Glutaral

Endpoint summary

Description of key information

Regarding absorption it can be concluded that via the oral route significant absorption occurs, while absorption via dermal exposure is limited. Following absorption, glutaraldehyde is rapidly and extensively metabolized to CO2, the metabolic pathway of glutaraldehyde (GA) probably consisting of a series of oxidation, decarboxylation and hydrolysis steps.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Oral

Following single oral administration of [2,4-14C]-glutaraldehyde (radioactive purity 98.1%) in rats, the radioactivity was rapidly absorbed from the gastro-intestinal tract (BASF, 2004). However, absorption was incomplete at both tested dose levels (5 and 75 mg/kg bw). The bioavailable part of the radioactive dose, which corresponded to the part excreted via urine, bile and expired air (14CO2), was about 33% of the total amount at a test dose of 75 mg/kg bw, and about 44% of the total amount at 5 mg/kg bw. This indicates that the gastro-intestinal absorption decreased with increasing test dose. Following absorption, the radioactivity was distributed in all organs/tissues. The excretion was very rapid and mainly occurred via the faeces and the expired air (14CO2). These findings were confirmed by the plasma kinetic data (BASF, 2004).

In a further rat study, following oral administration, glutaraldehyde was found to be systemically available in the blood, but also was rapidly removed from there, either by macromolecular binding or by metabolism (Dow, 2004).

In a recent study (Dow, 2007), 2 groups of 12 female rats received either 50 or 1000 ppm 14C-glutaraldehyde-fortified drinking water for up to 24 hours. After 24 hours, or if the allotment of drinking water was consumed first, the drinking water was changed to municipal water until sacrifice at 48 hours after the start of the study. Glutaraldehyde was rapidly absorbed and eliminated following drinking water administration, attaining measurable levels of radioactivity in blood one hour after the fortified water was presented. Parent glutaraldehyde, was present in blood at all time-points in the 1000 ppm dose group, but at concentrations 15- to 250-fold below 14C-levels; in contrast no circulating glutaraldehyde was found in the blood of the 50 ppm dose group. Parent glutaraldehyde was rapidly eliminated from the blood. Radioactivity was distributed in the tissues and total radioactivity recoveries were 63 and 72% of administered dose for the 50 and 1000 ppm dose groups.groups. These low recoveries are consistent with glutaraldehyde volatilized from drinking- water sippertubes drips, attributed to but not consumed by the rats, and/or not recovered by the system. The main amounts of radioactivity recovered in tissues were found, independently from the gastro intestinal tract, in liver and kidney and to a lesser extent in bone marrow and spleen. Glutaraldehyde-derived radioactivity was quickly eliminated in the feces, urine, and CO2, and feces, urine, and CO2 elimination accounted for 23, 13, and 14, and 40, 11, and 8% of the administered dose, for the 50 and 1000 ppm groups, respectively.The radioactivity recovered in the urine was consistent with the oral gavage study reported above, while the feces and CO2 accounted for ca. 64 and 50% of the respective amounts seen previously. Drinking water-derived radioactivity was distributed in the tissues in a fashion similar to that seen following a single dose oral gavage.

In a follow up study (Dow, 2007), the attempt was made to determine the metabolism profile of GA and the identify possible metabolites. For these purpose, rats of both sexes were administered a single oral dose of either 5 or 75 mg 14C-glutaraldehyde; the doses were selected on the basis of the previous oral study (BASF, 2004). Excreta were collected and analyzed via HPLC. Attempts were made to identify metabolites present greater than 5% of the administered dose. In addition, excreta from the female rats presented with either 50 or 1000 ppm of 14C-glutaraldehyde fortified drinking water in the Dow study were also analyzed for metabolite profile. There were a total of six and two peaks in the urine of the oral gavage and fortified drinking water rats, respectively. There were a total of four and three peaks in the feces of the oral gavage and fortified drinking water rats, respectively, in addition to two broad bands of radioactivity from each route of administration. Peak A was the only peak detected in all urine/fecal samples in both sexes, dose levels, and route of administration and ranged from 5-8 and 1 to 3% of the administered dose in the urine and feces, respectively. Attempts to identify Peak A were unsuccessful. Band 1 and band 2 were detected in the feces for all doses, sexes, and routes of administration and accounted for 8-16 and 8- 30% of the administered dose, respectively. Bands 1 and 2 were shown to be <2.5 kDa in size and are probably made up of many peaks that are glutaraldehyde or glutaraldehyde derived metabolites cross linked with extraneous or endogenous proteins, peptides or amino acids and none greater than 5% of the administered dose. Peak E ranged from 1-3 and 3% of the administered dose in the oral gavage urines from both dose levels and sexes and in the urine of the 1000 ppm fortified drinking water study. Peak E was only seen in the feces of the 5 mg/kg orally administered female, and the 50 and 1000 ppm fortified drinking water study (1-3% of the administered dose). Peak E was identified as glutaric acid.

In a study by the Bushy Run Research Center, four male Fischer 344 rats were exposed to radio-labeled glutaraldehyde via oral gavage. The 14C-labelled test substance was mixed with a defined amount of non-labelled test substance and physiological saline. The mean dose level was 68.5 mg/kg bw. Exhaled CO2, urine, feces, cages, blood, selected tissues, and carcassess were subjected to radioactivity measurements. The highest concentration of radioactivity was found in stomach and kidney. Increased radioactivity levels also were found in the esophagus and the trachea. The major radioactivity excretion route for all animals was via the feces whereas only little radioactivity was excreted via CO2 and urine.

Intravenous

McKelvey JA and coworkers (1992) published the results of a series of studies on absorption, distribution, excretion and pharmacokinetics of [1,5-14C]-labelled glutaraldehyde in adult Fischer 344 rats and New Zealand White rabbits of both sexes having been treated either by intravenous injection (i.v.) or dermal application of the test material. For i.v.-treatment, rats and rabbits were dosed with 0.075 and 0.75% test solution; for rats, the application volume of 0.2 ml; thus, test material dosage for males was 0.58 and 6.5 mg/ kg bw, and for females it was 0.85 and 8.7 mg/kg bw. For rabbits, the application volume was 2.5 ml, resulting in a dosage of 0.62 and 6.3 mg/kg bw for both males and females.

For both species, following i.v application, total recovery of radioactivity ranged between 86 and 101%; expiration was identified as the major route of elimination. Up to 80% and 71% of radioactivity was recovered as 14CO2 within 24 hours in rat and rabbit, respectively. In each case, 80% of the recovered 14CO2 as expired within the first 4 hours following treatment. In both species however, an increase in applied test concentration (i.e. from 0.075% glutaraldehyde to 0.75% glutaraldehyde) resulted in a decrease in the elimination of the radioactivity by 14CO2 expiration whereas radioactivity recovery in urine, carcass and tissues was increased. In fact, in rat recovered 14CO2 was 75-80% at a test concentration of 0.075%glutaraldehyde, and decreased to 65% at 0.75% glutaraldehyde. In contrast, urinary excretion amounted for 8% at the low concentration and 11% at the higher concentration, and recovery in carcass and tissues was approx. 9% and 15% for the low and high concentration, respectively. In rabbits, recovered 14CO2 was 66-71% at the low test concentration of 0.075% and decreased to 22-47% at the higher concentration of 0.75%; in contrast, urinary excretion amounted for 16% at the low concentration and up to 28% at the high concentration whereas recovery in carcass and tissues was approx. 13% and up to 41% for the low and the high concentration, respectively. According to the authors, the findings are indicative of a saturation process affecting the mechanisms involved in the disposition of the test substance, which again results in a shifting in the elimination pathway. Considering the distribution of glutaraldehyde and/or its metabolites after i.v application, the highest concentrations of radioactivity were found in blood cells and in spleen, lung and kidneys (i.e. in well-perfused organs); no organ/tissue showed conspicuously increased concentration of radioactivity when compared to others. According to the pharmacokinetic data reported by the authors, the terminal half-life values obtained for the i.v-treated rats and rabbits indicated an increased efficiency in elimination of glutaraldehyde and/or its metabolites for the rat when compared to the rabbit. The area under the curve values (AUC) indicated a lower bioavailability of the test material in the rat when compared to the rabbit. Considering the route of exposure, the terminal half-life values were lower for i.v injection than for dermal application. Analysis of time dependence of plasma concentration revealed abimodal exponential behaviour suggesting a two-compartment model.

Rats were treated with 14C-labelled glutaraldehyde by infusion into the jugular vein; the liver and the kidneys were examined and the clearance from serum, muscle, kidney and liver was determined for different time points ranging from 5 minutes to 7 days; expired gases and urine also were collected and analysed (Ranly DM and Horn D, 1990; Ranly DM et al., 1989). The findings of the present study were in accordance with the data reported above as a rapid metabolization and excretion of radiochemical via expired 14CO2 or urine was shown; clearance determination over 7 days showed that only a small portion of radioactivity remained in the major organs, liver (8%) and kidneys (7%). The treatment of the rats with glutaraldehyde affected neither the serum nor the urinary clinical parameters. Radiolabeled glutaraldehyde also was infused into rats in order to determine the distribution of glutaraldehyde between cellular and humoral fractions of the blood, the potential metabolism by red blood cells , the rate of excretion, and the nature of the urinary products (Ranly DM and Horn D, 1990). This study demonstrated that 14C-labelled glutaraldehyde was distributed between blood cells and plasma at a ratio greater than 1. Although the absolute radioactivity of both fractions dropped by 80% over 3 days, the percentage bound or incorporated increased over time.

Considering the identity of glutaraldehyde metabolites, radiochromatography revealed two major and one minor fraction (defined as A, B and C) in the urine of i.v.- treated rats (McKelvey, 1992); in rabbits, an additional fraction (B-1, acidic metabolite) was found (major fractions: A, B-1, minor fractions: B, C). Ranly DM and Horn D (1990) reported that despite of the extensive uptake by blood cells, these cells were unable to metabolize glutaraldehyde to CO2. In contrast, liver was shown to convert glutaraldehyde into CO2. Urinary excretion of the radiolabel was rapid, the predominant form in the urine being less than 1 kDa in size. All evidence suggested that it was not unchanged glutaraldehyde. The authors concluded that the blood cells can incorporate glutaraldehyde, but cannot metabolize it completely to CO2. Nevertheless, much of the infused glutaraldehyde was rapidly converted to non-reactive metabolites and eliminated by the kidneys.

Dermal

Glutaraldehyde was also investigated for its systemic bioavailability following percutaneous absorption (Dow, 2004). Glutaraldehyde was systemically available in the blood of the treated rats, but also was rapidly removed from there, either by macromolecular binding or by metabolism. The results of an in vitro approach suggested that most of the glutaraldehyde in blood is bound to blood proteins, with only small amounts of free glutaraldehyde remaining in the protein-free fraction.

As already mentioned, McKelvey JA and coworkers (1992) reported a series of studies on absorption, distribution, excretion and pharmacokinetics of [1,5-14C]-labelled glutaraldehyde in rat and rabbit having been treated either by intravenous injection (i.v.) or dermal application of the test material. For dermal treatment, rats were treated with 0.075,0.75 and 7.5% test solution with an application volume of 0.2 ml. Thus, dosage was 0.58, 6.5 and 63 mg/kg bw, and 0.85, 8.7 and 102 mg/kg bw, for males and females, respectively.The rabbits were treated with 0.75 and 7.5% test solution with an application volume of 2.5 ml, thus dosage was 6.3 and 60 mg/kg bw for both sexes. The authors reported that following dermal application to rat and rabbit, total recovery of radioactivity was about 61 to 75% for the rat and 72 to 100% for the rabbit, and was therefore reduced compared to the recoveries obtained from the i.v. application experiments; according to the author, this might have been due to evaporative losses during treatment. The major amount of the dermally administered dose was recovered associated with the skin of treated animals (rat: 45-61%; rabbit: 31- 45%). In rat, recovery in the urine was found to be the main route of excretion for the low and mid applied doses, reaching 1 to 2%. At the highest applied dose, excretion mainly occurred via CO2 expiration (2 to 3%). In rabbits, the excreted amounts of radioactivity via urine and 14CO2 were increased compared to the values obtained for rats (recovery in urine: 2 to 12%; 14CO2 recovery: 2 to 17%). Recovery in the carcass of rabbits also was increased compared to rat (5 to 36% versus 5 to 8%). By summing up recoveries for both species, it appeared that the dermal absorption of the radiochemical applied to the skin was higher for the rabbit than for the rat (50% versus 7 to 9% of the applied dose). In fact, if retention in skin was not taken into account, the interspecies differences in dermal absorption between rabbit and rat appeared to be due to a 5 times higher skin permeability of the rabbit. Similar to human skin, the rat skin is known to possess a barrier function, and moreover, the rat skin is grossly 2 to 10 times more permeable than human skin. Therefore and according to Ross JH et al. (Review, 2000), the skin absorption data obtained from rabbit and rat can be considered as an overestimation of expected human dermal absorption. The in vitro penetration of glutaraldehyde (10% aqueous solution) through isolated human thin stratum corneum (chest and abdomen), isolated human epidermis (abdominal), and human thick stratum corneum (blister tops from the sole of the foot) was investigated by Reifenrath WG et al. (1985); glutaraldehyde did not penetrate thick stratum corneum, while 2.8% to 4.4% of the applied dose penetrated the isolated epidermis, and 3.3% to 3.8% of the applied dose penetrated thin stratum corneum. Histologically, autoradiography revealed that in skin, localisation of the radioactivity was similar for all doses and concerned the stratum corneum, the outermost parts of the hair shafts and follicles and at the foci of dermal necrosis (Ballantyne B, 1986). Considering the distribution of glutaraldehyde and/or its metabolites in tissues following dermal absorption, the highest amounts of radioactivity were found in blood cells and in spleen, lung and the kidneys (i.e. in well-perfused organs); they were however below those resulting from i.v application. No organ/tissue showed conspicuously increased amounts of radioactivity.

Following dermal application of glutaraldehyde, a low absorption rate for the radioactive parent compound and/or its metabolites via the skin into the blood circulation was reported for the rat (McKelvey, 1992). The terminal half-life values obtained for this species indicated an increased efficiency in elimination of the radioactive parent compound and/or its metabolites when compared to the rabbit. The AUC values indicated a lower bioavailability of the test material in the rat when compared to the rabbit. Analysis of time dependence of plasma concentration revealed a bimodal exponential behaviour suggesting a two-compartment model.

As the data of the in vivo pharmacokinetic studies conducted by McKelvey (1992) showed that the major portion of dermally applied glutaraldehyde was recovered from skin at the application site. A study by Frantz et al. (1993) was performed to investigate further the finding reported above and to compare the subcutaneous absorption of glutaraldehyde for animal and human skin. The authors exposed in vitro, rat, mice, guinea pig, rabbit and human skin to 0.75 and 7.5% glutaraldehyde. An average of 0.5% of applied radioactivity for the lowest test dose (0.75%) and 0.7% for the highest test dose (7.5%) were recovered in the effluents of animal species. For human skin, the effluent recovery of applied dose of radioactivity for both test concentrations was 0.2%. The findings showed that glutaraldehyde did not penetrate any of the skin specimens to a significant degree, leading to the suggestion that only minimal amounts of glutaraldehyde may be available for systemic uptake and distribution after skin exposure.

In another in vito skin penetration test (Reifenrath 1985), glutaraldehyde was applied to human skin. Skin with either thick (blister tops from the sole) or thin stratum corneum (chest and abdomen) was tested. In addition, epidermis was tested after obtaining it by exposing the whole skin samples (abdomen) to ammonia vapour. The results of the experiment showed that glutaraldehyde did not penetrate thick stratum corneum, while 2.8%-4.4% of the applied dose penetrated the isolated epidermis, and 3.3%-13.8% of the applied dose penetrated thin stratum corneum.

Conclusion

Regarding absorption it can be concluded that via the oral route significant absorption occurs, while on the other hand, absorption via dermal exposure is limited. Up to now, no explicit chemical identification of glutaraldehyde metabolites was done. However and summing up, it could be shown that following absorption, glutaraldehyde is rapidly and extensively metabolized to CO2, the metabolic pathway of glutaraldehyde (GA) probably consisting of a series of oxidation, decarboxylation and hydrolysis steps. In their publication, Ballantyne B and Jordan SL (2001) proposed following metabolic pathway for glutaraldehyde:

Glutaraldehyde→oxidation→ Glutaric semialdehyde →oxidation→ Glutaric acid →metabolisation→ Glutaryl CoA →oxidation by Glutaryl CoA dehydrogenase→ Glutaconyl CoA →decarboxylation→ Crotonyl CoA →conversion by Enoyl CoA→ ß-hydroxybutyryl CoA →(1) synthesis of acetoacetate or (2) degradation to acetate and CO₂