The issue of formaldehyde release, as it pertains to toxicity and safety matters requires particular discussion. There is a significant discrepancy between the toxicity/mutagenicity of formaldehyde, per se, and formaldehyde donating compounds, such as the nitroalcohol class of compounds. Formaldehyde is a well-known compound that has widespread applications. As such, the potential for toxicity and carcinogenicity to humans through various exposure routes has been of significant interest to governmental regulatory agencies.
13 Formaldehyde is mutagenic to mammalian and bacterial cells and is carcinogenic in animal models. Although there is longstanding controversy regarding the carcinogenic potential in humans, the International Agency for Research on Cancer has recently changed its designation of formaldehyde from a class 2A (probably carcinogenic to humans) to class 1 (carcinogenic to humans).
14 In stark contrast to formaldehyde, mono-nitroalcohols have a favorable safety profile, making them particularly attractive for in vivo use. The oral LD
50 of 2nprop to chicks was reported to be >1300 mg/kg body weight
15 and has been fed to cattle without any apparent adverse effects.
16 When studied using the Ames mutagenicity assay,
17 neither 2nprop nor 3n2pent showed mutagenicity in three strains of
Salmonella. The nitro-triol HNPD has been studied extensively due to its widespread industrial usage. It has been placed in toxicity category III for acute oral, dermal, and inhalation effects (category I is highest and category IV is the lowest) and is not mutagenic under a battery of tests.
4,18 Table 2 is included to provide a general appreciation of the differences in in vivo toxicity between BNAs and formaldehyde. Unfortunately, most formaldehyde toxicity data are related to inhalational exposure, for which no BNA data are available. However, oral and intraperitoneal toxicity data are available for both formaldehyde and BNAs in mice and underscore the dramatic differences that exist between BNAs and formaldehyde regarding toxicity. As shown in
Table 2, the difference in LD
50 between formaldehyde and several BNAs for mice by either intraperitoneal injection or oral exposure is approximately 100×. That being said, although BNAs are clearly less toxic than formaldehyde when administered systemically, it remains to be determined whether these agents will ultimately be proven safe for ocular applications. The reason for the difference in safety between formaldehyde and nitroalcohols (as formaldehyde donors) is not clear based on a review of the existing literature. However, this difference presents a major advantage to using nitroalcohols for in vivo clinical uses. It may be that the slow, controlled release of formaldehyde from BNAs allows for rapid consumption by protein reactions in the local extracellular milieu. This prevents the accumulation of unreacted formaldehyde while maintaining low, effective concentrations. In this way, untoward cellular effects, such as that which occurs when using formaldehyde directly may be avoided.