Toxicological evaluation and limit values for Methyl-tertiary-butyl ether (MTBE), Formaldehyde, Glutaraldehyde, Furfural

2. Toxicokinetics

Inhalation
No information has been found.

Oral intake
No information has been found.

Dermal contact

A flow-through skin penetration chamber has been used to determine the in vitro skin penetration of glutaraldehyde over a 6 hours period of 0.75 and 7.5% [1,5-¹⁴C]-glutaraldehyde on excised skin from Fischer 344 rats, CD-1 mice, Hartley guinea pigs, New Zealand white rabbits, and human beings. Total recovery from all species ranged from 75-92% for both concentrations. Overall, <0.5% of the 0.75% and <0.7% of the 7.5% glutaraldehyde solution was absorbed through the skin of animals. For human breast skin in vitro, approximately 0.2% of the applied radioactivity penetrated the skin for both doses tested, and around 5% of the radioactivity was bound to the skin. About 70% of the dose was unabsorbed and total recovery was 75 and 76% for the two doses, respectively. (Frantz et al. 1993).

The metabolism of glutaraldehyde has not been studied in detail. It has been suggested that glutaraldehyde is oxidised to mono- or dicarboxylic acids by aldehyde dehydrogenase and then further oxidised through acidic intermediates to carbondioxide, which is expired. (McKelvey et al. 1992).

After an intravenous dose of a 0.075 or a 0.75% ¹⁴C-glutaraldehyde solution to rats (0.2 ml) and rabbits (2.5 ml), the excretion of radioactivity was followed. With the 0.075% solution, 75-80% of the dose in the rat and 66-71% in the rabbit was recovered as ¹⁴ C-carbon dioxide during the first 24 hours following administration; 80% of this carbon dioxide was recovered during the first 4 hours. With the 0.75% solution, the proportion of ¹⁴carbon dioxide decreased and the amount of radioactivity recovered in the urine, tissues and carcass increased. The average plasma concentration increased ten fold with a ten fold increase in concentration but the tissue concentration increased by a greater factor. Analyses of individual organs for radioactivity 24 hours after dosing revealed the highest amount of radioactivity in the lungs followed by blood cells, spleen, kidney, adrenal, thyroid, and lung. (McKelvey et al. 1992).

Groups of four male and four female Fischer 344 rats received a dermal dose of 0.2 ml 0.075%, 0.75% or 7.5% ¹⁴C-glutaraldehyde solution on an area of 7x7 cm² of the clipped dorsal skin. The treated area was covered by an occlusive bandage for 24 hours. Urine, faeces, and carbon dioxide was collected during the dosing period. After the dosing period, a material balance was set up based on the parameters given above and other relevant items, where radioactivity could be found, e.g. cage wash and application rod. Total recovery of radioactivity ranged from 75 to 61%, with the majority of the radioactivity being found at the application site (60-45%). Urinary excretion amounted to 1.71 to 0.54% of the dose, with the lower values being found at the 7.5% dose. Faecal excretion amounted to 0.59 to 1.05% of the dose without any dose relationship but females tended to excrete more radioactivity via faeces. Expired carbon dioxide contained 0.57-3.2% of the dose, with the higher values being found in females and in both sexes dose-dependently increasing in the 7.5% dose group. Tissues and carcass contained 0.20-1.02%, and 0.97-3.08% of the radioactivity, respectively. (McKelvey et al. 1992).

Groups of two male and two female rabbits received a dermal dose of 2.5 ml 0.75% or 7.5% ¹⁴C-glutaraldehyde solution on an area of 12x12 cm² of the clipped dorsal skin. The clipped area was covered by an occlusive bandage for 24 hours. Urine, faeces, and carbon dioxide was collected during the dosing period. After the dosing period, a material balance was set up based on the parameters given above and other relevant items where radioactivity could be found, e.g. cage wash and application rod. Total recovery ranged from 71 to 100% with 45 to 31% of the radioactivity being found at the application site. Urinary excretion amounted to 2.1-12.4% of the dose without any dose relationship. Faecal excretion amounted to 0.45 to 1.1% of the dose. Expired CO₂ contained 2.4 to 17.3% of the dose with the higher values being found in the 7.5% dose group. Carcass contained appreciable amounts of radioactivity with 4.7 to 36.2% of the radioactivity being found, apparently higher amounts were found at the low dose, but great variability existed between the individuals. In tissues 0.9 to 1.9% of the radioactivity was found with higher values in the high dose group. (McKelvey et al. 1992).

2.3 Toxicological mechanisms

Many of the uses of glutaraldehyde are related to its ability to react with and cross-link proteins. It can react with the a -amino groups of amino acids, the N-terminal amino groups of peptides and the sulfhydryl group of cysteine. The predominant site of reaction in proteins is the e -amino group of lysine. (Beauchamp et al. 1992).

Little information is available on the reaction of glutaraldehyde with DNA or the components of DNA. Products were formed on reaction of glutaraldehyde with deoxyadenosine, deoxyguanosine and deoxycytidine, but not with deoxythymidine. The adducts formed with deoxyadenosine were unstable but those formed on reaction with deoxyguanosine were relatively stable. (Beauchamp et al. 1992).