The charge to the committee is to (1) review the proposed AEGLs for scientific validity, completeness, internal consistency, and conformance to the NRC (1993) guidelines report; (2) review NAC’s research recommendations and—when appropriate—identify additional priorities for research to fill data gaps; and (3) periodically review the recommended standing operating procedures for developing AEGLs.
This interim report presents the committee’s conclusions and recommendations for improving the NAC’s AEGL document for five selected aliphatic nitriles: acetonitrile, isobutyronitrile, propionitrile, chloroacetonitrile, and malonitrile.
A revised document should be submitted to the committee for review.
At its meeting held on Ocober 27-39, 2010, the committee reviewed the technical support document (TSD) on the five selected aliphatic nitriles. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation.
Two overarching issues regarding data from developmental toxicity studies are noted.
Selection of the point of departure (POD): Both the maternal and fetal effects from developmental studies should be considered for the POD selection. The maternal toxicities from those studies specifically reflect sensitivity during pregnancy. The developmental effects are pertinent systemic toxicity end points. The consideration for windows of susceptibility for fetuses supports the use of no-observed-effect levels (NOELs) from repeated dosing regimen during organogenesis for a single-day acute toxicity scenario (van Raaij et al. 2003, 2009). Fetal death can occur during a narrow developmental window and does not necessarily require repeated exposures. Additional support from chemical-specific data is presented separately for each chemical.
Throughout this TSD, it was stated on several occasions that no reproductive or developmental toxicity was noted in the absence of maternal toxicity (e.g., page III-10, line 21; page IV-12, line 2; page V-8, line 19). These observations are pertinent for identifying risk agents that have fetal effects not indicative of maternal toxicity. However, for the purpose of setting AEGLs, these emphases can appear dismissive or can be potentially confusing since both maternal and fetal effects are pertinent end points regardless of whether one has a lower threshold than the other.
One additional point of consideration for setting the AEGL when maternal toxicity is present concomitantly with fetal toxicity is the distinction between the reversibility of observed maternal effects and the irreversibility of the developmental effects. For example, Willhite (1983) reported that fetuses from hamster dams that survived excessive salivation of acetonitrile at 5,000 ppm after 1 h of exposure had severe malformations (exencephalyencephalocoele and rib fusions). (page II-17, lines 39-40). This reversibility distinction between maternal and fetal toxicity could affect the selection of the POD for the AEGL-2 and AEGL-3.
Uncertainty factors: Animal studies are almost exclusively relied upon for data on maternal sensitivity and developmental effects. Thus, care must be taken in considering deviation or reduction from the default uncertainty factors based on comparison to human data when they do not include the evaluation of the maternal and fetal end points.
Specific Comments and Other Comments are provided below for each of the five selected aliphatic nitriles.
The following is excerpted from the Executive Summary of the TSD: