Glutaraldehyde

in Sheftel, Victor O. Indirect Food Additives and Polymers: Migration and Toxicology

Molecular Formula. C₆H₈O₂
M= 100.13
CAS No 111-30-8
RTECS No MA2450000
Abbreviation. GA.

Synonyms and Trade Names. 1,3-Diformylpropane; Glutaral; Glutaric dialdehyde; Glutarol; 1,5-Pentanedial; 1,5-Pentanedione.

Properties. Oily liquid. Soluble in water and ethanol at all ratios.

Applications. Used as a replacement for formaldehyde in the manufacture of paper and paperboard intended for food packaging; a bactericide.

Acute Toxicity. LD₅₀ of the 50% aquatic GA solution is reported to be 1.3 ml/kg BW in rats, and 1.59 ml/kg BW in rabbits; that of 25% aquatic solution is 1.87 and 8.0 ml/kg, and that of 5.0% aquatic solution is 3.3 and 16 ml/kg BW, respectively. In mice, LD₅₀ is found to be 0.1 g/kg BW.¹

According to Ohno et al., LD₅₀ in the young rats (5 to 6 weeks old) is 283 mg/kg BW; LD₅₀ in the old animals (57 to 60 weeks old) is 141 mg/kg BW.² Signs of intoxication include piloerection, red periocular and perinasal encrustations, sluggish movement, rapid breathing, and diarrhea. At necropsy, no gross pathology changes were noted in survivors; animals that died displayed distention, congestion and hemorrhage of the stomach and small intestine, lesions in the kidneys, liver, and lungs.¹

Short-term Toxicity. Gross pathology examination failed to reveal changes in the visceral organs of rats given 0.5, 2.5, and 5.0% GA in the diet for 3 months. This study affirmed the GRAS status of GA when it is used in the food industry to cross-link edible collagen sausage casings.³

Rats received 0.25% GA in their drinking water for 11 weeks. Animals exhibited no evidence of damage in the NS and CNS. There were no data indicating neurotoxic action of GA.⁴

Immunotoxicity. Contact hypersensitivity has been reported in mice and guinea pigs which resulted from dermal application of 0.3 to 3.3% GA for 5 to 14 days.⁵

Reproductive Toxicity. According to Ballantyne, there were no embryotoxic effects in the offspring of mice treated by gavage with up to 30 mg GA/kg BW on days 7 to 12 of gestation.¹

In the recent Ema et al. studies,⁶ rats were dosed by gastric intubation with 25 to 100 mg/kg BW on days 6 to 15 of pregnancy. The highest dose caused maternal toxicity and decreased fetal weights. Nevertheless, no teratogenicity or postimplantation loss was noted even at the dose of 100 mg/kg BW on days 6 to 15, which induced maternal toxicity.⁷

Mutagenicity. Exhibits mutagenic activity which could be explained as a result of oxidative damage to the DNA; GA is markedly cytotoxic.⁸

In vitro genotoxicity. GA is shown to be negative in E. coli.⁹ NTP results ranged from no activity to weakly positive in Salmonella reversion assay.⁸ However, Muller et al. reported GA to be mutagenic in Salmonella typhimurium strain TA102 assay in three different laboratories. ¹⁰ GA appeared to be a potent mutagen in the mouse lymphoma cell line.¹¹

According to other data, GA did not produce a significant genotoxic effect in Salmonella typhimurium, Chinese hamster ovary cells/HGPRT gene mutation system, the SCE test with Chinese hamster ovary cells, the frequency of unscheduled DNA synthesis in primary rat-hepatocyte cultures.¹²

In vivo cytogenetics. GA is shown to be negative in DLM test (30 to 60 mg/kg BW oral doses).⁹  

Chemobiokinetics. F344 rats and New Zealand rabbits were exposed i/v to 1,5-¹⁴C-GA. GA metabolism occurs through oxidation by rat liver mitochondria, and in the kidney. Excreted predominantly as CO₂. Urinary excretion of radioactivity was found to be in the range of 8.0 to 12% in rats and 15 to 28% in rabbits.¹ 

Regulations.

EU (1990). GA is available in the List of monomers and other starting substances which may continue to be used for the manufacture of plastic materials and articles intended to come into contact with foodstuffs pending a decision on inclusion in Section A (Section B).

U.S. FDA (1998) allowed the use of GA (1) as an antimicrobial agent in pigment and filler slurries used in the manufacture of paper and paperboard at levels not to exceed 300 ppm by weight of the slurry solids; (2) as a component of the uncoated or coated food-contact surface of paper and paperboard intended for use in producing, manufacturing, packaging, processing, preparing, treating, packing, transporting, or holding aqueous and fatty foods in accordance with the conditions prescribed in 21 CFR part 176.170; (3) as a slimicide in the manufacture of paper and paperboard that contact food as prescribed in 21 CFR part 176.300; and (4) in adhesives used as components of articles intended for use in packaging, transporting, or holding food in accordance with the conditions prescribed in 21 CFR part 175.105.

Standards. Russia (1995). MAC and PML: 0.07 mg/l.

1. Ballantyne, B., Review of toxicological studies and human health effects, in Glutaraldehyde, Union Carbide Corp., Danbury, CT, 1986.

2. Ohno, K., Yasuhara, K., Kawasaki, Y., et al., Comparative study of glutaraldehyde acute toxicity in the old and young rats, Abstract, Bull. Natl. Inst. Hyg. Sci., 109, 92, 1991 (in Japanese).

3. Devro, Inc., Glutaraldehyde oral toxicity tests indicate no related lesions, Food Chem. News., 26, 42, 1984.

4. Spencer, P. C., Bischoff M. C., and Schaumburg, H. H., On the specific molecular configuration of neurotoxic aliphatic hexacarbon compounds causing central peripheral distal axonopathy, Toxicol. Appl. Pharmacol., 44, 17, 1978.

5. Stern, M. C., Holsapple, M. P., McClay, J. A., et al., Contact hypersensitivity response to glutaraldehyde in guinea pigs and mice, Toxicol. Ind. Health, 5, 31, 1989.

6. Ema, M., Itami, T., and Kawasaki, H., Teratological assessment of glutaraldehyde in rats by gastric intubation, Toxicol. Lett., 63, 147, 1992.

7. Marks, T. A. et al., Influence of formaldehyde and Sonacide R (potentiated acid glutaraldehyde) on embryo and fetal development of mice, Teratology, 22, 51, 1980.

8. Tamada, M., Sasaki, S., Kadono, Y., et al., Mutagenicity of glutaraldehyde in mice, Bobkin Bobai, 6, 62, 1978.

9. Beauchamp, R. O., St Clair, M. B. G., Fenell, T. R., et al., A critical review of the toxicology of glutaraldehyde, CRC Crit. Rev. Toxicol., 22, 143, 1992.

10. Muller, W., Engelhart, G., Herbold, B., Jackh, R., and Jung, R., Evaluation of mutagenicity testing with Salmonella typhimurium TA 102 in three different laboratories, Environ. Health Perspect., 101 (Suppl. 3), 33, 1993.

11. Hawort, S., Lawlor, T., Mortelmans, K., et al., Salmonella mutagenicity tests results for 250 chemicals, Environ. Mutagen., Suppl. 1, 3, 1983.

12. Slesinski, R. S., Hengler, W. C., Guzzie, P. J., and Wagner, K. J., Mutagenicity evaluation of glutaraldehyde in a battery of in vitro bacterial and mammalian systems, Food Chem. Toxicol., 21, 621, 1983.

source: Sheftel, Victor O. Indirect Food Additives and Polymers: Migration and Toxicology (Boca Raton 2000) p.917