Critical Reviews in Toxicology, 22(3,4): 143-174 (1992)
A Critical Review of the Toxicology of Glutaraldehyde Robert 0. Beauchamp, Jr., M.A., Mary Beth G. St. Clair, Ph.D.,*" Timothy R. Fennel/, Ph.D., David 0. Clarke, Ph.D., *** and Kevin T. Morgan, Ph.D.
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CIIT, P.O. Box 12137,Research Triangle Park, NC 27709
Frank W. Kari, Ph.D. NIEHS, Research Triangle Park, NC 27709 *Towhom all correspondence should be addressed. **North Carolina State University, Raleigh, NC ***Eli Lilly and Company, Greenfield. IN
ABSTRACT: Glutaraldehyde, a low molecular weight aldehyde, has been investigated for toxicity in humans and animals. Examination of this dialdehyde was indicated from previous studies with other aldehydes in which carcinogenicity of formaldehyde and toxicity of acetaldehyde and malonaldehyde have been disclosed. Information gaps concerning the actions of glutaraldehyde have been identified in this review and recommendations are suggested for additional short- and long-term studies. In particular, information regarding irritation of the respiratory tract, potential neurotoxicity, and developmental effects would assist in a complete hazard evaluation of glutaraldehyde. Further study related to disposition, metabolism, and reactions of glutaraldehyde may elucidate the mechanism of action.
KEY WORDS: glutaraldehyde review, human toxicity, animal toxicity, reproductive toxicity, genotoxicity, metabolism, toxicokinetics, protein macromolecules, environment, health effects, aldehyde composition, uses.
I. INTRODUCTION Glutaraldehyde is a specialty chemical with no single large-scale use. However, given its widespread use as a bactericide, a tanning agent, and a fixative, humans may be exposed to this chemical. This potential for human exposure, together with the reactive nature of glutaraldehyde, has generated concern over possible adverse health effects associated with glutaraldehyde exposure. The activity of formaldehyde as a nasal carcinogen in rats and mice' and the toxicity of other low molecular weight aldehydes, such as acetaldehyde and malonaldehyde, have prompted further interest in this class of chemicals.2 Similar cellular mutation results reported for these aldehydes suggest carcinogenic potential.
This review represents a comprehensive survey of the toxicity of glutaraldehyde, its metabolism and disposition, reactions with macromolecules, in v i m and in vivo animal and human toxicity, genotoxicity and carcinogenicity, developmental toxicity, and environmental effects. Cited reference studies have been examined, and experimental design and results critically evaluated. The reference material has been summarized and evaluated to reveal information gaps for future investigations. Recommendations are proposed for consideration in such studies. While the primary focus of this review is on the toxicity of glutaraldehyde, additional information on the physical and chemical properties of glutaraldehyde, its production, uses, reactions, analysis, and regulation are also included.
1040-8444/92/$.50
0 1992 by CRC Press, Inc. 143
II. PHYSICAL AND CHEMICAL PROPERTIES, AND PREPARATION A. Physical Properties
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Glutaraldehyde, a five-carbon dialdehyde, is a highly reactive compound that has been isolated as an oil and is usually stored as an aqueous solution. On storage, it forms mixtures containing hydrates, pyrans, and polymers. The principal physical properties of glutaraldehyde are summarized in Table 1.
TABLE 1 Glutaraldehyde
B. Chemical Properties Several studies have dealt with the determination of the composition of pure glutaraldehyde under a variety of circumstances. When chemical purity is a requirement, commercial solutions should be analyzed prior to use because the glutaraldehyde solution may not be limited to the monomeric form. When considering the chemical nature of glutaraldehyde in solution, two types of studies have been conducted: those considering the equilib-
- Physical Properties
Structure - glutaraldehyde (I)
OHC
Ref.
CHO I
CAS Registry Number: 111-30-8
Molecular weight: 100.13 Physical state: Water-soluble oil Freezing point: - 14째C Boiling point: "C 187-1 88 (dec) 106-1 08 71-72 60-61
233
Pressure (mm) 760 50 10 1
Vapor pressure 0.0152 torr (50% aq. solution) at 20째C 0.0012 torr (2% aq. solution) at 20째C
66 66
Vapor density: 3.4 (air = 1)
235
Density: 0.72 (water = 1)
233
Refractive index: 1.43300(at 25째C; 589 nm)
236
Odor: pungent
144
14 15 14 234
13,237
Solubility: Soluble in all proportions in water and ethanol; soluble in benzene or ether
66
Storage conditions: Stability of glutaraldehyde is decreased as the pH and temperature are increased; pH effects were reported on two commercial solutions (containing 2% glutaraldehyde) revealing that a solution of Aldetex (pH 7.70) was more stable than a solution of Cidex (pH 8.55)
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rium forms in purified solutions, and those examining the forms, including polymers, present in commercially available preparations. The purity of glutaraldehyde solutions is frequently evaluated spectrophotometrically by measuring the ratio of absorbance at 235 and 280 nm to obtain a purification index. The absorbance at 280 nm corresponds to the n-n* transitions of the carbonyl bond of glutaraldehyde, whereas the absorbance at 235 nm corresponds to n-T* transitions of the C=C bonds of a,P-unsaturated polymers. Generally, glutaraldehyde is stable to light, but is oxidized in air and polymerizes when heated. Studies have been directed toward elucidating the equilibrium conditions for glutaraldehyde under different conditions to indicate chemical modification of the parent structure and variation in its reactivity. The intermediate chemical forms are also considered in Section V1.C and D. In a carefully monitored study, a 25% aqueous solution of glutaraldehyde was purified to a single peak with a UV absorbance maximum of 280 nm.3 The subsequent detection of a second peak at 235 nm indicated the formation of alternate forms, such as polymers, in investigations of the influence of pH, temperature, and buffering on polymerization rate. No polymerization occurred when a solution of glutaraldehyde was stored for 5 months at - 14째C. There was a slight increase in the 235 nm peak with storage at 4"C, and then a rapid increase in this peak beginning with storage around 20째C and continuing to 60째C. The polymerization rate of glutaraldehyde was increased when the pH was slightly acidic or basic; the rate of polymerization was decreased somewhat by the addition of buffers. If a 50% degree of polymerization can be tolerated, samples may be stored at 4째C and pH 6.5 for up to 7 months. A number of IH-NMR studies have been carried out on the nature of glutaraldehyde in aqueous solution and suggest the presence of the monohydrate, dihydrate, and cyclic hemia~etal.~ More recent studies have used I3C-NMR spectroscopy to examine the equilibrium in solution. In an extensively purified neutral solution of glutaraldehyde at 23"C, 4% free aldehyde (I), 16% hemihydrate (11), 9%dihydrate (111), and 35% each of cis- and truns-isomers of the cyclic hemiacetal
(IV) were reported.' The equilibrium was found to be temperature dependent. In a further study,6 similar equilibrium proportions were observed, which were not greatly affected by pH or concentration. The isolation and identification of polymers of glutaraldehyde (V) from aqueous solution have been the subject of several investigations (Figure 1). Oligomers have been isolated and characterized from aqueous solutions of glutaraldehyde. 'JThe para-glutaraldehyde (VI) , a trimer, is the principal trioxane derivative, with the pentamer (VII) and heptamer (VIII) present in small amounts (Figure 2). The polymerization of glutaraldehyde is pH-dependent , with increasing polymerization at higher pH. Isolation of the various derivatives was performed by HPLC, with characterization by IR and NMR spectroscopy. Commercial 25% glutaraldehyde solutions may contain precipitates that result from aldol condensation.' This condensate contains aldehyde groups conjugated with ethylenic double bonds and may react with amino groups in amino acids to yield imino groups. The ethylenic bond and the imino bond are stabilized by resonance, and this stable form will not allow Michael-type addition reactions.
n
n
OHC
CHO
OHC
I
CH(OHk
n
(HOLCH CH(OHh
111
II
IV
V
FIGURE 1. Equilibrium structures of glutaraldehyde in aqueous solution.
Other types of polymers reported to be in a 2% alkaline glutaraldehyde sterilizing solution (pH 7.5 to 8.5) were trioxane oligomers (oligomers of VI) of molecular weights > 12,000. l o The characterization of a dimer (IXa) from an aqueous alkaline solution of glutaraldehyde has been reported recently (Figure 3). I ' This dimer is formed by a dimolecular aldol condensation, and may exist in equilibrium with the cyclic hemiacetal form (IXb).
145
H20, HOAC
n
OHC
ocy
Reflw, 1 hour
CHO
I
X VI
VII (Pentamer)
(Tdrner)
FIGURE 4. Principal commercial preparation of glutaraldehyde from 2-methoxy-3,4-dihydro-2H-pyran(X).
111. USES R
R
R
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Vlll (Heptemer)
FIGURE 2. Oligomers of glutaraldehyde in aqueous scluticn. R :epresen!s (CH,),C!-!O.
oHcQCHO
O
1x0
FIGURE 3.
H
C
aOH
IXb
Dimers of glutaraldehyde.
C. Preparation Recent production figures for glutaraldehyde are not available. The principal manufacturer in the U.S. is Union Carbide Corporation; nondomestic producers include BASF AG in Europe and Daicel Chemical Industries, Ltd. in Japan. In 1976, an approximate production volume of >5000 lbs. was listed. I 2 . I 3 Production figures have not been reported in the published literature. Isolation and characterization of glutaraldehyde from the ozonolysis of cyclopentene were first reported by Harries and Tank. l4 More recent methods utilize alkoxy-pyran derivatives as the source of the 5-carbon chain of glutaraldehyde. The principal method of commercial production of glutaraldehyde (I) is the acid hydrolysis of a 2-alkoxy-3,4-dihydro-2H-pyran(X) (Figure 4).I
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Major uses of glutaraldehyde depend on its highly reactive chemical properties where reaction may occur with proteins or polyhydroxy compounds to modify the surface characteristics or internal properties of the treated substrate. Tanning of animal skins with glutaraldehyde is a prime example involving reaction with proteins as well as preparing tissues by various fixative processes for microscopic study. This strong reactivity of glutaraldehyde also exhibits a broad spectrum of biocidal activity. Many disinfectant and sterilizing procedures require special bactericidal, slimicidal, sporicidal, fungicidal, or viOther principal applications rucidal activity. of glutaraldehyde include the treatment of various skin disorders, an adhesive in dentistry, and a component in the manufacture of tissue transplants. The tanning of leather with glutaraldehyde produces leather of outstanding durability, uniformity, and feel and improves the properties of lining, sole, gloving, horsehide, and pigskin. Water-resistance or insolubilization is imparted to cork in the manufacture of gaskets and washable wallpaper. Increased water-resistance and wet strength have been extended for treated paper towels when rapid wetting without tearing is required. Textile sizing mixtures prepared from polyhydroxy materials such as polyvinylacetate and polyvinyl alcohol and followed by addition of glutaraldehyde at elevated temperatures yielded effective materials for use under high-humidity conditions. The preservative or antimicrobial effect of glutaraldehyde has found broad application in cosmetic, toiletry, and chemical specialty product^'^ due to its ready water solubility and usefulness in systems containing secondary I6s1'
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amines, tertiary amines, quaternary ammonium compounds, or protonated amines. The broad biocidal activity is due to the cross-linking capacity of the difunctional aldehyde with primary amines, such as lysine residues present in the microbial cell The antimicrobial activity of glutaraldehyde is suitable for numerous hospital settings requiring a readily available, noncaustic liquid sterilant usable under ambient conditions for surgical and examination instruments. Glutaraldehyde is an effective sporicidal agent requiring about 3 h for almost complete elimination of spores. Grampositive and Gram-negative bacteria, fungi, and viruses are also susceptible to the lethal action of glutaraldehyde.21Care should be exercised to remove or minimize any residual aldehyde to prevent sensitization reactions for the operator or patient. Glutaraldehyde has been used in the development of vaccines against a variety of allergens including Bordella pertussis, ragweed, and grass pollen^.^^-^^ Using glutaraldehyde-fixed simian immunodeficiency virus (S1V)-infected cells, a vaccine was produced that protected macaques from SIV infection; all eight monkeys vaccinated with the glutaraldehyde-modified antigen were protected from a challenge with active SIV.25 Glutaraldehyde is available in several different commercial preparations, providing the user with a choice for a particular application. Two preservative formulations containing glutaraldehyde are sold under the trade names of Ucaricide Preservative 225 and Ucaricide Preservative 250.19The Ucaricide 225 contains 25%by weight glutaraldehyde and the Ucaricide 250, 50% by weight glutaraldehyde with pH ranges from 3.1 to 4.5. Other glutaraldehyde products include additional Ucaricides, and tradename products Piror, Uconex, Ucarsan, and Aqucar - all containing glutaraldehyde and available for special uses.26These preservatives are recommended for use in controlling bacterial growth in cosmetics, toiletries, oil field operations, pigment and filler slurries, metal working fluids, farm equipment, and housing. Preservatives are also recommended as water treatment in cooling towers and filtering systems, and chemical specialty prod-
ucts. Inactivation of glutaraldehyde may occur in the presence of ammonia and primary amines. In an early report, the stability and bactericidal effectiveness of a buffered formulation of glutaraldehyde were increased from 14 to 28 days after activation. The activation process is carried out by mixing the individual ingredients of the separate formulations. A 2% glutaraldehyde solution containing a surfactant to promote wetting plus sodium nitrite as a corrosion inhibitor and buffered to a pH of 7.5-8.0 was stable for up to 28 days. 27 An unformulated alkaline glutaraldehyde solution retained its bactericidal activity for only 14 days.28An additional important property of the stable formulation is its ability to retain bactericidal activity in the presence of organic matter. Recent information on the storage stability of several Ucaricides disclosed that no change was observed in the concentration of glutaraldehyde for up to 52 weeks at 25 and 37"C.26 Glutaraldehyde is used in various clinical applications involving skin treatment ,29 dentistry30 and tissue implants, as well as in the manufacture of contact lenses and preservation of blood products. Skin problems that are effectively treated include the removal of warts and excessive sweating of the hands and feet. The common wart, verruca vulgaris, is treated effectively with a A 25% solution 10% glutaraldehyde ~olution.~' was also effective, but a buffered 10% solution with sodium bicarbonate to pH 7.5 was preferred. Other skin disorders treated successfully with glutaraldehyde are epidermolysis bullosa, herpes simplex, herpes zoster, and pitted kerat o l y s i ~ . While ~ ~ - ~contact ~ dermatitis from the use of high concentrations of glutaraldehyde on the soles of the feet is rare, exposure of other regions of the body to more dilute concentrations of glutaraldehyde caused sensitizati~n.~~ These observations have been interpreted in terms of extensive binding of glutaraldehyde to the keratin of the skin of the soles of the feet and the relative paucity of Langerhans cells in this area.39 A palmar antiperspirant formulation containing 5% glutaraldehyde was recommended over a 10% solution to minimize tanning during the sweat reduction process. The nonalkalinized solution is applied three times per week.34Excessive sweat-
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ing of the feet (hyperhydrosis) was treated with a 10% buffered solution of glutaraldehyde and the sweating was relieved within 24 h.37 Glutaraldehyde is used in the preparation of grafts and bioprostheses, often from nonhuman tissues, that are to be transplanted into humans. Glutaraldehyde treatment of xenografts stabilizes and preserves them, and glutaraldehyde-treated graft materials elicit fewer allergic reactions than formaldehyde-fixed materials,40 presumably due to decreased tissue antigeni~ity.~'*~* Problems associated with glutaraldehyde-treated xenografts most commonly are due to calcification or mechanical failure of the graft.4347Co-treatment of graft materials with glutaraldehyde and aminopropanehydroxydiphosphonate or chondroitin sulfate may reduce destructive graft calCiiEICaiioii.4R 49 G~~txald&liyde is albu used b cross-link collagen in applications for surgical implant materia148*50-52 and has been used for linking materials intended to improve biocompatibility to synthetic graft^.^^.^^ Tissue degradation and humoral antibody induction are reduced by this treatment. Artificial pretreated polyester vessels and valves are rendered antithrombogenic by final cross-linking with glutaraldehyde.53An improved collagen implant crosslinked with glutaraldehyde, Zyplast, gives longerlasting corrections in improving acne scars than without the cross-linking process.5o Immunogenic responses to Dacron prostheses are reduced when the device is coated with albumin or collagen and then cross-linked with glutaraldeh ~ d e Glutaraldehyde-treated .~~ grafts appear to be important in human medicine, but efforts should continue toward improving glutaraldehyde fixation of these tissues in order to obtain satisfactory fixation while maintaining a low potential for rejection and calcification. Soft contact lenses, prosthetics, films, and fibers were prepared from gelatin and cross-linked with glutaraldehyde. Flexible, clear, and dimensionally stable products were obtained by this procedure.56 Glutaraldehyde has been used to stabilize hemoglobin in the preservation of blood products requiring a long shelf life. The life of glutaraldehyde-treated red blood cells is extended, but further improvements are needed to prevent rigidity, antigenicity, and reduced o~ygen-affiity.~~
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Fixation of tissue specimens using glutaraldehyde when preservation of the ultrastructure for study by electron microscopy and cytochemistry was required has been in use since the early 1960~.'~ Glutaraldehyde was reporteds9to be preferred over formaldehyde because the fine structure is stabilized and gross distortion during embedding is prevented. It was also found to cause the least protein conformational changes. Some caution has been indicated in its use in cytochemistry by an early report showing evidence of activation of a nucleic acid phosphatase enzyme with glutaraldehyde.@' In some applications, glutaraldehyde followed by osmium tetroxide was more effective than osmium tetroxide alone in revealing granular vesicles in the pineal body. However, it has one drawback in that it is rlui capabie of rendering iipids insoiubie in organic solvents and thus will not allow demonstration of cellular membranes. Glutaraldehyde penetrates tissues much less than formaldehyde, probably due to its greater reactivity, and slightly less than osmium tetroxide.
IV. ADVERSE HEALTH EFFECTS IN HUMANS
Humans can be exposed to glutaraldehyde in numerous clinical and occupational settings, as indicated by the many different uses of this chemical. A majority of the adverse health effects reported for glutaraldehyde are associated with disinfection or sterilization procedures performed by hospital personnel or its use in a variety of clinical settings. Clinical exposures result from its use in removal of skin warts, dental adhesives, the sterilization of health care equipment, and the manufacture of tissue implants and prosthetic devices. Glutaraldehyde has been used successfully in the treatment of a number of skin disorders, including epidermolysis bullosa, hyperhydrosis, herpes zoster, herpes simplex, dyshidrosis, onychomycosis, and warts. Undesirable effects of these treatments have ranged from skin discolration,^^-^^,^^ to contact dermatitiP and ulceration.62 A patient was exposed to residual glutaraldehyde via a crack in an anesthesia mask,
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which resulted in eye i r r i t a t i ~ nAn . ~ ~accidental subdural injection of glutaraldehyde proved to be fatal." Recently, potential occupational hazards to personnel and patients exposed to either formaldehyde or glutaraldehyde in hospital operating and patient rooms have been reported in Germ a n ~ When . ~ ~ cleaning solutions containing 0.038% formaldehyde or 0.025% glutaraldehyde were used in these settings, the maximum allowable airborne concentrations were not exceeded, i.e., 0.5 ppm formaldehyde or 0.2 ppm for glutaraldehyde. However, when cleaning solutions were formulated with either 0.228% formaldehyde or 0.15% glutaraldehyde, unacceptable airborne concentrations resulted. Exposure concentrations of 5.1 ppm formaldehyde and 0.57 ppm glutaraldehyde were detected; acceptable shortterm levels are 1.0 ppm for formaldehyde and 0.4 ppm for glutaraldehyde. Human exposure to low concentrations (<1 ppm; odor threshold is 0.04 ppm of glutaraldehyde) either by inhalation or skin contact may cause irritation of the skin and/or mucous membranes.% Contact dermatitis, eye irritation, and/ or skin discoloration are frequently observed from such occupational exposure^.^^-^^ Elevated concentrations of glutaraldehyde and extended penods of human exposures may cause respiratory distress and secondary infections resulting from severe irritation and ulceration of exposed sites. Rhinitis and encrustation of mucous membranes have also been reported. 83 Glutaraldehyde is a moderate sensitizer of human kin,^^.^^.^^.^^ but was scored as a nonirritant in the in v i m cultured corneal endothelial cell assay. 88 Because of the frequent combined use of glutaraldehyde and formaldehyde (e.g., in the disinfectant Cidex [CAS #37245-61-71), as well as the frequent use of these two compounds in the same workplace settings (e.g., funeral homes, histology laboratories), the issue of crosssensitization between the two compounds has been investigated. 37*89*90No evidence of sensitization to glutaraldehyde resulting from formaldehyde exposure, or vice versa, was found. Skin sensitization has been reported from exposure to glutaraldehyde-tanned leatheP and to a hair conditioner containing glutaraldehyde as a preservative.91
Glutaraldehyde is employed in human dentistry to prevent spread of disease in decayed teeth both by its antibacterial and cross-linking activities30 and was found to have a number of advantages over formocresol in this capacity.92-94In addition, an aqueous solution of glutaraldehyde and 2-hydroxymethacrylate sold under the tradename GLUMA (Bayer) has been used as a bonding agent between the restorative resin and the dentin of the t o ~ t h . The ~ ~ .bond ~ ~ was formed by reaction with the amino groups of collagen initially and then with the methacry late ester. Pretreatment with EDTA (ethylenediaminetetraacetic acid) is needed to free the collagen from the imbedding apatite. This adhesive is markedly cytotoxic to cultured human buccal epithelial cells. In vivo studies revealed that cheek pouches of non-human primates exposed to GLUMA bond exhibited extensive necrosis and ~lceration;~' however, this formulation markedly decreased the incidence of bacterial infections in filled teeth, compared to another bonding agent.98 Minor irritation has been reported in humans whose root canal sites were prepared with glutaraldehyde-containing bonding agents .94 Glutaraldehyde was shown to decrease dentin demineralization, potentially acting to prevent tooth decay.w In contrast to formocresol, glutaraldehyde is not extensively absorbed from pulpotomy sites, loo thus limiting systemic exposure. Comparative studies of the toxicity of glutaraldehyde and formaldehyde on penapical tissues suggest that glutaraldehyde is useful and safe when applied to pulpotomy sites, as long as prolonged contact with surrounding tissues does not occur. '01-'03 The cytotoxicity of residual glutaraldehyde in xenografted tissues prepared for transplantation into humans has been the subject of several investigations. Sufficient residual glutaraldehyde to cause cell death in various cell lines was found in a number of graft material^.^'*^@'-^^^ In 1980, NIOSH published a National Hazard Survey citing 35,083 occupational exposures to glutaraldehyde for the period 1972-1974. lo' This number represents about twice the number of exposures for either benzaldehyde or furfural, and five times that for acrolein (NCR Committee on Aldehydes, 198 l), indicating that glutaraldehyde exposure represents a substantial proportion of human exposure to aldehydes in industry.
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Based on the foregoing information, indicating that exposure to glutaraldehyde may cause respiratory tract or dermal irritation, and coupled with data indicating the potential for glutaraldehyde to induce DNA damageIw as well as cell proliferation, l l 0 human exposure to glutaraldehyde must be minimized by the use of protective clothing, respirators, and adequate ventilation. In addition to the irritating effects of glutaraldehyde, sensitization has been reported. Clinicians should be aware of this possibility when using glutaraldehyde to treat skin disorders. Tissue implants and prostheses prepared with glutaraldehyde should be tested carefully to ascertain the absence of residual available glutaraldehyde prior to transplantation. Precaution in the use of glutaraldehyde as a tissue fixative is indicated in the guidelines for histotechnology and electron microscopy. Its similarity to formaldehyde has been noted and represents a potential skin and eye irritant. 1 1 1 - 1 1 3
V. GOVERNMENT REGULATIONS OSHA published a final rule for the ceiling concentration (PEL - permissible exposure limit) on glutaraldehyde of 0.8 mg/m3 (0.2 ppm) based on irritant effects to the eyes, nose, and throat associated with short-term exposures. I l4 Ceiling concentration is a peak not to be exceeded at any time during the working day. Previously, OSHA had no limit for glutaraldehyde, but had proposed establishing the limit at 0.2 ppm based on the recommendation of ACGIH published in 1986.66 NIOSH concurred with this proposed limit and the final rule in 1989 established this limit. No values have been published for the 8-h timeweighted average or short-term limit (duration for 15 min, unless otherwise noted) for glutaraldehyde. The threshold recognition level for glutaraldehyde has been reported to be 0.04 ppm by volume in air." However, eye and respiratory tract irritation was not noted until the concentration reached 0.3 ppm, or about seven times the odor threshold.66 The environmental consequences of glutaraldehyde have been considered in the Soviet
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Union in two settings, and restrictions were reported. The recommended maximum threshold concentrations of glutaraldehyde in large water reservoirs is 0.07 mg/1.'15 In the case of circulating vapors and aerosols in factory environments, a maximum allowable concentration for glutaraldehyde has been set at 5 mg/m3, or six times the present concentration allowable in the U.S. Reuse of glutaraldehyde-containingdisinfectant solutions and other dialysis supplies is being considered as part of the Health Care Financing Administration (HCFA) Medicare program. An airborne exposure ceiling of 0.2 pprn glutaraldehyde was established in this application in accordance with the previous OSHA limit. The food additive regulation was amended by FDA to allow use of glutaraldehyde as a slimicide in the manufacture of paper and paperboard that may come in contact with food."* A proposed rule was published by the MSHA (Mine Safety and Health Administration) in which a Hazard Communications Chemical List was included for chemicals that may be present or shipped to a mine site.119The rule proposes that employees and employers must be provided with information concerning potential hazard for such chemicals as glutaraldehyde that may be utilized in mining processes. Processes may include flotation procedures involving natural products that contain a variety of chemicals. The final rule is not expected until 1993. In reviewing the literature, no risk assessments or exposure standards for glutaraldehyde, other than the OSHA PEL and ACGIH Threshold Limit Value, were identified.
VI. METABOLISM, PHARMACOKINETICS, AND REACTIVITY A. Absorption and Disposition The uptake of glutaraldehyde has been investigated in a variety of biological systems typical of the potential routes of exposure associated with glutaraldehyde use. These include absorption through skin and from the pulp chamber of
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teeth. Dermal absorption studies conducted in vitro using human stratum corneum from the chest, abdomen and sole, and epidermis from the abdomen, demonstrated that glutaraldehyde does not penetrate the thick stratum corneum of the sole.12oHowever, 3.3 to 13.8% of the applied dose penetrated the thin stratum corneum of chest and abdomen, and 2.8 to 4.4% of the applied dose penetrated the isolated epidermis. In a more recent study of the in vitro penetration of glutaraldehyde in samples of skin from F-344 rats, CD-I mice, rabbits, guinea pigs, and humans, <1% of the applied glutaraldehydepenetrated the skin. Material balance studies have been camed out in vivo in both male and female F-344 rats, and in New Zealand white rabbits.Iz2 [1,5''C]Glutaraldehyde was administered intravenously (0.2 ml for rats and 2.5 ml for rabbits of either 0.075 or 0.75% solutions) and dermally (0.2 ml of 0.075, or 7.5% solutions in rats, and 2.5 ml of 0.75 or 7.5% solutions in rabbits). Following intravenous administration in both rats and rabbits, the majority of the radioactivity was excreted as I4CO2,with approximately 80% being exhaled in the first 4 h. Urinary excretion of radioactivity was considerably lower, ranging from 8 to 12% in the rat, and 15 to 28% in the rabbit. At the higher dose, excretion of I4CO, as a percentage of total dose was less than at the lower dose, particularly in the rabbit, where urinary excretion and tissue retention were increased. Following dermal administration, the majority of the administered radioactivity was recovered at the application site in the rat, with only approximately 5% of the applied dose being absorbed. This contrasts with findings in the rabbit, in which between 32 to 53% of the dermal dose was absorbed and either excreted or found in tissues. Pharmacokinetic investigations were also carried out in both the rat and rabbit using intravenous and dermal routes of administration. lZ2 Pharmacokinetic analyses were performed on the levels of radioactivity in plasma. The dermal absorption rate constants were low, ranging from 0.2 to 2.0 h-' in both species. The long terminal half-lives calculated for glutaraldehyde may result from a combination of binding to protein and slow excretion of its metabolites.
Absorption studies of glutaraldehyde following its use as a fixative in human root canal preparations have been carried out. On imgation of the root canals of human teeth with an unspecified amount and concentration of 14C-glutaraldehyde, radioactivity remained localized in the canal and its borders, with no detectable diffusion into the surrounding tooth structure.'O' Glutaraldehyde absorption was investigated in vital pulpotomy sites in the canine and incisor teeth of mongrel dogs.Io3A cotton pellet containing 5.6 pCi of [1,5-'4C]glutaraldehyde as a 2.5% solution was inserted into each of 16 pulpotomies per animal. After 5 min, the pellets were removed, and blood, urine, and expired air were collected for 90 min. Tissues were removed for assay of radioactivity. Approximately 3% of the total applied dose was absorbed systemically. Urinary excretion accounted for 8% of the absorbed dose, and pulmonary excretion about 4%. Tissue-toplasma ratios for I4Cindicated that binding probably occurred in red blood cells (2.21), and to a lesser extent in other tissues.
B. Metabolism Extensive metabolism of glutaraldehyde to expired CO, has been described in a number of in vivo studies following dermal, intravenous, and pulpal e x p o ~ u r e ' ~ in ~ which * ~ ~ ~[ 1,5''C]glutaraldehyde was used as tracer. Excretion of urinary metabolites of glutaraldehydehas been r e p ~ r t e d , ' ~but ~ . 'none ~ ~ of the metabolites have been characterized. Glutaraldehyde is oxidized by rat liver mitochondria in vitro, as measured by an increase in oxygen consumption.123The oxidation is under the control of the electron transport system, and results in reduction of NAD+ and consumption of two atoms of oxygen per molecule of glutaraldehyde. Glutaraldehyde is oxidized extensively to CO, in rat tissue slices, with the highest activity in the kidney, followed by the liver.'25 The activity is localized in the mitochondria1fraction of the kidney. The ability of a number of enzyme systems to metabolize glutaraldehyde has been investigated. For the isoenzymes I, IIa, and IIb of human liver aldehyde dehydrogenase (aldehyde:
151
NAD oxidoreductase, EC 1 .2.1.3), glutaraldehyde was a poor substrate compared with other aliphatic aldehydes. While isoenzyme I had a low activity for oxidation of glutaraldehyde compared with acetaldehyde, isoenzymes IIa and IIb had similar K, and V,, values for these two aldehydes. Glutaraldehyde was reported to be a poor substrate for an aldehyde dehydrogenase isolated from liver microsomes of rats treated with clofibrate, which had previously been shown to increase the specific activity of the enzyme.”’ Glutaraldehyde was also a poor substrate for two isoforms of cytosolic aldehyde dehydrogenases isolated from rat liver.Iz8 An enzyme that had been considered as an isoenzyme (E4, ALDH IV) of human liver aldehyde dehydrogenase (EC 1.2.1.3), now identified as glutamic-y-semialdehyde dehydrogenase or 1-pyrroline-5-carboxylate dehydrogenase (EC 1.5.1.12), had a high capacity for metabolism of glutaric semialdehyde, which would be produced on oxidation of glutaraldehyde. The NAD -dependent succinic semialdehyde dehydrogenase (EC 1.2.1.24), isolated from human brain mitochondria was capable of using glutaric semialdehyde as a substrate for oxidation, but at a lower rate than succinic semialdehyde.I3O The metabolism of glutaraldehyde has been followed with [ 1,5-’4C]glutaraldehyde,and while it has been determined that the majority of radioactivity is transformed both in vivo and in vitro to 14C02,103~122~123~125 the fate of the unlabeled carbon atoms has not been directly established. Although direct identification of metabolites has not been carried out, it is probable that glutaraldehyde undergoes oxidation to glutaric semialdehyde, and then to glutaric acid. A postulated metabolism scheme for glutaraldehyde is outlined in Figure 5. This acid can undergo further metabolism by synthesis of a coenzyme A thioester, either by a thiokinase reaction or by transfer of CoA from succinyl CoA catalyzed by a thiophorase.”’ The glutaryl CoA produced then undergoes reduction by glutaryl CoA dehydrogenase (EC 1.3.99.7) to give glutaconyl CoA and decarboxylation to crotonyl CoA.I3I Glutaryl CoA is normally produced from a-ketoadipyl CoA, formed during the catabolism of tryptophan, lysdeficiency of gluine, and h y d r o x y l y ~ i n e A . ~ ~~ taryl CoA dehydrogenase is the primary defect
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+
NAD+ 2 NAD+ 2
OCHCyC H.$ YCHO
NADH
OC HC Y C Y C Y C OOH
NADH
HOOCCyCH&H&OOH
J
HOOC C I+C
OSCoA
FADY HOOCCI+CH-CH:OSCoA
h
‘I - c q C H& K C H:OSC OA
J
C H& HOH: Y C OSC oA
+
152
I
+ I
C H& OSC oA I I I
t CQ
FIGURE 5. Postulated metabolism scheme for glutaraldehyde. (1) Oxidation of glutaraldehyde to glutaric y-semialdehyde and (2) further oxidation to glutaric acid; (3) synthesis of glutaryl Coenzyme A; (4) oxidation to glutaconyl CoA; (5) decarboxylation to give crotony1 CoA; (6) hydration to p-hydroxybutyryl CoA; (7) conversion to acetyl CoA; (8) oxidation to CO,.
associated with the inherited human metabolic disorder, glutaric aciduria type I, which is characterized by highly elevated glutaric acid in the can urine.’33Enoyl CoA hydratase (EC 4.2.1.55) then convert this compound to P-hydroxybutyryl CoA, which can subsequently be used for synthesis of acetoacetate, or be degraded to acetate and then to CO,. Further metabolic studies on glutaraldehyde should consider this overall se-
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quence in the isolation and characterization of urinary metabolites. The principal metabolism of glutaraldehyde to CO,, and the potential for the metabolite incorporation into macromolecules, complicates the assessment of the fate of glutaraldehyde in vivo. While the deposition of radioactivity at the site of administration may be due to binding to macromolecules, it currently cannot be distinguished from the metabolic incorporation of radiolabel into the normal monomers required for synthesis of macromolecules. Thus, an understanding of the products formed on reaction of glutaraldehyde with macromolecules is essential to the measurement of covalently bound glutaraldehyde. C. Reaction with Proteins Many of the uses (tanning agent, tissue fixative, biocide) of glutaraldehyde are related to its ability to react with and cross-link proteins. '34 Glutaraldehyde can react with the a-amino groups of amino acids, the N-terminal amino groups of peptides, and the sulfhydryl group of cysteine. 135 The predominant site of reaction in proteins was at the â&#x201A;Ź-amino groups of lysine, with some reaction also with tyrosine, histidine, and sulfhydry1 residues. The reaction with proteins is rapid and pH dependent, with the rate increasing at alkaline pH. 136 Glutaraldehyde-treated proteins develop a yellow color, and undergo an increase in UV absorbance between 250 and 300 nm, with a blue shift in absorbance maximum of about 5 nm. Gels or precipitates are formed on treatment of some proteins with glutaraldehyde. The mechanism of reaction of glutaraldehyde with protein has been the subject of debate. Although it has been suggested that unsaturated polymers formed by aldol condensation of glutaraldehyde are responsible for the reaction with p r ~ t e i n , ~ .the ' ~ 'reaction of proteins with purified and unpurified glutaraldehyde are almost identical, suggesting that the initial presence of polymers is not required.*O The mechanisms of reaction of glutaraldehyde with amino acids are outlined in Figure 6. It is generally assumed that glutaraldehyde initially reacts with amino acids to form Schiff bases with reactive amino groups.'38 The reaction of amino acids with glutaraldehyde has been inves-
tigated using lysine and 6-aminohexanoic acid as a model system.139Reactions were carried out at room temperature in an aqueous unbuffered solution. The products were purified and characterized as polymeric 1,3,4,5-tetrasubstitutedpyridinium salts (XXI). These could be formed by the initial reaction of three molecules of glutaraldehyde with one of lysine. Further reaction with a lysine side chain and two additional molecules of glutaraldehyde could lead to the formation of a cross-link. On treatment of ovalbumin with glutaraldehyde in an aqueous solution at pH 4.5 and isolation of the reaction products from the hydrolyzed protein, several products were identified. 1-(5-Amino-5-carboxypentyl)pyridiniumchloride (XIX) was formed by reaction of a single molecule of glutaraldehyde with lysine to give a cyclic dihydropyridine derivative, which could then undergo oxidation to the pyridinium derivative. The isolation of 1-(5-amino-3-carboxypenty1)-3- [ 1-(5- amino-5-carboxypentyl)-2-piperidyllpyridinium chloride (anabilysine, XXII), formed by reaction of two molecules of glutaraldehyde with two lysine residues, was also described. Glutaraldehyde reaction with primary amines is known to consume oxygen, which is thought to be involved in the oxidation of dihydropyridine derivatives to pyridinium compounds. 14' it was suggested that, In an earlier following initial reaction of glutaraldehyde with amines to form Schiff bases, further reaction with glutaraldehyde forms a conjugated Schiff base, which then reacts with additional lysine molecules, either by Michael addition or by reaction at the free aldehyde groups. The complexity of the reaction products, the ability of glutaraldehyde to polymerize, and the difficulty associated with examining the crosslinking process have made this a difficult area of study. The elucidation of the mechanism of the cross-linking process will require further investigation. D. Reaction with DNA Little information is available on the reaction of glutaraldehyde with DNA or the components of DNA. Products were formed on reaction of 153
H I
-
R-N D
C
H
O
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t
J
Q I
R
XVll I
R
XIX
XXI
FIGURE 6. Possible reactions of glutaraldehyde with the â&#x201A;Ź-aminogroups of peptide-bound lysyl residues. R-NH, represents a peptide-bound lysine residue, Glut the carbon backbone of glutaraldehyde, and n = 1-40. XI is a Schiff base formed on reaction between the amine and glutaraldehyde. XI1 is a Schiff base formed by reaction with an a$-unsaturated dimer." Xlll is a subsequent Michael addition product. XIV represents a cross-link formed by generation of a Schiff base. XV and XVI are Schiff bases formed by reaction of amines with glutaraldehyde polymers. XVll and XVlll represent the dihydropyridine and dihydropyridinium compounds described by Hardy et al.,140 and XIX and XX the pyridinium derivativesformed on o ~ i d a t i o n . ' ~XXI ~ ~ 'and ~ ' XXll (anabilysine) are cross-linked products proposed by Hardy et a1.139p140 (Adapted from Reference 142.)
glutaraldehyde with deoxyadenosine, deoxyguanosine, and deoxycytidine, but not with deoxythymidine. 143 The adducts formed with deoxyadenosine were unstable, but those formed on reaction with deoxyguanosine were relatively stable. Based on the reactivity of glutaraldehyde with various substituted guanosine derivatives, the UV and fluorescence spectra of the adducts, and the retention of radiolabel on reaction with [8-3H]guanosine, the position of substitution is most probably the exocyclic amine group.
154
The reaction of DNA or RNA with glutaraldehyde, as measured by increasing absorbance at 260 nm, occurs only at elevated temperatures (>6OoC), at which the nucleic acids undergo melting. 14'No evidence for intermolecular DNADNA cross-linking was observed. DNA-protein cross-linking was detected by alkaline elution in replicating human TK6 lymphoblasts treated with sublethal concentrations of glutaraldehyde.145 The reaction of glutaraldehyde in biological systems to form DNA adducts or DNA-protein cross-links
could have considerable consequences and is an area that requires additional investigation.
VII. TOXICITY STUDIES
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The studies described in this review have focused mainly on glutaraldehyde preparations that also contain oligomers and polymers. No studies have addressed the potential toxic effects of the oligomers and polymers alone, or in combination with monomeric glutaraldehyde.
A. In Vivo Studies Many studies designed to assess the toxicity of glutaraldehyde have limited relevance to the principal routes of human exposure in the workplace, where inhalation and dermal exposures are by far the most common. Several toxicity studies rely on drinking water as the route of exposure,’22 which may relate to only a limited number of food products. A more appropriate assessment of human risk resulting from exposure to glutaraldehyde would be possible with systematic examination of the respiratory tract following longterm inhalation exposure to low levels of this compound, or examination of skin lesions following repeated dermal exposure. In this section, findings of studies to assess the in vivo toxicity of glutaraldehyde are examined. A detailed list of acute (LD50, LC,J studies is followed by a summary of glutaraldehyde toxicity resulting from exposure by various routes (e.g., intravenous, oral, dermal, ocular, and inhalation). The acute toxicity of glutaraldehyde, either alone or diluted with water or corn oil, has been investigated in a variety of species. The results are reported in Table 2. Following a single oral administration of aqueous solutions of glutaraldehyde (0.5 to 50% w/w), signs of toxicity in rats included piloerection, red periocular and perinasal encrustation, sluggish movement, rapid breathing, and diarrhea. Survivors showed no gross pathological lesions at necropsy, whereas the animals that died displayed distension of the stomach with congestion and hemorrhagic areas in the stomach wall,
congestion and distension of the small intestine, and variable congestion of the adrenals, kidneys, liver, spleen, and lungs. 122 Glutaraldehyde caused no morphologically identifiable lesions in a 3month study in which rats received 0.5, 2.5, or 5% glutaraldehyde in the diet. This study was performed to affirm the Generally Recognized As Safe (GRAS) status of glutaraldehyde, which is used in the food industry to cross-link edible collagen sausage casings. 146 Following 11 weeks of administration of 0.25% glutaraldehyde in drinking water, rats exhibited no evidence of damage in the peripheral or central nervous systems. 14’ These studies were conducted because of glutaraldehyde’s structural similarity to the neurotoxicant 2,Shexanedione. However, no data are available that indicate neurotoxic effects of glutaraldehyde. The results of a 13-week subchronic study with dogs exposed to glutaraldehyde by drinking water were expected to be published in an updated review during 1991.26 Glutaraldehyde is presently classified as a primary dermal irritant, and dermal application to the skin of rabbits caused moderate irritation.26 Several reports have linked glutaraldehyde exposure to irritation and/or allergic-type responses. Glutaraldehyde proved to be strongly positive in the mouse ear sensitization assay. 14* Severe local inflammation and punctate necrosis were observed following an occluded patch test on rabbit skin using 25% glutaraldehyde. The concentration threshold for glutaraldehyde-induced erythema was judged to be 1%.’49 Contact hypersensitivity has been reported in mice and guinea pigs resulting from dermal application for 5 to 14 days of 0.3 to 3.3% glutaraldehyde. I5O Other investigators have demonstrated the induction of a weak immunologic response in rabbit^.^^,'^^ Glutaraldehyde also caused a 90% inhibition of graft-vs.-host reactions in mice. 152 Glutaraldehyde administered subcutaneously to male rats for 35 days at 25 or 125 mg/kg/day caused an increased number of white blood cells, decreased levels of hemoglobin and lymphocytes, hypertrophy of white pulp in the thymus, atrophy of the thymus, and degeneration of renal tubules. Urine and blood chemistries were essentially in the normal range except for elevated serum urea nitrogen and urine total protein levels. 153
155
TABLE 2 Acute Toxicity of Glutaraldehyde (LD,dLC,)
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Species
LD,value
Route
Rat
Inhalation
Rat (male) Rat (female) Rat
Inhalation
Oral
Rat
Oral
Rat
Oral
Rat
Oral
Rat
Oral
Rat Rat Rat Mouse Mouse
S.C.
Mouse (male) Mouse (male) Mouse Mouse Rabbit
Oral
Rabbit
Oral
Rabbit
Oral
Rabbit
Skin
Inhalation
i.p. i.v. Oral Oral
S.C.
i.p. i.v. Oral
5000 ppm (LC50) 24 PPm (LC50) 40 PPm (Lc50) 1.30 ml/kg 50% aq. soh. (wlw) 1.87 ml/kg 25% aq. soh. (wlw) 3.3 ml/kg 5% aq. soln. (w/w) 12.3 ml/kg 1% aq. soln. (w/w) 96.1 mglkg 2% Cidex formultn. 2390 mglkg 17900 pglkg 15300 pg/kg 100 rng/kg 1300 mglkg 25% olive oil soln. 122 mg/kg 2% Cidex formultn. 1430 mg/kg 13900 pg/kg 15400 pg/kg 1.59 ml/kg 50% aq. s o h (w/w) 8.0 ml/kg 25% aq. soh. (w/w) >16 ml/kg 5% aq. soh. (w/w) 2560 pglkg
Solutions of glutaraldehyde (instilled as a single application and observed for 14 days) were markedly irritating to the eye, causing conjunctivitis at concentrations >0.1% and corneal inIn contrast, jury at concentrations <0.5%.21,149 glutaraldehyde was scored as a noninitant in the in vitro cultured human corneal endothelial cell assay; this test in intended for use as a replacement for the in vivo Draize test used to determine eye-irritating potential. 89 Observations from a number of single exposure and short-term repeated exposure inhalation studies in which rodents were exposed to glutaraldehyde in the parts per million range re-
156
Comment
Ref.
4-h period
239
4-h period
122
4-h period
122 122 122 122 122 153 153 239 239 239 240 153 153 239 239 122 122 122 239
vealed that these exposure levels were associated with significant respiratory distress, as is subsequently discussed. A single 24-h inhalation exposure of NMRI mice to either 33 or 133 mg/l of glutaraldehyde vapor resulted in nervous behavior, excessive washing and panting, accompanied by toxic hepatitis in six of ten mice in the high dose group.'54 A single 8-h inhalation exposure of rats to saturated glutaraldehyde vapors resulted in signs of toxicity and irritation including excess lacrimation and salivation, audible breathing, and mouth breathing, but no deaths during a 14-day follow-up period.IZ2Single inhalation exposures of rats to statically generated
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glutaraldehyde vapors (with chamber concentrations decreasing from 11 to 2 ppm over a 6-h period) caused sensory and respiratory tract irritation. 149 Inhalation exposure of rats to glutaraldehyde (0 to 3.1 ppm, 6 Wday, 9 days) resulted in significant mortality at the high concentration, depressed body weight gain, signs of sensory irritation, and inflammation of the nasal mucosa at 3.1 and 2.1 ppm.’49The acute toxicity of glutaraldehyde was studied in CD/CrlBr rats by instilling into one nostril 40 pl of aqueous solutions This procedure ranging from 20 to 40 mM.’5s.1s6 resulted in minimal response, despite clear concentration-related toxic histopathological changes in the nose. Nasal lesions induced by a single instillation of glutaraldehyde included inflammation, epithelial degeneration, respiratory epithelial hypertrophy, and squamous metaplasia. These lesions were associated with local increases in cell replication and were considered by the to closely resemble lesions induced in the nasal passages of rodents by acute inhalation exposures to a number of irritant gases, including glutaraldehyde. It was proposed that direct application of the test article to the surface of interest (nasal epithelium) made this technique useful for studies of upper airway toxicity. However, the authors stated that this is a “non-physiologic” approach,’56 and care should therefore be taken when interpreting nasal instillation studies for risk assessments of inhaled materials. The effects of long-term inhalation exposure to glutaraldehyde have not been thoroughly examined. A 90-day inhalation study in mice and rats (exposure concentrations 0 to 1000 ppb) sponsored by National Toxicology Program (NTP) was completed recently. Preliminary published results reveal that glutaraldehyde caused nasal epithelial lesions with increased cell proliferation (measured by tritiated thymidine incorporation) in the anterior nasal cavity at 1000 ppb, with less severe lesions at 500 ppb and minimal to no changes at concentrations of 250 ppb and below. The glutaraldehyde-induced nasal lesions were not considered to be preneoplastic in nature. Is6 The glutaraldehyde-induced lesions occurred more anteriorly in the nose of the rat than those reBoth neoplastic ported for formaldehyde. and non-neoplastic formaldehyde-induced nasal lesions occur principally in the lateral meatus and 1573158
on the mid-ventral nasal septum. Following inhalation exposure of rats and mice to concentrations of glutaraldehyde of 250 to 1000 ppb, there was damage to the squamous epithelium of the nasal vestibule and to the respiratory epithelium closely adjacent to this region.lS9Both the distribution and the morphological characteristics of the lesions induced by glutaraldehyde differed from those of formaldehyde. Furthermore, the preneoplastic changes reported for formaldehyde following a 90-day exposure to 10 or 15 ppm formaldehydelm were not observed with glutaraldehyde. 159 An earlier subchronic inhalation study revealed that daily exposure to 0 to 194 ppb of glutaraldehyde resulted in perinasal wetness and significantly decreased body weight gain at 49 and 194 ppb. No evidence of damage to the nasal mucosa was found in this study, and despite elevated serum enzymes (phosphokinase, lactate dehydrogenase, hydroxybutyric dehydrogenase), no histopathological lesions were found in any organ system.161Comparison of chronic/ neoplastic responses to glutaraldehyde with those of formaldehyde and other aldehydes awaits completion of a chronic inhalation study of glutaraldehyde at concentrations of 250 ppb or above. Cardiotoxic effects of simple aliphatic aldehydes including glutaraldehyde and related compounds were investigated in dogs following a single intravenous exposure (1 to 10 mg/kg). Glutaraldehyde and formaldehyde caused prolonged Q-T periods, resulting in ventricular fibrillation but no significant sympathomimetic effect. 16* Structure activity relationships indicated that the aldehyde group caused the Q-T prolongation, but an adjacent free methyl or hydroxyl group to the aldehyde group eliminates the effect. Residual Cidex (a commercial disinfectant formulation containing 2% glutaraldehyde) on instruments used for arthroscopic surgery has been suspected as the cause of postsurgical complications. Synovial irritation occurred when rabbit joints were injected with 0.5 ml of various dilutions of Cidex, beginning at 10 ppm (0.1 kg glutaraldehyde). The degree of synovial inflammation was directly proportional to the concentration of Cidex to which the joint was exposed. These studies demonstrated the need for careful rinsing of instruments following Cidex disinfection to avoid chemical irritation of joints. 163 This
157
response was judged to be a chemical rather than an allergic response. In vivo studies strongly suggest the potential for adverse effects at the site of application resulting from dermal, ocular, or inhalation exposure to glutaraldehyde. However, the likelihood of systemic toxicity following in vivo exposure would appear to be slight, given the extreme reactivity of glutaraldehyde and its tendency for limited distribution from the site of applicatiodexposure. Io1 -lo3
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B./n Vitro Studies The effects of glutaraldehyde solutions and vapor on the viability and dividing ability of nuiliei-oiis lilies of cultured cells have been investigated. A number of these studies were of limited value because cells were treated with elevated concentrations of glutaraldehyde in the range used for tissue fixation (1.25 to 2.5 M, corresponding to 2 to 4% glutaraldehyde). Other in v i m data were reported from studies investigating the potential use of glutaraldehyde in novel clinical applications. High concentrations of glutaraldehyde (0.58 to 10 M) were toxic to cultured L cells;164these cells were found to be more sensitive to formaldehyde than to glutaraldehyde, with decreased growth, but no loss of viability observed at 160 d formaldehyde and 400 mM glutaraldehyde.I6â&#x20AC;&#x2122; Glutaraldehyde (25 mM) was found to be extremely cytotoxic to cultured HeLa cells. Millimolar concentrations of glutaraldehyde inhibited mitosis in eggs of Triturus helveticus Raz., acting on kinetochores in a manner similar to quinoline, but unlike antitubulin agents such as colchicine, vinblastine, or podophyllotoxin. 167.168 Glutaraldehyde also decreased proliferation of HL60 leukemia cells, with the appearance of numerous polyploid cells at a glutaraldehyde concentration of 100 mM. 169 Glutaraldehyde vapor inhibited the propagation of unspecified lines of cultured cells.17oExposure of human TK6 lymphoblasts to 10, 15, and 20 @I4 glutaraldehyde in serum-free media for 30 min resulted in the death of 10, 50, and 90% of the cells, respectively. 109-145*171Primary hepatocyte cultures tolerated 100 JLM glutaraldehyde for 18 h with minimal damage. l w 158
A number of investigationsdemonstrated that glutaraldehyde can kill or reduce the malignancy of a number of tumor cell lines. Glutaraldehyde was used in mechanistic studies of foreign-body tumor induction171and in studies of density-dependent growth inhibition. 172 Dilute solutions of glutaraldehyde have been shown to be effective in killing Ehrlich carcinoma cells in mice and for the prevention of recurrent tumors at anastomotic suture lines following surgical resection of colon cancers. 173 Glutaraldehyde treatment reduced the malignancy of 4C 1 cells. 174 Glutaraldehydetreated malignant cells were shown to be more susceptible to antibody-dependent, macrophagemediated cytolysis than nonglutaraldehyde-treated tumor cells, and glutaraldehyde-treatedmalignant cells have been successfully used to produce tumor immunopropnyiaxis in mice against a variety of tumor line^.'^^-'^^ Glutaraldehyde was compared to a series of alkylating agents and other aldehydes for immunosuppressive activity. Glutaraldehyde (50 mM) was more effective in lymphocyte deactivation in vitro than chloroacetaldehyde, which is a metabolite of the immunosuppressive drug cyclophosphamide.152 Numerous reports on the effects of glutaraldehyde modification on red blood cells and hemoglobin (Hb) have resulted from efforts to improve the shelf life of blood products using glutaraldehyde as a preservative. Glutaraldehyde concentrations up to 50 mM had no effect on the density, mean cell volume, or potassium-retaining ability of red blood cells.57Glutaraldehydemodified Hb reversibly bound oxygen. l8O.I8l However, Hb extensively modified by glutaraldehyde did not contribute to oxygen transport in artificial red blood cells. Glutaraldehyde has been shown to either or i n c r e a ~ e ] ~ ~ . ~ ~ ~ the affinity of Hb for oxygen. Glutaraldehyde decreased the osmotic fragility and deformability of red blood cell^,'^^^^^ presumably due to stabilization of cytoskeletal and surface proteins. Glutaraldehyde altered the surface charge and electrophoretic mobility of red blood cells186and decreased catecholamine-stimulated CAMP formation. 187 Several reports disclose the use of glutaraldehyde-modified proteins to enhance drug delivery to target tissues. Microcapsules comprised of glutaraldehyde-cross-linkedproteins, intended for
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the delivery of anticancer drugs to tumors, caused reversible inhibition of proliferation of cultured cells (e.g., human erythroleukemic cell line K562) at the G2 phase of the cell cycle.’88In addition, glutaraldehyde treatment of erythrocytes loaded with adriamycin provided an efficacious dosing regimen in B6C3F1 mice.Is9 This modified drug formulation, which was found to be less cardiotoxic, was excreted at a slower rate and remained at the site of action (lung or liver tumor) for longer periods of time. A moderate increase in plasma transaminase and alkaline phosphatase activities was observed after injection of the modified drug form, but histopathology revealed no hepatocellular injury. Potential neurotoxic effects of glutaraldehyde were investigated by observing the changes in excitability and conduction in the frog sciatic n e r ~ e . ’ ~ ~Immersion .’~’ of the nerve in a Ringer solution containing glutaraldehyde revealed irreversibly decreased amplitude of nerve action potential, causing a complete action potential block, purportedly due to inactivation of sodium and potassium ion channels. A 1% solution of glutaraldehyde was found to be an effective inhibitor of adenosine uptake in rat brain synaptosomes, 192 while lower concentrations of glutaraldehyde specifically inhibited the temperatureinduced allosteric modification of high-affinity [3H]tryptamine-binding sites. 1 9 3 C. Genotoxicity of Glutaraldehyde Short-term genotoxicity tests with glutaraldehyde have yielded inconsistent responses, ranging from no activity to unequivocal mutagenicity. The variability stems primarily from the choice of biological test system. Early reviews of the genotoxicity of glutaraldehyde suggested that the compound was nonmutagenic, 194,195 but recently more sensitive assays investigating specific genomic lesions have yielded positive results. Glutaraldehyde was found to be negative in the Escherichia coli WP2 uvrA reversion assay (without activation) when tested at six concenThese trations ranging from 20 to 10,000 &.Ig6 same investigators also found glutaraldehyde to be unreactive in uitro using 4-(p-nitrobenzyl)pyridine or deoxyguanosine as the alkylation tar-
gets. Glutaraldehyde also proved to be nonmutagenic in the SOS-chromotest using E. coli F‘Q37 as the tester strain. 19’ Results of the genotoxicity tests in the NTP ranged from no activitylg8 to weakly positive activity (causing an approximate doubling of background mutants) in Salmonella reversion assays when tested in strains TA100, TA1535, TA1537, and TA98 at doses ranging from 33 to 3333 pg/plate.199The greatest activity was observed in strain TAlOO at doses ranging from 10 to 200 pg/plate. Convincing mutagenicity data were reported from tests employing Salmonella strains TA102 and TA104,200-202 which were developed for increased sensitivity toward carbonyl compounds. In the absence of activation, glutaraldehyde (25 pg/plate) caused a 2.5-fold increase in mutation frequency above background in TA 102. Using a semiquantitative approach, glutaraldehyde was found to be one of the most active mutagenic carbonyl-containing compounds, with 100 pg/plate causing a 13-fold increase in reversion frequency without activation in TA104.201Glutaraldehyde was also found to be mutagenic, independent of S9 activation, in the umu test. 203 Glutaraldehyde-induced DNA damage was also indicated by positive results in the liquid r e c - a s ~ a y . ~ ~ ~ ~ * ~ In other genotoxicity assays, glutaraldehyde (8 pg/ml) was a potent mutagen in the mouse lymphoma cell line.2o5Likewise, glutaraldehyde treatment (10 to 20 cl.M> caused an approximately sevenfold increase in the trifluorothymidine-resistant mutant fraction in cultured human TK6 lymphoblasts. 145 Glutaraldehyde was negative in the Drosophila sex-linked recessive lethal test.206 Oral doses of glutaraldehyde (30 to 60 mg/kg) were negative in the mouse dominant lethal assay.*07 Glutaraldehyde (2.5%) caused damage (irreversible swelling) of chromosomes isolated from cultured Chinese hamster B14 and Don C cells in vitro.z08Mixed results were obtained in cytogenetic evaluations of glutaraldehyde. In one report, glutaraldehyde (1 1 to 15 pg/ml) did not induce sister chromatid exchange (SCE) in Chinese hamster ovary cells,2o9 while another laboratory reported these same doses to be positive with or without activation.210 Evaluation of glutaraldehyde-induced unscheduled DNA synthesis (UDS) in the male rat liver following oral administration of the com-
159
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pound revealed that glutaraldehyde did not induce DNA damage repaired by an excision process.2" However, because of the ability of glutaraldehyde to react rapidly and irreversibly with proteins, it is unlikely that any unreacted glutaraldehyde actually reached the liver under this treatment regimen. Assessment of glutaraldehyde-induced UDS in primary hepatocyte cultures treated with 0 to 100 @I4 glutaraldehyde revealed a modest dose-related response, with only the highest dose exhibiting a statistically significant increase over controls. 145 In order to affirm the GRAS status of glutaraldehyde used in sausage production, glutaraldehyde-treated edible sausage casings were subjected to short-term genotoxicity testing. The casings did not prove to be mutagenic in either an Aliies test (usiag liri u n q ~ e ~ i l i zsirain d of Salmonella) or in the mouse lymphoma cell In conclusion, glutaraldehyde exhibits mutagenic activity, and the majority of the positive studies suggest that glutaraldehyde induces oxidative damage to DNA in cells exposed to the compound. Glutaraldehyde is also markedly cytotoxic. This combination of adverse effects raises concern about the safety of individuals to repeated exposure to glutaraldehyde via the skin and/or respiratory tract.
D. Carcinogenicity Currently, there are no adequate long-term bioassay studies on the potential carcinogenicity of glutaraldehyde reported in the published literature. Glutaraldehyde has been nominated for evaluation of chronic toxicity and carcinogenicity by NTP.
E. Developmental Toxicity Only a few studies have reported the potential embryotoxicity of glutaraldehyde, even though it is used as a disinfectant in hospitals and as a fixative in laboratories, where a high level of female employment exists. Although most of the cited literature does not provide data on occupational exposure levels, the cumulative available information from human epidemiological
160
studies as well as laboratory animal investigations indicates a low hazard for developmental toxicity from glutaraldehyde exposure. Perhaps the most valuable data have been obtained from retrospective epidemiological studies that assessed the incidences of spontaneous abortions and fetal malformations in Finnish hospital nurses and instrument sterilizing staff who had been exposed to sterilizing agents (glutaraldehyde, formaldehyde, and ethylene oxide) and/or cytostatic drugs, anesthetics, and X-irrad i a t i ~ n . ~ These ~ ~ . ~ studies '~ suggested an increased frequency of spontaneous abortions with exposure to ethylene oxide, as well as an association between maternal use of cytostatic drugs and fetal malformations in offspring of staff involved in such sterilization procedures .214However, there was no significant increase in risk of either endpoint in staff performing sterilization or nurses exposed to glutaraldehyde or formald e h ~ d e . ~In~the ~ . 1982 ~'~ the reported increase in the crude rate of spontaneous abortions correlated with exposure to glutaraldehyde before adjusting for age, parity, decade of pregnancy, smoking, and alcohol and coffee consumption. The authors indicated that, while it is less potent than ethylene oxide, glutaraldehyde may not be absolutely safe.214No information on birth defects was reported in these studies. Investigations in experimental animals also indicated a low occurrence of developmental toxicity as a result of glutaraldehyde exposure during pregnancy. A study conducted by Marvishi Pharmaceutical Company found no embryotoxic effects in the offspring of mice treated by gavage with up to 30 mg/kg of glutaraldehyde on days 7 through 12 of gestation.'22 Sonacide (acidified glutaraldehyde containing 2% glutaraldehyde w/v; Ayerst Laboratories, Inc., New York, NY) was embryotoxic following oral administration to CD- 1 mice during days 6 to 15 of gestation. Although highly toxic to pregnant dams at concentrations above 2.0 ml/kg/day (40 mg glutaraldehyde/kg/day), Sonacide only affected fetuses at the highest dose of 5 ml/kg/day, which also killed more than half of the dams.21s At this dose, the average fetal weight was significantly reduced and 11.7% of the fetuses were malformed. Similarly, oral doses of 25 and 50 mg/kg of glutaraldehyde given to albino rats on
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days 6 to 15 of pregnancy were maternally toxic but were not fetotoxic.Iz2 Preliminary results of a prenatal toxicity study in which rabbits were given glutaraldehyde by gavage ( 5 , 15, and 40 mg/kg/day for 13 consecutive days) have recently been reported.216The high dose was severely maternally toxic and caused a significant increase in implantation loss and reduction of the mean body weight of surviving fetuses. The two lower doses were apparently nontoxic to either the dam or embryo/fetus. While rodent studies have not assessed the developmental effects of inhalation exposure to glutaraldehyde, indirect evidence suggests that significant systemic absorption and distribution would not occur, probably due to high chemical reactivity and metabolism . O 1 lo3, I 22 Using a mouse embryo culture system, quality-control analyses of media preparations for human in vitro fertilization programs have provided information on the effects of glutaraldehyde on preimplantation embryo development. Extreme toxicity to cultured mouse embryos was observed when the culture medium was passed, prior to use, through an oocyte aspiration needle that had been sterilized with either Cidex or Cidex-7, formulations that contain 2% glutaraldehyde each. Cidex-7 also contains ingredients to mask the odor of glutaraldehyde and has a shelf life of 28 days, in contrast to 14 days for Thorough washing of instruments with 1.5 to 3 .O I of sterile water reversed the embryotoxicity of Cidex-sterilized instruments, but had no effect on toxicity caused by sterilization with Cidex7.220These findings suggest that the method of instrument sterilization could be a contributing factor to unsuccessful in vitro fertilization attempts in humans. Studies of potential early embryo losses following in vivo glutaraldehyde administration to laboratory animals during the preimplantation period are currently lacking. In summary, maternal exposure in occupational settings does not appear to contribute to spontaneous abortions or fetal malformations. On the other hand, studies in laboratory animals have demonstrated adverse effects of glutaraldehyde on the developing embryo and fetus. Direct contact with preimplantation embryos in vitro was shown to be embryolethal, and postimplantation exposure to glutaraldehyde was developmentally
toxic in mice and rabbits. However, because glutaraldehyde exposures that induced embryo/fetotoxicity in animals in vivo also caused severe maternal toxicity, it is difficult to delineate the cause of the embryo/fetotoxicity. Based on these studies, glutaraldehyde should be regarded as a potential developmental toxicant, but effective doses may be above those that elicit toxicity in the adult, i.e., having low developmental hazard.2z' Further studies are necessary to more fully characterize these effects and the associated human risk.
F. Reproductive Toxicity of Glutaraldehyde
9
There is currently little published information that specifically addresses the potential reproductive toxicity of glutaraldehyde. No studies were found that investigated glutaraldehyde effects on female reproductive function and fertility. Dosing during the organogenesis period of pregnancy, however, revealed no adverse effects on embryonic development except at high doses that were also severely maternally toxic. One study examined the effects of glutaraldehyde on male reproductive function using the dominant lethal assay.2o7 Male mice were administered a single oral dose of 30 or 60 mg/kg glutaraldehyde and mated for the next 6 weeks with virgin females. There was no evidence of reduced fertility in treated males and no statistically significant effects on embryo/fetal viability were recorded.
VIII. ENVIRONMENTAL EFFECTS The antimicrobial properties of glutaraldehyde have been applied in many hospitals where cold sterilization was required. 78 This application represents an occupational hazard to the hospital staff, causing irritation and sensitization to eyes, skin, and respiratory tract. It has been suggested that precautions be taken by keeping the aldehyde atmospheric concentration below 0.2 ppm, wearing protective gloves and gowns, providing facilities for decontamination of eyes and skin, and
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testing for sensitivity to asthma or allergic dermatitis. Sterilization of several polymeric materials in the hospital environment was performed and residues of glutaraldehyde were detected on catheters and feeding tubes. Io5 The concentration of the aldehyde in these materials increased with time of contact. Rinsing with heparin in a sodium chloride solution was not effective for removing the aldehyde residues. The effect of glutaraldehyde in water was analyzed with respect to taste, smell, and antimicrobial action on saprophytic microflora in large water reservoirs. The organoleptic (taste and smell) properties of water were reported to be unaffected by glutaraldehyde at a maximum concentration of 100 mg/l. Saprophytic microflora are not affected at a concentration up to 0.1 mg/i. i 5 Bifunctional organic compounds, such as glutaraldehyde, contribute to the formation of suspended particulate matter and to aerosol components in the atmosphere.z22Some products escaping into the atmosphere are derived from photochemical degradation of cyclic alkenes to form derivatives such as glutaraldehyde by reaction with ozone and hydroxyl radicals. A simple procedure was devised to determine the relative toxicity of effluents containing aldehyde contaminants from purification plants. z23 The method is based on the BOD (biological oxygen demand) of an ordinary effluent sample and a chemically contaminated effluent sample in which the microorganisms present in each effluent are allowed to consume oxygen. The test is focused on the consumption of oxygen by the microorganisms (unspecified species) not inhibited by toxic agents. Thus, a sample having a high oxygen demand would be ranked less toxic than one with a low oxygen demand. Of four aldehydes examined, the glutaraldehyde sample consumed the least amount of oxygen, closely followed by formaldehyde. Propionaldehyde was the least toxic, followed by acetaldehyde. These results indicate a need for caution in discharging effluent containing glutaraldehyde.
IX. RECOMMENDATIONS 1.
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In future studies designed to assess toxic effects of glutaraldehyde, the test material
should be characterized as to composition because of the ready spontaneous formation of polymers. 2. An essential component of the assessment of risk posed by exposure to glutaraldehyde is the evaluation of hazard. Evaluation of the effects of long-term exposure on the respiratory tract and the potential neurotoxic, developmental, and behavioral effects of glutaraldehyde would provide a more complete hazard evaluation. 3. An important factor in the disposition and metabolism of glutaraldehyde is its extensive reactivity with macromolecules, with much of the administered material remaining at the site of application. The effect of exposure by routes such as inhalation requires investigation and may assist in elucidation of the mechanism of action. 4. The products formed on cross-linking of glutaraldehyde with proteins and nucleic acids should be investigated. These could serve as biomarkers and provide additional insight into the toxicological action of glutaraldehyde. 5 . Data provided from these foregoing recommended studies should be incorporated into a risk assessment for glutaraldehyde.
APPENDIX A
- CHEMICAL REACTIONS
Glutaraldehyde is very reactive chemical due to the presence of two aldehydic groups. Glutaraldehyde undergoes the usual reactions associated with aliphatic aldehydes, but in many reactions both terminal aldehyde groups may be involved yielding various cyclic derivatives. This review lists representative reactions of the bifunctional aldehyde that may have some relationship to biological systems and environmental conditions. The principal types of reactions between glutaraldehyde and other chemical species have been classified into three categories. Illustrative reaction sequences are outlined in Table 3 for each of these classes. Several reactions have been reviewed by Evanszz4and original cited references should be examined for description of the experimental conditions used by earlier workers.
TABLE 3 Glutaraldehyde Reactions Glutaraldehyde (G) and active hydrogen compounds Water-hydrated forms of GZ4’
1.
n
OHC
n
WOW2
(H0)zCH CH(OH)2
HoQOH
111
II
H
IV
O
O
V
O
L
Alcohols [ROH; glycols; pentaerythritol yields polymers]
n
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(RO)&H
CH(OR)2
RO
ch
Ethylene glyc01~25
(CH2)3
9
Amines {aliphatic or aromatic amines (RNH,))242 RNH2
+
I
4
0-
Piperidines
6 -O-N~ Benzene
+ I
Mp 49-5O’C
Reflux 24 % yield
Primary amine (RNH,) condensation)
+
RCOOH (Mannich-type
Hydrazines {H,N-NHR; H,N-NRR’}
H =NH l r H R
G + adenosine I cytidine guanosine (or equivalent deoxyribonucleoside)
CH =NH-NR2
Nucleic aid^^^^,^^ + RNh 4
RN=CH(CH&CH-NR
or Nofe: Schiffbase products revert to original compounds unless reduced to form amines. Amino acidsT4,
NH2
I
+
I
R-CH-COOH
4
Schm Bases Subttttuted plperidiner
Polymers 163
TABLE 3 (continued) Glutaraldehyde Reactions Thi~phenolsâ&#x20AC;?~
RSH
+
I
L RSO
S
OSR
RS\
+
R
sH(CH SR RS 2hCe
Thioglycolic acida4
HSCH2COOH
+
I
4
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S
CH2tCHCOCH3
+ I
-
CH~COCHZCH~CO
\
P I 3 CHaCOCH&H&O 3.
Reduction reactions (see also Schiff bases
â&#x20AC;&#x153;O\
HOCH,(CH&CH2OH
L
1,bpentanediol
G-bishemiacetal
From the illustrative reactions of glutaraldehyde in which cyclic tetrahydropyran or piperidine derivatives are formed, consideration should be given to the formation of cis and trans isomers with the asymmetric carbon atoms in the heterocyclic rings. These two isomeric forms of cyclic tetrahydropyrans are illustrated in Figure 7. The potential biological activity of one isomer in contrast to the other, or even a mixture of the two, should be considered in product applications.
APPENDIX B
HO
0
IVa
H OH
HO
n
O
0
H
H
IVb
FIGURE 7. Cis and trans isomers of the tetrahydropyran form of IV glutaraldehyde.
- ANALYSES
A procedure was published recently for the analysis of glutaraldehyde in the a s z s using gas chromatography in which concentrations of 0.03 to 2 ppm of the aldehyde can be determined. An oxazolidine derivative is formed from the reaction of glutaraldehyde and 2-hydroxymethylpip-
164
H-. f i H
eridine, which yields two peaks (UV) due to the presence of diastereoisomers .(Figure 8). An alternate rapid test for the presence of low concentrations (1 to 2 mg/l) of aldehydes such as glutaraldehyde is the addition of a reagent containing a p-rosaniline compound, a phosphate compound (sodium monobasic orthophosphate),
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FIGURE 8. Reaction of glutaraldehyde with 2-hydroxymethyl-piperidineto form an oxazolidine derivative.
and water.226This test is effective for determining glutaraldehyde in rinse solutions on medical equipment. Glutaraldehyde concentrations have been measured in workplace atmospheres containing several contaminants by means of an HLPC method.227This method can be adapted to both particulates and vapors. The aldehydes are derivatized to form 2,4-dinitrophenylhydrazones, which are ideally suited for HPLC analysis and also absorb strongly in the UV range. A similar procedure was used for the analysis of a mixture of aldehydes (glutaraldehyde, formaldehyde, and acrolein), converting them to the corresponding hydrazones prior to UV analyses.22*Limits of detection of these aldehydes in an air sample by means of a UV spectrophotometer were estimated as follows: glutaraldehyde, 0.02 mg/m3; formaldehyde, 0.04 mg/m3; and acrolein, 0.015 mg/ m3. A recent report using a similar procedure for separate detection of formaldehyde and glutaraldehyde disclosed limits of 0.05 ml/m3 and 0.02 mum3, respectively, in 5-1 The dinitrophenylhydrazone derivative of glutaraldehyde has also been utilized in the OSHA Analytical Laboratory229for detecting the aldehyde in an air sample at a concentration of 4.4 ppb (or 18 pg/m3). The sample was analyzed by means of HPLC using a UV detector. A novel photoreduction-fluorescence (PRF) method that detected aldehydes, alcohols, or ethers involves the reduction of anthraquinone in the absence of oxygen.23oThe resultant highly fluorescent hydroquinone allowed detection limit of 31 ng of glutaraldehyde. An index of purification has been proposed by comparing the UV spectra of both commercial and vacuum-distilled glutaraldehyde samples.23' The impure material exhibited a higher extinction at 280 nm than the purified product at 235 nm, while the reverse was seen with distilled aldehyde. The index of purification (I,) was stated to be valid only if the temperature and concen-
trations of glutaraldehyde were known at the time of sample measurements: I, = E235/E280. Prior analyses of commercial glutaraldehyde substantiated the pure aldehyde peak at 280 nm and also the importance of storage at low temperatures (<2OoC) for extended periods.232The rate of deterioration in an inert atmosphere, such as in nitrogen, was slightly less than a glutaraldehyde sample over an 8-month storage period at low temperature (<O째C) in air.
ACKNOWLEDGMENTS The authors wish to convey their grateful appreciation to the reviewers who contributed much in focusing on the principal issues and potential concerns for glutaraldehyde. The reviewers included Drs. Gregory Kedderis, Frank Welsch, Julian Preston, Russell Cattley , Rajendra Chhabra, and Dan Morgan. Special acknowledgement is expressed for the support and encouragement from Chemical Industry Institute of Toxicology, The Procter & Gamble Company, and National Institute of Environmental Health Sciences in the preparation of this publication as an adjunct in the study of aldehydes. The Information Services staff at CIIT has assisted greatly at all stages in the production of this manuscript and personal thanks are extended to Linda Smith, Willanna Griffin, Beth Williamson, and Rita Berman.
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