Exposure extrapolation duration subchronic studies

Vermeire et al. (1999) reviewed several studies comparing NOAELs from chronic and subacute/subchronic studies in order to evaluate the distribution of the extrapolation factor for duration of exposure. The ratios of observed NOAELs from oral studies using historical data for various compounds were calculated. The most likely distribution of the ratios was considered to be lognormal and the parameters of the distributions of the ratios were estimated, see Table 5.8. 

The oral RfD for naphthalene was 0.02 mg/kg/day, and a study by Battelle (1980) was used to calculate the RfD. Decreased body weight was the most sensitive end point in groups of Lischer 344 rats given 0, 25, 50, 100, 200, or 400 mg/kg for 5 days/week for 13 weeks. These doses were also duration-adjusted to 0, 17.9, 35.7, 71.4, 142.9, and 285.7 mg/kg/day, respectively. The NOAEL for a > 10% decrease in body weight in this study was 71 mg/kg/day. The UL of 3000 was based on 10 for rats to humans extrapolation, 10 for human variation, 10 to extrapolate from subchronic to chronic, and 3 for database deficiencies including lack of chronic oral exposure studies. 

The authors noted that it may be expected that the NOAELs from subacute/subchronic smdies tend to be larger than NOAELs from chronic studies and it was considered that the GM ratios for the NOAELs assessed in the studies most likely overestimated the median of the distribution of the extrapolation factor for duration of exposure. The authors also noted that it is very likely that the databases used in these studies overlap each other significantly. It was also pointed out that the distributions presented in Table 5.8 were based on rather variable exposure periods for the subchronic NOAELs, included interspecies variation (no matching for species) for... 

In the risk assessment, some steps are not well described. For example, subchronic toxicity studies and not chronic toxicity studies are used in the risk assessment. Exposure duration and frequency considerations are not discussed. Route-to-route extrapolation is considered acceptable implicitly, without further evaluation of the various issues involved. The rationale for using a dermal absorption default of 10 %, in the absence of data is also not discussed. 

Goldman et al. 1988). The subcommittee believes, however, that because the exposure duration of the critical study (7 days) is too short to be considered a subchronic exposure study, a factor of 10 should be assigned to UFs to account for the greater uncertainty involved with extrapolating such data to chronic exposures. 

---