Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 (1996)

Hector D. Garcia, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

National Aeronautics and Space Administration

Houston, Texas

Glutaraldehyde, an aliphatic dialdehyde, is a highly reactive compound that has been isolated as a water-soluble oil and usually is stored as an aqueous solution to inhibit polymerization (Sax, 1984). Unbuffered aqueous solutions of glutaraldehyde are stable for long periods of time, have a mildly acid pH, a negligible odor, and are not potently antimicrobial. When buffered to an alkaline pH of 7.5 to 8.0 with sodium bicarbonate, the glutaraldehyde is activated; it has a strong pungent odor, and its antimicrobial activity is greatly enhanced for periods of up to 14 days (Stonehill et al., 1963).

Glutaraldehyde is widely used in embalming; in the manufacture of adhesives, sealants, and electrical products; as a cross-linking agent for proteins and polyhydroxy compounds; in microcapsules containing flavoring agents; and as a tissue fixative in electron microscopy, the paper and leather tanning industries, and x-ray film developing solutions. It is also used as a sterilizing agent for plastics, rubber, thermometers, lenses, and other surgical, dental, and hospital equipment (Stonehill et al., 1963; Lahav, 1977; Biophysics Research and Consulting Corporation, 1980; Hemminki et al., 1982; Wiggins et al., 1989). Glutaraldehyde is an effective sporicidal agent, requiring about 3 h for an almost complete kill of spores as well as gram-negative and gram-positive bacteria, fungi, and viruses. Glutaraldehyde has been used in surgical procedures including colonic anastomoses (D'Ovidio et al., 1981) and dental pulpotomies (Ranly et al., 1989; Feigal and Messer, 1990; Ketley and Goodman, 1991). Glutaraldehyde solutions (5-25%) are used clinically to treat skin disorders, including warts, hyperhidrosis (excessive sweating of the hands or soles of the feet), herpes simplex, and herpes zoster, and in the preparation of grafts and bioprostheses (Beauchamp et al., 1992). The preservative and antimicrobial properties of glutaraldehyde have found broad application in cosmetic, toiletry, and chemical specialty products because of glutaraldehyde's water solubility and usefulness in systems containing secondary or tertiary amines, quaternary ammonium compounds, or protonated amines (Beauchamp et al., 1992).

Glutaraldehyde solutions often are used as cell and tissue fixatives in biochemical experiments during space-shuttle flights.

No data were found on the uptake, distribution, metabolism, or elimination of inhaled glutaraldehyde vapors. The discussion below relates to percutaneous or intravenous routes of exposure.

The extent of systemic distribution of glutaraldehyde that was applied to a pulpotomized tooth of a rat was estimated to be 40 nmoles, or 25 % of the applied dose. Metabolic studies using that preparation showed that glutaraldehyde was eliminated in the urine (the urinary metabolites

have not been characterized) and in expired gases (as CO₂); 90% was cleared from the rats' body tissues in 3 d (Ranly et al., 1989).

Percutaneous penetration of topically applied glutaraldehyde solutions was studied in vitro using human stratum corneum from the chest, abdomen, and sole, and epidermis from the abdomen (Reifenrath et al., 1985). The results showed that glutaraldehyde does not penetrate the thick stratum corneum of the sole, but that 3.3% to 13.8% of the applied dose penetrated the thin stratum corneum of the chest and abdomen, and 2.8% to 4.4% of the applied dose penetrated the isolated epidermis. More recent studies reported < 1% penetration by glutaraldehyde through the skin of rats, mice, rabbits, guinea pigs, and humans (Tallant et al., 1990).

In studies of rats and rabbits given 0.075% or 0.75% [1, 5-¹⁴C]-glutaraldehyde intravenously, the majority of the radioactivity was excreted as ¹⁴CO₂; approximately 80% was exhaled in the first 4 h. The fate of the unlabeled carbon atoms has not been directly established, and direct identification of metabolites has not been carried out (Beauchamp et al., 1992). Determination of the fate of glutaraldehyde in vivo is complicated by the fact that ¹⁴CO₂ produced during metabolism of [1,5-¹⁴C]glutaraldehyde could be recycled and incorporated into the normal monomers required for synthesis of macromolecules. Thus, deposition of radioactivity at the site of administration does not necessarily represent only covalent binding of glutaraldehyde to macromolecules.

Relatively few toxicity studies have been done on glutaraldehyde, considering its widespread use. Many of the studies that have been done test the toxicity of glutaraldehyde solutions rather than glutaraldehyde vapors. A study comparing the acute oral toxicities versus the acute inhalation toxicities of 108 chemicals concluded that, although a positive correlation of 0.53 (p = 0.001) was demonstrated for toxicities via the two routes of exposure, the magnitude of the correlation was so low that the predictive value of one for the other was limited (Kennedy et al., 1991). Thus, even though mention will occasionally be made

below of toxicities due to noninhalation exposures, these will not be used to set acceptable concentrations for inhalation exposures.

Glutaraldehyde is a relatively strong irritant to the nose and a less strong irritant to the eyes and skin (Anonymous, 1976). The odor threshold is 0.04 ppm (Beauchamp et al., 1992). Sensory irritation and inflammation of the nasal mucosa, as well as depressed weight gain, were noted in rats exposed to glutaraldehyde via inhalation for 6 h/d for 9 d at 2.1 or 3.1 ppm; significant mortality was seen at 3.1 ppm (Ballantyne et al., 1985). Fischer 344 (F344) rats exposed to glutaraldehyde for 6 h/d, 5 d/w, for 3 mo at 0.049 or 0.194 ppm showed perinasal wetness and significantly decreased weight gain but no damage to the nasal mucosa and no histopathological lesions in any organ, although the activities of several serum enzymes (phosphokinase, lactate dehydrogenase, and hydroxybutyric dehydrogenase) were increased (Greenspan et al., 1985).

A solution concentration of 1% was reported to be the threshold for glutaraldehyde-induced erythema in rabbit skin (Ballantyne et al., 1985). Instillation of 20-40 mM glutaraldehyde into the nasal cavities of rats caused epithelial changes characteristic of inhalation exposure to a number of irritating gases (St. Clair et al., 1990).

A single 8-h inhalation exposure of rats to saturated glutaraldehyde vapors (concentration not measured) produced excess lacrimation and salivation, audible breathing, and mouth breathing (Ballantyne, 1986). Single exposures (6-8 h) of rats to statically generated steady-state vapor atmospheres produced only signs of sensory irritation to the eyes and respiratory tract (Ballantyne et al., 1985; Ballantyne, 1986). Measurements indicated an initial glutaraldehyde concentration of 11 ppm,

decreasing to 2 ppm at 6 h, and an average of 4.3 ± 3.4 (standard error) ppm (Ballantyne, 1986).

In 2-w inhalation exposures of rats and mice to glutaraldehyde at 0, 0.16, 0.5, 1.6, 5, and 16 ppm for 6 h/d, 5 d/w, all rats and mice exposed to glutaraldehyde at 5 or 16 ppm died before the end of the studies, as did all mice exposed at 1.6 ppm (Kiri, 1992). The deaths were attributed to severe respiratory distress. Mice appeared to be more sensitive than rats because the small airways of the nasal passage were more easily blocked by cell debris and keratin. Lesions noted in the nasal passage and larynx of rats and mice included necrosis, inflammation, and squamous metaplasia. At higher concentrations, similar lesions were present in the trachea of rats and mice and in the lung and tongue of rats (Kiri, 1992).

Similar lesions in the respiratory tract were seen in 13-w studies of rats and mice exposed to glutaraldehyde at 0, 0.0625, 0.125, 0.25, 0.50 and 1.0 ppm, but the evidence of systemic toxicity was unclear following histopathological or clinical pathology assessments (Kiri, 1992). Lesions of the nasal passages in rats were seen at concentrations as low as 0.125 ppm; the severity increased with increasing concentrations. In mice, a no-observed-adverse-effect level (NOAEL) was not reached, because inflammation was found in the anterior nasal passage at concentrations as low as 0.0625 ppm (Kiri, 1992).

A single 24-h inhalation exposure of NMRI mice to glutaraldehyde vapor at 33 ppm induced toxic hepatitis in 9 of 10 mice, and 8 ppm caused local inflammation of the liver, possibly not of toxic origin, in 1 of 10 mice (Varpela et al., 1971).

In rats, the 4-h LC₅₀ values for dynamically generated glutaraldehyde vapor were 24 (17-33) ppm for males, and 40 (15-106) ppm for females (Ballantyne et al., 1985). As noted above, however, single exposures (6-8 h) of rats to statically generated, saturated glutaraldehyde-vapor

atmospheres up to 11 ppm produced only signs of sensory irritation to the eyes and respiratory tract (Ballantyne et al., 1985; Ballantyne, 1986). The LC₅₀ value (5000 ppm) listed in the National Institute for Occupational Safety and Health's Registry of Toxic Effects of Chemical Substances (RTECS) (NIOSH, 1987) is from a 1972 Czecholovakian publication (Marhold, 1972) and is given little credence because it is so much higher than the values reported by others in more recent studies. The large discrepancy between the LC₅₀ values of Ballantyne et al. (1985) and RTECS could be explained if the concentrations reported in the Czech article on which the RTECS value is based were nominal rather than analytical. The concentrations reported by Ballantyne et. al. (1985) were analytical concentrations. The high reactivity of glutaraldehyde makes it very difficult to maintain atmospheric concentrations at nominal values.

Glutaraldehyde was found to be negative for genotoxicity in some in vitro and in vivo genotoxicity assays. Negative results were observed at concentrations spanning cytotoxic to noncytotoxic doses in the following test systems: mutagenicity in Salmonella strains TA 98 and TA 100 with and without microsomes (Hemminki et al., 1980; Slesinski et al., 1983), the Chinese hamster ovary cell and hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT) gene-mutation system (Slesinski et al., 1983), the sister-chromatid-exchange (SCE) test with CHO cells (Slesinski et al., 1983), and the primary rat hepatocyte unscheduled DNA synthesis (UDS) system (Slesinski et al., 1983). No increase was seen in the dominant lethal index in mice exposed orally to glutaraldehyde at 30-60 mg/kg (Tamada et al., 1978).

Glutaraldehyde was positive for genotoxicity in other in vitro assays (Sasaki and Endo, 1978; McGregor et al., 1988; St. Clair et al., 1991; Jung et al., 1992). They include induction of DNA-protein cross-linking in human TK6 lymphoblast cells and dose-related increases in mutations at the thymidine kinase locus in the same cells (St. Clair et al., 1991). In primary rat hepatocytes, glutaraldehyde induced a marginal increase in UDS (St. Clair et al., 1991). In a collaborative study by three laboratories, glutaraldehyde was found to be mutagenic in Salmonella typhimurium TA 102 by all three laboratories (Jung et al., 1992).

Of 12 rats per group exposed 6 h/d for 9 d to glutaraldehyde at 3.1 ppm, seven males and six females died between the sixth and ninth exposure days (Ballantyne, 1986). Nine of 10 male rats and 7 of 10 female rats died after exposure to glutaraldehyde at 2.1 ppm for 6 h/d for 9 d, as did 1 of 10 male rats exposed at 0.63 ppm (B.J. Greenspan, Pacific Northwest Laboratory, Richland, Wash., personal commun., 1992).

Rats exposed 6 h/d for 9 d to glutaraldehyde at 3.1 ppm showed signs of irritation; the signs were audible breathing and periocular and perinasal encrustation; increases in neutrophil count, erythrocyte count, hematocrit, and hemoglobin concentration; and decreased organ weights for liver, kidney, lung, heart, and testes (Ballantyne, 1986). At 1.1 ppm, half of the animals demonstrated mouth and abdominal breathing and the same hematological and organ-weight effects as seen at 3.1 ppm except that lung weights were not decreased. At 0.3 ppm, there were no signs of irritation, no significant hematological effects, and only a slight increase in lung weight. (Ballantyne, 1986). Histological examination of tissues from survivors sacrificed the day after the final exposure at 3.1 ppm revealed hepatocellular atrophy, rhinitis, and mild atrophy of the olfactory mucosa. Rhinitis and squamous metaplasia of the nasal mucosa occurred at 1.1 ppm. No histological abnormalities were seen in animals exposed at 0.3 ppm (Ballantyne, 1986).

There are numerous reports of mild-to-severe contact dermatitis in humans and animals resulting from occasional or incidental contact with glutaraldehyde solutions or vapors. Contact dermatitis, particularly in medical personnel who use 2% glutaraldehyde solutions to sterilize

equipment, has been reported (Jordan et al., 1972; Bardazzi et al., 1986; Di Prima et al., 1988; Nethercott et al., 1988a, b; Stern et al., 1989; Jachuck et al., 1989; Charney, 1990). There appears to be substantial variation in individual susceptibility to glutaraldehyde-induced dermatitis, which, in a few individuals, appears to be due to allergic reactions developing after repeated contact with glutaraldehyde.

Numerous reports describe the risks of occupational exposure to glutaraldehyde vapors in hospital staff involved in cold sterilization of endoscopes and other medical equipment. In a study by Jachuck et al. (1989), exposed hospital personnel (eight of nine exposed) complained of headache, respiratory difficulty, rhinitis, and watering of the eyes. Measurements of the glutaraldehyde vapor concentration in a nurse's breathing zone showed 0.12 ppm (Jachuck et al., 1989). A single individual also reported nausea, but this symptom was not reported in any of the other literature found. A case study by Charney (1990) reported hives, chest tightness, and watery eyes in 19 workers in an area where glutaraldehyde was used in counter-top baths for bronchoscope disinfection and where ambient and breathing-zone samples yielded concentrations up to 0.25 ppm. In other similar studies, personal breathing-zone samples in two hospitals ranged up to 6.1 and 8.1 ppm and an area sampling ranged up to 3 ppm (Charney, 1990). A case report by Benson (1984) of a nurse who worked in an endoscopy unit and who complained of constant eye irritation indicated that lung function was reduced from about 400 L/min to about 300 L/min during the work week but fully recovered on the weekends when no exposure occurred. No measurement of vapor concentrations was made, and other workers doing the same job did not have similar complaints. In a survey on routine exposures of English hospital workers, Leinster et al. (1993) collected 77 samples (39 personal and 38 static) from 14 locations in six hospitals. Measured concentrations ranged up to 0.70 ppm for a 15min sample during the cleaning of suction bottles with Cidex (2% glutaraldehyde); more typical values for other operations were 0.04 ppm to 0.22 ppm (Leinster et al., 1993). The typical pattern of exposure was contact for 4 to 5 min every 30 min throughout the shift when endo-

scopes were put into or removed from cleaning units (Leinster et al., 1993). Spontaneous complaints of rhinitis during this survey imply that some persons can experience adverse effects at concentrations below the current occupational exposure standard (Leinster et al., 1993).

Rats exposed 6 h/d, 5 d/w, for 14 w to glutaraldehyde at concentrations of 0.194, 0.049, or 0.021 ppm showed signs of irritation consisting of periocular and perinasal encrustation at 0.194 and 0.049 ppm, but showed no significant hematological, organ-weight, histological, urinary, or gross pathological effects (Ballantyne, 1986). Thus, subchronic exposures at low concentrations ranging from 49 to 194 ppb produce signs of sensory irritation, and exposures at 20 ppb produce transient reduced body-weight gain, indicating mild sensory irritation but not toxicity (Ballantyne, 1986).

No significant increases in the risk of spontaneous abortions and fetal malformations were found in retrospective epidemiological studies of Finnish hospital staff performing sterilization or nurses exposed to glutaraldehyde or formaldehyde (Hemminki et al., 1982, 1985). The same studies found that exposure to ethylene oxide was associated with an increased frequency of spontaneous abortions, and maternal use of cytostatic drugs was associated with fetal malformations.

Studies with rodents also have indicated a low teratogenicity due to glutaraldehyde exposure during pregnancy. Glutaraldehyde given by gavage to pregnant albino mice on d 6-15 of gestation was judged not to be teratogenic at doses up to 100 mg/kg/d, which killed 19 of 35 dams and produced a significant increase in the number of stunted fetuses (Marks et al., 1980).

No rodent studies were found that assessed the effects of inhalation of glutaraldehyde vapors on fetal development, but given the known data on glutaraldehyde's high chemical reactivity, metabolism, and toxicokinetics, it seems unlikely that significant systemic absorption and distribution would occur.

No studies were found that assessed the effects of glutaraldehyde on female reproductive function or fertility. Glutaraldehyde did not reduce the fertility of exposed male mice given a single oral dose of glutaraldehyde at 30 or 60 mg/kg, and there were no significant effects on

embryo-fetal viability in a dominant lethal assay (Tamada et al., 1978).

A Union Carbide Corporation study of rats given glutaraldehyde in drinking water at concentrations of 0, 50, 250, or 1000 ppm for 2 y showed a significantly increased incidence of large-granular-cell leukemia at 50, 250, and 1000 ppm in females only (Behen, 1991). Because this tumor type occurs spontaneously (23% to 24%) in females of the strain of rats used, the results might represent a modulating effect on this spontaneously occurring tumor rather than a direct chemical carcinogenic effect.

Although related aldehydes (formaldehyde, acetaldehyde, and malonaldehyde) have been shown to be carcinogenic in laboratory animals, the National Institute of Occupational Safety and Health has stated that the data are insufficient to allow conclusions about the carcinogenicity of glutaraldehyde (NIOSH, 1991). It is not known if that opinion took into account the results of the 2-y Union Carbide study described in the preceding paragraph.

No reports of interactions or synergistic effects with other chemicals were found.

To set SMACs for glutaraldehyde, acceptable concentrations (ACs) are set for each adverse effect or group of effects for each desired exposure duration, i.e. 1 h, 24 h, 7 d, 30 d, and 180 d. The ACs for the most sensitive adverse effects are set as the SMAC values for those exposure durations. Because of recent data that showed nasal lesions in rodents at very low glutaraldehyde concentrations, the ACs for respiratory tract lesions dominate the resulting SMACs, which are presented in Table 10-3.

Since about 1962, when 2% glutaraldehyde was introduced as a sterilizing solution (Stonehill et al., 1963), until about 1990, when the toxicity of glutaraldehyde was recognized, medical personnel had routinely worked with 2% glutaraldehyde solutions in open trays (Benson, 1984; Corrado et al., 1986; Burge, 1989). In a study by Jachuck et al. (1989), the atmospheric concentrations in the breathing zones of the workers measured 0.12 ppm (1-h sample). Such exposures produce some watering of the eyes, rhinitis, headache, and tightness of the chest. Thus, the 1-h AC for these end points was set equal to the lowest reported occupational exposure concentration that produced irritation (assumed to be for 8 h/d):

1-h AC = 0.12 ppm.

For the 24-h AC, the 0.12-ppm AC was reduced (divided by 3), because the degree of irritation tolerable for 8 h might become intolerable for 24 h. Thus,

24 h AC = 0.12 ppm/3 = 0.04 ppm.

For exposures lasting longer than 24 h, no irritation is acceptable; therefore, the 0.12-ppm lowest-observed-adverse-effect level (LOAEL) must be extrapolated to a NOAEL for irritation. To estimate a NOAEL, the ACs for the end points were set equal to one-tenth of the 0.12-ppm effect concentration. Experience has shown that these effects are threshold effects, rather than cumulative effects, such that below a certain concentration, no effects are seen, independent of the length of exposure.

7-d, 30-d, 180-d ACs = 0.12 ppm/10 = 0.012 ppm.

In a recently published 13-w intermittent (6 h/d, 5 d/w) inhalation study in mice, 0.0625 ppm was a LOAEL for inflammation of the ante-

rior nasal passage from exposure to glutaraldehyde (Kiri, 1992). That exposure corresponds to 390 total hours of exposure or about 16 d of continuous exposure. To calculate a concentration that will protect against respiratory-tract lesions during a 7-d exposure, the 16-d LOAEL is divided by 10 to estimate a NOAEL. This 16-d NOAEL is not increased in extrapolating to an AC for 7 d. No adjustment is made for interspecies differences in susceptibility, because experience with formaldehyde has demonstrated that rodents are no less sensitive (Kerns et al., 1983) than humans and probably are more sensitive than humans to aldehyde-induced nasal lesions:

7-d AC = 0.0625 ppm/10 (LOAEL to NOAEL) = 0.006 ppm.

To calculate a concentration that will protect against respiratory-tract lesions during a 30-d exposure, the 16-d LOAEL is divided by 10 to estimate a NOAEL and multiplied by (16/30) to adjust for the longer exposure time:

30-d AC = 0.0625 ppm/10 (LOAEL to NOAEL) × (16 d/30 d)

= 0.003 ppm.

To calculate a concentration that will protect against respiratory-tract lesions during a 180-d exposure, the 16-d LOAEL is divided by 10 to estimate a NOAEL and multiplied by (16/180) to adjust for the longer exposure time:

180-d AC = 0.0625 ppm/10 (LOAEL to NOAEL) × (16 d/180 d)

= 0.0006 ppm.

Using the 32-ppm 24-h exposure of mice, a 24-h AC for hepatitis can be set by applying factors of 10 for species differences and 10 to estimate a NOAEL from a LOAEL. Thus,

24-h AC = 32 ppm/10 (species)/10 (to NOAEL) = 0.32 ppm.

A 7-d AC can be calculated by dividing the 24-h AC by 7:

7-d AC = 0.32 ppm/7 = 0.05 ppm.

Of the end points induced by exposure to glutaraldehyde, none would be affected by launch, microgravity, or re-entry. Thus, no spaceflight factor was used in calculating any ACs.

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