D-gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

other: clinical case reports

Adequacy of study:

other information

Study period:

1987 - 2006

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Hibiclens keratitis

Author:

Hamed S, Ellis FD, Boudreault G, Wilson FM & Helveston EM

Year:

1987

Bibliographic source:

Am J Ophthalmol 104, 50-56

Reference 2

Reference Type:

publication

Title:

Corneal edema related to accidental hibiclens exposure

Author:

Phinney RB, Mondino BJ, Hofbauer JD, Meisler DM, Langston RHS, Forstot SL & Benes SC

Year:

1988

Bibliographic source:

Am J Ophthalmol 106, 210-215

Reference 3

Reference Type:

publication

Title:

Corneal damage due to eye contact with chlorhexidine digluconate

Author:

Tabor E, Bostwick DC & Evans CC

Year:

1989

Bibliographic source:

J Am Med Assoc 261, 557-558

Reference 4

Reference Type:

publication

Title:

Hibiclens keratopathy

Author:

Varley GA, Meisler DM, Benes SC, McMahon JT, Zakov ZN & Fryczkowski A

Year:

1990

Bibliographic source:

Cornea 9, 341-346

Reference 5

Reference Type:

other company data

Title:

Unnamed

Year:

2006

Materials and methods

Study type:

clinical case study

Test material

Test material information

Constituent 1

Reference substance name:

D-gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)

EC Number:

242-354-0

EC Name:

D-gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)

Cas Number:

18472-51-0

Molecular formula:

C22H30Cl2N10.2C6H12O7

IUPAC Name:

N',N'''''-hexane-1,6-diylbis[N-(4-chlorophenyl)(imidodicarbonimidic diamide)] - D-gluconic acid (1:2)

Results and discussion

Clinical signs:

A number of cases have been described in the medical literature of severe eye irritation and eye damage following the accidental contact of the eye with Hibiclens. According to the Material Safety Data Sheet and the Product sheet (Moelnlyke, 2006) for this compound (which is only marketed in the USA), hibiclens contains 4 % chlorhexidine digluconate, 4 % propan-2-ol and further, not-specified ingredients. According to Hamed et al. (1987), Hibiclens also contains detergents.
Hamed et al. (1987) described two cases of severe keratitis with permanent corneal opacification and blindness after accidental exposure of the eye to Hibiclens during ophthalmic surgery. In one case, a large central epithelial defect in the cornea remained 38 days after surgery. Though the epithelial effect gradually healed over a course of six weeks, the cornea became progressively opaque, ecstatic, and vascularised over the next 18 months. In the second case, Hibiclens was accidentally introduced into the eye during the scrub prior to eye surgery for cataract. Starting one day, an epithelial cornea defect developed and progressed, and the cornea became opaque. Four months after surgery, the a large epithelial defect persisted, a dense yellow-white sequestration was present, and the underlying cornea was thinned to one-fourth its normal thickness.
Further 5 cases were described by Phinney et al. (1988) where patients developed corneal lesions after accidental exposure to Hibiclens. All patients complained of postoperative ocular pain, had conjunctival inflammation, corneal epithelial defects, corneal edema 2 to 10 weeks later, and all developed corneal vascularization. Edema of 3 patients gradually cleared after months, but progressed to bullous keratopathy in 2 patients. Histopathological examination revealed lacking or degenerating keratocytes, loss of endothelial cells and an abnormal posterior collagenous layer. Permanent visual impairment was noticed in 2 patients.
Tabor et al. (1989) described two additional cases in which chlorhexidine digluconate solutions were used for preparing a patient's facial skin prior to surgery and accidentally got into the eyes. Exposure led to irreversible corneal damage with eye redness, pain and diminished vision.
A further case of keratopathy following accidental exposure of the eye to Hibiclens during preoperation preparation of the face was described by Varley et al. (1990). The patient developed epithelial and stromal oedema and later bullous keratopathy which led to penetrating keratoplasty 10 months later. The authors also mention further cases of similar eye damage described in the medical literature and discuss that the deep penetration of chlorhexidine into the cornea could be facilitated by detergent components present in the Hibiclens formulation.

Applicant's summary and conclusion

Executive summary:

A number of case reports described in the medical literature show that a product (Hibiclens) containing a 4 % solution of chlorhexidine digluconate and other ingredients presents a severe hazard to the eye and may cause severe corneal damage. The presence of detergent may facilitate the penetration of chlorhexidine.