Proposed extension toxicology

Despite its low toxicity, there have been extensive toxicological studies on EGME. The subacute percutaneous administration of this compound in male rats dosed 5 days/week for 4 weeks resulted in testicular and bone marrow damage at doses of 1000 mg/kg/day (Eairhurst et al. 1989). HPLC and isotope- dilution analysis indicated that the major metabolites were methoxyacetic acid [625-45-6] and methoxy-acetyl glycin (Moss et al. 1985). Foster et al. (1986) proposed that 2-methoxyacetaldehyde [10312-83-1] was a possible metabolite that played an important role in EGME-induced testicular toxicity. The former produced specific cellular toxicity to pachytene spermatocytes in mixed testicular cell cultures. Subchronic vapor inhalation studies in rats and rabbits showed that overexposure to EGME produced adverse effects on testes, bone marrow, and lymphoid tissues... 

The inhalation toxicity of NF on animals has been studied extensively (37—40). These studies provide the basis of emergency exposure limits (EEL) that have been proposed for NE. The NAS—NRC Committee on Toxicology recommends that the EEL for NE be 10 min at 2250 ppm, 30 min at 750 ppm, and 60 min at 375 ppm. Gaseous NE is considered to be innocuous to the skin and a minor irritant to the eyes and mucous membranes. NE does give a weakly positive metabotically activated Ames test but only at concentrations greater than 2% or 10 times the 10 minute EEL. 

There have been several attempts over the years to classify adverse drug reactions, primarily based on the perception of what can and what cannot be predicted given knowledge of the pharmacology and toxicology of the drug. For example, Edwards and Aronson [13] proposed what is probably the most extensive classification system ... 

The use of food additive petitions and GRAS procedures to evaluate the safety of a proposed new excipient would apply to the oral route of administration for the excipient and would not generally apply to other routes of administration. Some routes of administration (e.g., inhalation) result in unique toxicological requirements, and data would have to be developed for the specific route of administration. While toxicological data from systemic studies are important for excipients used for nonoral applications, separate data would be needed for the specific route of administration. Nevertheless, the amount of safety data, specifications, and intake information required for a food additive review is extensive, and therefore could provide a firm basis of safety for a new excipient. 

All INDS include an extensive review of outside (generally published) literature, with particular focus on any administration of the proposed drug to human subjects or on any published toxicology or preclinical studies that may indicate any possible adverse reactions. An eventual 505(b)(2) NDA will rely on some of these studies, in combination with IND-proposed pivotal new clinical studies, to support the application. This plan will be outlined in the IND study proposal and/or discussed at the pre-IND FDA conference. 

Note that protein pharmaceutical products require extensive biochemical and bioactivity comparability studies for materials used for toxicology, clinical, and proposed market supplies. 

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