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4. Toxicity, animal data

Inhalation

LC₅₀-values (4 hours exposure) in rats of 0.1, 0.17, 0.29-0.39, 0.8, 0.48 mg/l have been reported (IUCLID 1996).

In male Fischer 344 rats exposed (72 hours) to 10, 20 or 40 mM glutaraldehyde by intra-nasal instillation, no lesions were observed at the lowest concentration. Following instillation of 20 or 40 mM glutaraldehyde, acute inflammatory changes (neutrophilic infiltrates and epithelial erosion) as well as extensive regions of respiratory epithelial hyperplasia and squamous metaplasia were observed; the effects were dose-related. Increased cell proliferation was also observed in these groups. The lesions observed resembled, both in nature and in severity, the changes observed after acute inhalation exposure of rats to carcinogenic concentrations of formaldehyde gas. (St Clair et al. 1990 - quoted from Beije & Lundberg 1997).

In 2-week inhalation studies, groups of 5 F344/N rats and 5 B6C3F1 mice of each sex were exposed to vapours of glutaraldehyde by whole-body inhalation at concentrations of 0, 0.16, 0.5, 1.6, 5, and 16 ppm (0, 0.7, 2.1, 6.7, 21, 67 mg/m³) for 6 hours per day, 5 days per week. (NTP 1993 - quoted from Beije & Lundberg 1997, CIR 1996, and from Ballantyne 1995).

All rats exposed to 5 or 16 ppm died before the end of the study. When exposed to 1.6 ppm, male rats did not gain weight and female rats showed decreased body weight; in the 0.5 and 0.16 ppm groups, body weight gain was normal. In the 1.6 and 5 ppm groups, breathing through the mouth, laboured breathing, ocular and nasal discharge, and rough fur were observed; no clinical signs were observed in rats exposed to 0.5 and 0.16 ppm. At necropsy, gross lesions were observed only in the animals that died or were moribund; these lesions included crusted exudate at the anterior tip of the nares, grey and thickened laryngeal mucous, and exudate or crust on the surface of the tongue. Exposure related histopathological lesions were found in the nasal passages and larynx of the rats exposed to concentrations from 0.5 ppm; the lesions included necrosis and acute (neutrophilic) inflammation of the respiratory and olfactory epithelium and hyperplasia and squamous metaplasia of the respiratory epithelium.

All mice exposed to concentrations from 1.6 ppm died or were moribund before the end of the study. Marked respiratory difficulties, breathing through the mouth, ocular and nasal discharge, and cessation of eating and drinking were observed in these animals. All mice exposed to 0.5 and 0.16 ppm survived the study and body weight gain was comparable to that observed with control mice. No clinical signs of toxicity were observed in these groups. At necropsy, red crust at the anterior nares and grey, thickened laryngeal mucous were observed in the mice of the 16.0 ppm group. Exposure related histopathologic lesions of the nasal passages were observed in mice exposed from 1.6 ppm and included minimal to mild necrosis and acute (neutrophilic) inflammation of the respiratory and olfactory epithelium and squamous metaplasia of the respiratory epithelium. Necrosis of the mucosa and squamous metaplasia of the respiratory epithelium of the larynx were also observed. Lesions of the trachea, consisting of inflammation and necrosis of the respiratory mucosa, were observed only in mice exposed to 16 ppm.

Groups of 10 male and 10 female Fischer 344 rats were exposed to 0, 0.2, 0.63, and 2.1 ppm glutaraldehyde (0, 0.8, 2.6, and 8.8 mg/m³) vapour for 6 hours/day for 9 days over an 11 day period. Sixteen rats exposed to 2.1 ppm and one rat exposed to 0.63 ppm died between days 3 and 9. Excess lacrimation, salivation, and nasal discharge were observed in rats from all treatment groups. Animals exposed to 0.63 and 2.1 ppm also had labored breathing. Loss of initial body weight and decreased feed consumption were observed in the mid- and high-dose groups. Decreased absolute weights for liver, lung, kidney, and testes were seen at 0.63 ppm. (Union Carbide Corporation 1983 - quoted from Ballantyne 1995).

Groups of 12 male and 12 female Fischer 344 rats were exposed to glutaraldehyde concentrations of 0.3, 1.1 and 3.1 ppm (1.3, 4.6, and 13 mg/m³). Over an 11-day period, the rats were exposed for 6 hours a day for 9 days. Mortality occurred in the 3.1 ppm group (13/24 animals). Signs of toxicity (audible breathing, labored breathing, mouth and abdominal breathing), body weight decreases, and food and water consumption decreases, were observed in a concentration-related manner at 1.1 and 3.1 ppm, whereas no effects on these parameters were observed at 0.3 ppm. Haematological and clinical changes as well as changes in organ weights at 1.1 and 3.1 ppm were probably related to body weights and hydration changes. Rhinitis, squamous metaplasia of the olfactory mucosa, and olfactory atrophy were clearly present at 1.1 and 3.1 ppm. At 0.3 ppm only rhinitis (10% of the animals) was seen. Light and electron microscopic examination of sciatic nerves from the 0.3 and 1.1 ppm groups showed no structural abnormalities. (Union Carbide Corporation 1983 - quoted from Ballantyne 1995).

For assessment of nasal toxicity, male Swiss OF1 mice (10 animals per group) were exposed to glutaraldehyde vapour for 6 hours/day, 5 days per week to concentrations of 0.3, 1.0, or 2.6 ppm (1.3, 4.2, 11 mg/m³) for 4, 9 or 14 days. Recovery was studied in 30 mice exposed to 1.0 ppm (4.2 mg/m³) for 14 days; groups of 10 mice were sacrificed 1, 2, or 4 weeks after the end of exposure. (Zissu et al. 1994).

In mice exposed to 1.0 and 2.6 ppm, respiratory difficulty (gasping, lung rales, and mouth breathing) was observed. The 2.6 ppm exposure was interrupted after 5 days because of the death of 4 of the 10 mice. In the 1.0 ppm group, mice showed marked excitation (nervously running around, abdominal swelling, rougher hair and unhealthier looking. In the 0.3 ppm group, no clinical signs of toxicity was observed. Lesions were observed in all exposed mice and affected exclusively the respiratory epithelium of the septum, the naso- and maxilloturbinates and also to a lesser extent the lateral wall, but not the olfactive one. The respiratory epithelium showed areas of deciliation, squamous metaplasia, focal cell damage with exfoliation and necrosis. The severity increased with glutaraldehyde concentration from 0.3 to 1.0 ppm and remained constant from 1.0 to 2.6 ppm, but it did not depend on exposure time. In mice exposed to 1.0 ppm for 14 days and sacrificed after a recovery period, the respiratory epithelium showed the same severe change after rest priods of 1 and 2 weeks, but changes were not so significant after a rest period of 4 weeks. None of the exposed mice showed any lesions in the lungs.

The sensory irritation of glutaraldehyde was determined in male Swiss OF1 mice (6 mice per group) by using the breathing frequency as an indeks. The breathing frequency was monitored before and during a 60-minute exposure period (oronasal exposure) to concentrations of 0.7, 1.3, 1.7, 3.2, 4.3, or 4.5 ppm (2.9, 5.5, 7.1, 13.4, 18, 19 mg/m³). The onset of the maximum response was rapid (within 2 minutes). The effect was steady during the exposure period for the low concentrations (0.7-1.7 ppm) but decreased in the response with time at the higher concentrations (3.2-4.5 ppm). After the exposure, recovery was rapid and concentration-dependent. The RD₅₀ was calculated to 2.6 ppm (11 mg/m³). (Zissu et al. 1994).

In a respiratory irritation study, groups of 4 ND4 Swiss Webster mice were exposed to seven different glutaraldehyde vapour concentrations in the range of 1.6 to 36.7 ppm (6.7-154 mg/m³). Concentration related decreases in the respiratory rate was measured with a maximum at 3 to 20 minutes. The RD₅₀-value was calculated to be 13.9 ppm (58 mg/m³). (Werley et al. 1995 - quoted from Beije & Lundberg 1997, Union Carbide Corporation 1994 - quoted from Ballantyne 1995).

The respiratory sensitising potential of glutaraldehyde vapour was studied in male Dunkin Hartley guinea pigs (8 animals per group) exposed for one hour per day for five consecutive days to an inducing concentration of 13.9 ppm (58 mg/m³). Challenge exposure to 4.4 ppm (18 mg/m³) at 14, 21, and 35 days after the final induction exposure did not produce any evidence of respiratory sensitisation. (Ballantyne 1995, Werley et al. 1995 - quoted from Beije & Lundberg).

Oral administration

LD₅₀-values for glutaraldehyde in rats ranging from 2380 mg/kg for a 25% solution to 252 mg/kg for a 2% alkaline solution have been reported. Using the 2% solution, irritation of the gastro-intestinal tract with haemorrhagic irritation at larger doses was observed at necropsy. Congestion of the lungs and of the abdominal viscera was observed in many animals. (Smyth et al. 1962, Stonehill et al. 1963 - both quoted from CIR 1996).

In IUCLID (1996), LD₅₀-values for rats ranged from 233-733 mg/kg for a 50% solution to 99-123 mg/kg for a 1% solution of glutaraldehyde. No experimental details were provided, so the studies can not be properly evaluated. A possible explanation for the higher toxicity of the less concentrated solutions could be that the more concentrated solutions may produce severe irritation and possibly corrosive effects to the gastrointestinal tract which may compound significantly with any systemic effects in determining acute peroral toxicity.

In mice, LD₅₀-values ranged from 100-352 mg/kg (CIR 1996, IUCLID 1996).

For guinea pigs, an LD₅₀-value of 50 mg/kg has been reported (IUCLID 1996).

Drinking water containing 0, 10, 100, or 1000 ppm glutaraldehyde was given to Fischer 344 rats (10 males and 10 females per group) for 14 days. Decreased feed and water consumption in males and decreased water consumption in the females were observed in the high-dose group. No other clinical signs of toxicity, alterations in serum chemistry and haematology, or effects on organ weights were observed. Histology revealed mild gastric mucosal gland hyperplasia. (Union Carbide Corporation 1985 - quoted from Ballantyne 1995).

Groups of CD-1 mice (10 males and 10 females per group) were given drinking water containing 0, 100, 250, or 1000 ppm glutaraldehyde for 14 days. Decreased water consumption was seen at 1000 ppm (both sexes) and at 250 ppm (males only). Decreased body weight gain occurred with males of the two highest dose groups. No other clinical signs of toxicity, alterations in serum chemistry and haematology, and gross or microscopic pathology were observed. Relative kidney weight was increased for 1000 ppm females. (Union Carbide Corporation 1988 - quoted from Ballantyne 1995).

Dermal contact

The LD₅₀-values for rats and mice are given as >2000 and >4500 mg/kg, respectively. For rabbits, values ranging from 897 to >2825 mg/kg are given. (IUCLID 1996).

In a study to determine the potential for systemic toxicity by short-term repeated skin contact, groups of 5 male C3H/HeJ mice had 10 daily 50 ml applications of 0.05, 0.25, 0.5, 2.5, 5, 25, and 50% solutions of glutaraldehyde in water to the clipped dorsal trunk skin. Doses were applied for 5 consecutive days and, after a 2-day rest period, for a further 5 consecutive days. All mice receiving 25 or 50% solutions died within nine applications; no consistent necropsy findings were observed. Slightly decreased body weights were observed in mice receiving 5% solution. Skin irritation was seen at doses of 5% and higher. (Union Carbide Corporation 1981 - quoted from Ballantyne 1995).

Fisher 344 rats (10 males and 10 females per group) were given 20 epicutaneous applications of aqueous glutaraldehyde solutions over a 26-day period. Dosages used were 2.0 ml of 2.5, 5.0, or 7.5% solutions being equivalent to 50, 100, and 150 mg/kg b.w./day. Five consecutive daily 6-hour occluded applications were made to the clipped dorsal trunk skin each week for the 4-week treatment period. The control group received filtered water at the same dose volume. No signs of systemic toxicity were observed. Local skin irritation was minimal, mainly minor erythema and occasional edema. Pathological findings were limited to the treated areas of skin, and were dose-related. (Union Carbide Corporation 1994 - quoted from Ballantyne 1995).

Skin irritation

The skin irritating properties of glutaraldehyde have been studied in a number of tests with varying concentrations of glutaraldehyde. The best described study is given below.

A 0.5 ml dose of 1, 2, 5, 10, 25, 45, and 50% aqueous glutaraldehyde solutions was applied under an occlusive dressing for 4 hours to the shaven dorsal trunk skin of groups of rabbits (6 animals per group), and the treatment sites were observed for 21 days. A dose-response relationship was observed for severity and duration of inflammatory effects. The 45 and 50% solutions produced moderately severe inflammation, with full-thickness necrosis of the skin. With the 25% solution, moderate inflammation was present, but less marked than with the higher concentrations. Minor to moderate inflammation occurred with solutions of 1-10%. The threshold for skin irritation was around 1%. (Ballantyne 1995).

Eye irritation

An alkaline 2% glutaraldehyde solution (0.1 ml) was instilled into the conjunctival sac of one eye of each of 12 rabbits. The eyes of 3 of the rabbits were rinsed 30 seconds later. Severe corneal opacity and irritation of the iris and conjunctiva were observed in unrinsed eyes during the 7-day observation period. Irritation of the conjunctiva, which was similar in rinsed eyes, also lasted 7 days. However, irritation of the iris and cornea was less in rinsed eyes than in unrinsed eyes, and recovery was partial. The 2% alkaline glutaraldehyde solution was thus a severe eye irritant. (Miner et al. 1977 - quoted from CIR 1996 and from Beije & Lundberg 1997).

Differing volumes, in the range of 0.005 to 0.1 ml of aqueous glutaraldehyde solutions from 0.1 to 45% were instilled into the eyes of rabbits. Eyes were inspected periodically thereafter, up to 3 weeks, for signs of ocular and periocular injury and inflammation. There was a clear dose-response relationship for corneal injury and conjunctivitis. The lowest concentration producing transient minor corneal injury (at 0.1 ml) was 1.0%, and the no-effect concentration was 0.1%. At higher concentrations, corneal injury became more marked and prolonged, being severe at 5% (0.1 ml). The threshold for conjunctival irritation was 0.2%, and the no-effect concentration was 0.1%. (Ballantyne 1995).

Sensitisation

According to IUCLID (1996), various skin sensitisation tests have been carried out. Of these the closed patch test, the skin painting test, the open epicutaneous tests, and the mouse ear swelling test were positive, while the Buehler test was negative. No Guinea Pig Maximisation Test was included. In the two open epicutaneous tests, one in mice and one in guinea pigs, a dose related contact hypersensitivity was observed.

A contact hypersensitivity study has been conducted in female albino Hartley strain guinea pigs and female B6C3F1 mice. Induction concentrations were 0.3, 1.0, and 3.0% glutaraldehyde, and challenge was with 10% glutaraldehyde. Guinea pigs received 100 µl induction doses by direct skin application for 14 consecutive days, and mice received 20 µl epicutaneously for 5 or 14 consecutive days. Rest periods before challenges were 7 or 14 days for guinea pigs, and 4 or 7 days for mice. Measurement of contact hypersensitivity was by both visual evaluation and a radioisotopic assay. Both guinea pigs and mice showed an applied dosage dependent contact hypersensitivity response. A significant response was seen in mice at 0.3% and in both species at 1 and 3%. (Stein 1989 - quoted from Beije & Lundberg and from Ballantyne 1995).

In a subchronic inhalation study, F344/N rats and B6C3F1 mice (10 animals of each sex per group) were exposed to glutaraldehyde by whole-body inhalation at concentrations of 0, 62.5, 125, 250, 500, and 1000 ppb (0, 0.26, 0.53, 1.1, 2.1, 4.2 mg/m³) for 6.5 hours per day, 5 days a week for 13-weeks. In addition to histopathology, evaluations included clinical pathology and assessments of sperm morphology and oestrous cycle length. (NTP 1993 - quoted from Gross et al. 1994, Beije & Lundberg 1997, CIR 1996, and from Ballantyne 1995).

No exposure-related deaths occurred in rats, whereas all mice exposed to 1000 ppb and two females exposed to 500 ppb died before the end of the study. Mean final body weights and body weight gains were significantly lower for rats exposed to 1000 ppb; lower body weight gain was also noted for females exposed to 500 ppb. In mice, mean final body weight was reduced in a concentration-related manner, and was significant in the 250- and 500-ppb groups. There was no clear evidence of systemic toxicity in rats or mice by histopathologic or clinical pathology assessments. Treatment-induced lesions (including epithelial erosions, inflammation, and squamous metaplasia) were confined to the anterior third of the nose and were present in both sexes and species. In rats, lesions were most extensive in rats exposed to 1000 ppb, but were also noted in the 250- and 500-ppb groups, and in one male exposed to 125 ppb. In mice, lesions were most severe in animals in the 1000-ppb group, but were noted at concentrations down to 62.5 ppb. Mice appeared to be more sensitive than rats. The NOAEL was 125 ppb for respiratory lesions in rats. A NOAEL was not reached for mice as effects were noted at the lowest exposure level of 62.5 ppb.

According to Gross et al. (1994), the lesions induced by glutaraldehyde were more anterior in the nose than those produced by formaldehyde, they differed in character, and no evidence of "pre-neoplastic" lesions or karyomegaly, as reported for formaldehyde, was observed with glutaraldehyde.

In another study, Fischer 344 rats (20 males and 20 females per group) were exposed to glutaraldehyde vapour concentrations of 20.8, 49.3, or 194.2 ppb (0.09, 0.2, 0.8 mg/m³) for 6 hours per day, 5 days a week for 14 weeks. Decreased body weight and minor signs of ocular and nasal irritation were observed at 49.3 and 194.2 ppb; at 20.8 ppb there was only minor transient body weight decrease. There were no biochemical or morphological indications of any specific organ toxicity. (Union Carbide Corporation 1982 - quoted from Ballantyne 1995).

Groups of three rats were given drinking water containing 0, 0.05, 0.1, or 0.25% of glutaraldehyde for 11 weeks. All of the animals had a "largely normal" rate of weight gain and appeared normal clinically. The rats were killed at the end of the experiment and nervous system tissue was examined microscopically. No signs of adverse effects were found. (Spencer et al. 1978 - quoted from CIR 1996 and from Beije & Lundberg 1997).

Fischer 344 rats (numbers per group not stated) were given 0, 50, 250, or 1000 ppm glutaraldehyde in the drinking water for 13 weeks. An additional 10 animals of each sex were added to the control and high concentration groups as recovery animals and sacrificed 4 weeks after the 13-week dosing period. The daily intakes were given as 5, 25, and 100 mg/kg b.w. per day for males and 7, 35, and 120 mg/kg b.w. per day for females. A dosage-related decreased food and water consumption was observed at 250 and 1000 ppm. Body weights and body weight gains were reduced in high-dose males during the treatment period, with partial recovery in the 4-week postdosing period. A dose-related increase in absolute and relative kidney weights in females, and relative kidney weights in males was present at 13 weeks in the 250 and 1000 ppm groups; values were similar to those of the controls at the end of the recovery period. There was no evidence, morphological or biochemical, for systemic tissue or organ toxicity. The dose of 50 ppm was a no-effect level in this study. (Union Carbide Corporation 1985 - quoted from Ballantyne 1995).

In a 2-year carcinogenicity study, Fischer 344 rats (100 males and 100 females per group) received 0, 50, 250 or 1000 ppm glutaraldehyde in the drinking water. Interim sacrifices (10 males and 10 females of each group) were performed at 52 and 78 weeks after the start of dosing. Based on the water consumption values, the daily intake of glutaraldehyde was calculated to 3.6, 17.1, and 63.9 mg/kg b.w. per day for males and 5.5, 25.1, and 85.9 mg/kg b.w. per day for females of the 50, 250, and 1000 ppm groups, respectively. (Union Carbide Corporation 1994 - quoted from Ballantyne 1995).

None of the dosages had any effect on mortality or survival. There were dose-related decreases in drinking water consumption for mid- and high-dose males and females. A reduced food consumption was observed at 1000 ppm and a trend to reduced food consumption at 250 ppm. Dose-related decreases in absolute body weight and body weight gain were seen in males (250 and 1000 ppm) and in females (1000 ppm). Absolute and relative kidney weights were increased in all males and in mid- and high-dose females. Gastric irritation was significantly greater in high-dose animals compared with the controls. Tubular pigmentation and basophilia were seen in the kidneys of males (1000 ppm) and females (250 and 1000 ppm); according to the author, these lesions were probably related to hemolytic changes associated with large granular lymphocytic leukaemia (LLGL), see 4.5.

CD-1 mice (numbers per group not stated) were given 0, 100, 250, or 1000 ppm glutaraldehyde in the drinking water for 13 weeks. An additional 10 animals of each sex were added to the control and high concentration groups as recovery animals and sacrificed 6 weeks after the 13-week dosing period. The daily intake was given as 25, 61 and 200 mg/kg b.w. per day for males, and 31, 74, and 238 mg/kg b.w. per day for females. Water consumption was reduced in the high-dose group, but returned to control values over the recovery period. Relative kidney weight was increased in high-dose females at the end of the dosing period but not at the end of the recovery period. There was no evidence for any target organ or tissue systemic toxicity. (Union Carbide Corporation 1985 - quoted from Ballantyne 1995).

Beagle dogs (2 males and 2 females per group) were given glutaraldehyde in the drinking water at concentrations of 0, 50, 150, or 250 ppm for 13 weeks. The daily intake was given as 3.3, 9.6, and 14.1 mg/kg b.w. per day for males, and 3.2, 9.9, and 15.1 mg/kg b.w. per day for females. Vomiting was seen in the 150 and 250 ppm groups. A trend for reduced water consumption were seen in males (150 and 250 ppm) and in females (250 ppm) for the first 6 weeks of dosing. There was no evidence for any target organ or tissue systemic toxicity. (Union Carbide Corporation 1990 - quoted from Ballantyne 1995).

A 0.5 ml dose of a 2% alkaline glutaraldehyde solution was applied daily for 6 weeks to the closely clipped skin of albino rabbits. The solution was spread with a brush and allowed to dry. No evidence of systemic toxicity was observed. (Stonehill et al. 1963 - quoted from CIR 1996).

In the 13-week study of NTP (reported in section 4.2), no adverse effects were observed on sperm morphology and vaginal cytology in F344/N rats exposed to up to 1000 ppb (4.2 mg/m³) glutaraldehyde vapour. In B6C3F1 female mice, the 250 and 500 ppb groups (1.1 and 2.1 mg/m³) spent more time in oestrus and dioestrus and less time in metoestrus and prooestrus (500 ppb only) than the control animals. There were no effects in any of the reproductive parameters studied in male mice. (NTP 1993 - quoted from CIR 1996).

In a two-generation study, CD rats (28 males and 28 females per group) were given 0, 50, 250, or 1000 ppm glutaraldehyde in the drinking water for 10 weeks prior to mating and throughout mating, gestation, and lactation. After weaning, the F₁ generation was founded using 28 males and 28 females. These animals were given the same concentration of glutaraldehyde as their parents for 10 weeks prior to mating and throughout mating, gestation, and lactation. Parental animals and ten weanlings of each sex and dose group were necropsied. (Bushy Run Research Center 1994 - quoted from CIR 1996, Union Carbide Corporation 1994 - quoted from Ballantyne 1995).

In the 250 and 1000 ppm groups, there was a consistent reduction in water consumption. During gestation and lactation, water consumption remained reduced in the dams of the 250 and 1000 ppm dose groups. Reduced food consumption was observed in the high-dose females near the end of gestation. No effects on mating, fertility, gestational factors, litter size and sex ratio were observed. In the 1000 ppm F₁ and F₂ pups, body weights and body weight gains were reduced.

Pregnant Wistar rats (25 animals per group) received 0, 50, 250, or 750 ppm glutaraldehyde in the drinking water from day 6 to 16 of gestation in a study carried out according to OECD guideline 414 and GLP. The daily intake of glutaraldehyde was estimated to 5, 26, and 68 mg/kg b.w. per day for the 50, 250, and 750 ppm dose groups, respectively. In the 750 ppm group, intake of drinking water was clearly reduced from day 6 to 16 and in the 250 ppm group, the drinking water intake was slightly reduced from day 10 to 15. No embryo- or foetotoxic and no teratogenic effects were seen at any doses. (IUCLID 1996, Union Carbide Corporation 1990 - quoted from Ballantyne 1995).

Pregnant Himalayan rabbits (15 animals per group) received glutaraldehyde once daily by gavage (in water) from day 7 to 19 of gestation at dosages of 5, 15, and 45 mg/kg b.w. per day in an OECD guideline 414 and GLP study. The control group was given distilled water. (IUCLID 1996, Union Carbide Corporation 1990 - quoted from Ballantyne 1995).

In the high dose group, 5 out of 15 animals died. The food intake was clearly reduced during the dosing period and the day after. Maternal body weight was clearly reduced from day 11 to 29. Diarrhoea and/or congestion was observed. At necropsy, irritation of the gastrointestinal tract, reduced uterus weight, and increased number of postimplantation losses were observed. Nine out of ten surviving does had no live foetuses. Trend for reduced placental weights and reduced foetal body weight were observed. In the the lower dose groups, no signs of maternal or developmental toxicity were observed.

Glutaraldehyde was mutagenic in Salmonella typhimurium strains TA100, TA102, and TA104 with and without S9 metabolic activation as well as in mouse L5178Y lymphoma cells in the absence of S9. It induced sister chromatid exchanges in Chinese hamster ovary cells with and without S9. In one laboratory, chromosomal aberrations were induced in Chinese hamster ovary cells in the absence of S9 only; no increase in chromosomal aberrations was observed with or without S9 in a second laboratory. Glutaraldehyde did not induce sexlinked recessive lethal mutations in germ cells of male Drosophila melanogaster treated as adults by feeding or injection or treated as larvae by feeding. (NTP 1993 quoted from IUCLID 1996).

In CIR (1996), review results of more than 30 in vitro genotoxicity tests using glutaraldehyde are given. Most of these tests are from the early 1980ties. In all, 12 of these tests were reported as positive.

In view of the fact that most of the in vitro tests carried out by NTP were positive, glutaraldehyde should be considered a positive genotoxicant in vitro.

Only two reports on the in vivo genotoxicity of glutaraldehyde are given in the CIR (1996) review. These were negative (unscheduled DNA synthesis (UDS) in male rat hepatocytes isolated following oral administration). (Mirsalis et al. 1989, 1985 - quoted from CIR 1996).

In IUCLID (1996), a mouse dominant lethal assay (using doses of 0, 30, or 60 mg/kg b.w.), a micronucleus test in mice (using gavage dosing of 80, 160, or 250 mg/kg b.w. and exposure for 24, 48, or 72 hours), a rat UDS test (using gavage dosing of 30, 150, or 600 mg/kg b.w. and exposure for 2 or 12 hours), and a rat bone marrow chromosome aberration test (using gavage dosing of 25, 60, or 120 mg/kg b.w. to males and 15, 40, or 80 mg/kg b.w. to females and exposure periods of 12, 24, and 48 hours) are reported as negative in vivo genotoxicity tests.

4.5 Carcinogenic effects

In a 2-year carcinogenicity study, Fischer 344 rats (100 males and 100 females per group) received 0, 50, 250 or 1000 ppm glutaraldehyde in the drinking water. Based on the water consumption values, the daily intake of glutaraldehyde was calculated to 3.6, 17.1, and 63.9 mg/kg b.w. per day for males and 5.5, 25.1, and 85.9 mg/kg b.w. per day for females of the 50, 250, and 1000 ppm groups, respectively. (Union Carbide Corporation 1994 - quoted from Ballantyne 1995).

For general toxicity, see 4.2. The major finding was an increase in large granular lymphocytic leukaemia (LGLL) in all female dose groups. The incidence of LGLL in spleen and liver is given below:

* statistically significant.

The increase in LGLL was statistically significant for the females of all dosed groups, but not for the males. LGLL is a commonly occurring spontaneous neoplasm in Fischer 344 rats. According to the author "the incidence of LGLL in control Fischer 344 rats varies between different laboratories, and within the same laboratory. Thus, whilst the average incidence of LGLL in female Fischer 344 rats is usually cited as 24-27%, the individual incidence in some conducted studies has been reported up to 52% in control female groups. In a previous study from the same laboratory, the incidence of LGLL in control groups of male and female Fischer 344 rats were, respectively, 66 and 44%." With respect to the interpretation of the increased incidence of LGLL in females, the author stated "that it appears unlikely that the increase in LGLL in female rats is due to a direct chemical carcinogenic effect, but was a result of the chronic administration of glutaraldehyde in drinking water having a modifying influence on one or more of the factors influencing the expression of this spontaneously occurring neoplasm in the female Fischer 344 rats".

A carcinogenicity study (inhalation) on rats and mice performed by the NTP has not yet been finalised (Beije & Lundberg 1997).

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