. Post-coital contact dermatitis from methyldibromo glutaronitrile. Contact Dermatitis. 2004;50(1):48.
58.
JongCTStathamBN. Methyldibromoglutaronitrile contact allergy—the beginning of the end?Contact Dermatitis. 2006;54(4):229.
59.
Lujan-RodriguezDPenate-SantanaYHernandez-MachinBBorregoL. Connubial allergic contact dermatitis to Euxyl K 400. Contact Dermatitis. 2006;54(2):122–123.
60.
ErdmannSMSachsBMerkHF. Allergic contact dermatitis due to methyldibromo glutaronitrile in Euxyl K 400 in an ultrasonic gel. Contact Dermatitis. 2001;44(39):40.
61.
SfiaMDhaouiADossN. Consort allergic dermatitis to cosmetic agents in a 10-year-old young girl. Contact Dermatitis. 2007;57(1):56–57.
62.
WilliamsJDFrowenKENixonRL. Allergic contact dermatitis from methyldibromo glutaronitrile in a sanitary pad and review of Australian clinic data. Contact Dermatitis. 2007;56(3):164–167.
63.
MarcanoMEHerasFConde-SalazarL. Occupational allergic contact dermatitis to methyldibromoglutaronitrile in hand degreasing toilet paper. Contact Dermatitis. 2007;57(2):126–127.
64.
Aalto-KorteKJolankiREstalanderTAlankoKKanervaL. Occupational allergic contact dermatitis caused by Euxyl K 400. Contact Dermatitis. 1996;35(3):193–194.
65.
ArmstrongDKBSmithHRRycroftRJG. Contact allergy to methyldibromo glutaronitrile presenting as severe scalp seborrhoeic eczema. Contact Dermatitis. 1999;40(335):335.
