In human risk assessment, time extrapolation factors (EFs) account for differences in exposure duration of experimental studies. We calculated EFs based on N(L)OEL (no (lowest) observed effect level) ratios, dividing shorter-term by longer-term values. The 'oral' datasets comprised 302 EFs (subacute-subchronic) and 1059 EFs (subchronic-chronic). The 'inhalation' datasets contained 67 EFs (subacute-subchronic) and 226 EFs (subchronic-chronic). The experimental EF distribution oral:subchronic-chronic showed that study parameters like deviation in dose selection and spacing influence mainly the data variance. Exclusion of these influences led to a dataset representing more realistically the difference of N(L)OELs with prolonged treatment. This dataset showed a GM of 1.5, indicating that the impact of a longer treatment period on the study N(L)OEL is on average not high. A factor of 1.5 seemed to be also sufficiently conservative for subacute-subchronic and subchronic-chronic extrapolation (inhalation or oral exposure). EFs for groups of similar compounds did not differ, but for compounds with low and high NOEL values. Relatively toxic compounds (GM 1) might thus not require time extrapolation. Within and between chemical variance was analysed in the dataset oral:subchronic-chronic (GSD 4.8). The variance between chemicals should be considered within extrapolation by selecting an appropriate percentile for which a chemical variance factor is suggested. In risk assessment, often a combination of EFs is required. Our analysis indicates that such a combination will result in an accumulation of non-toxicological variance and therefore unrealistically high EFs. Further evaluations are needed to identify appropriate chemical variance factors for these situations.

中文翻译：

---

监管风险评估中的时间外推：研究差异对外推因子的影响。

在人类风险评估中，时间外推因子（EFs）解释了实验研究中暴露时间的差异。我们根据N（L）OEL（无（最低）观察到的影响水平）比率计算EF，用短期值除以长期值。“口头”数据集包括302个EF（亚急性-亚慢性）和1059个EF（亚慢性-亚慢性）。“吸入”数据集包含67个EF（亚急性-亚慢性）和226个EF（亚慢性-亚慢性）。实验性EF分布口服：亚慢性-慢性表明，研究参数（如剂量选择偏差和间隔）主要影响数据差异。排除这些影响导致更实际地代表了经过长期治疗的N（L）OEL的差异。该数据集的GM为1.5，表明较长的治疗期对研究N（L）OEL的影响平均不高。对于亚急性，亚慢性和亚慢性外推法（吸入或口服暴露），系数1.5似乎也足够保守。相似化合物组的EF值没有差异，但NOEL值低和高的化合物的EF值相同。因此，相对有毒的化合物（GM 1）可能不需要时间推断。在oral：subchronic-chronic（GSD 4.8）数据集中分析了化学差异之内和之间。应在外推法范围内考虑化学品之间的差异，方法是选择一个适当的百分位数，以针对其提出化学差异因子。在风险评估中，通常需要结合使用EF。我们的分析表明，这种组合将导致非毒理学差异的累积，从而导致不切实际的高EF。需要进一步评估，以找出适合这些情况的适当化学方差因子。