ACRYLONITRILE

The committee reviewed the AEGL TSD on acrylonitrile that was presented by Julie Klotzbach of SRC, Inc. Table 1 presents a summary of the proposed AEGL values for acrylonitrile and their basis. The committee recommended that the basis for those AEGL values be re-evaluated, and that the revised TSD be reviewed again at a future meeting.

AEGL Comments

The committee is concerned that the developmental toxicity end points presented in Section 3.3 were not adequately considered in the selection of the point-of-departure for AEGL values for acrylonitrile. The argument that the results are inconsistent between the study by Murray et al. (1978), which found fetal malformations (lowest-effect level of 80 ppm, and a no-effect level of 40 ppm), and the study by Saillenfait et al. (1993), which reported lower fetal weight and negative absolute maternal weight gain (lowest-effect level [LOEL] of 25 ppm, and a no-effect level [NOEL] of 12 ppm), are not an adequate basis for excluding the end points from consideration. Consideration should be given to whether in vitro studies of embryotoxicity could help with interpretation of studies (e.g., Saillenfait et al.1992; 2004). If appropriate, it might be possible to translate the in vitro concentration from these studies to inhalation concentrations by applying the pharmacokinetic model described in EPA’s 2011 toxicological review of acrylonitrile (EPA 2011). Below are comments on the use of developmental toxicity data specific to the AEGL-2 and AEGL-3 values.

AEGL-2 Values: In the TSD, an arbitrary threshold of 100 ppm was presumed for developmental toxicity, and was compared with the proposed 2-h AEGL point-of-departure of 305 ppm in adult nonpregnant rats in the study by Dudley and Neal (1942). However, further consideration should be given to reductions in maternal weight gain observed in both the Saillenfait et al. (1993) and Murray et al. (1978) studies, which had a LOEL range of 25-40 ppm and a NOEL of 12 ppm. In the Murray study, effect on maternal weight gain was evident at the first measurement, supporting the relevance of the end point to a single exposure scenario. Thus, the lower NOEL value from the Saillenfait study could be pertinent to AEGL-2 values if it is affirmed that there are no corresponding detrimental fetal effects.

TABLE 1 Summary of Proposed AEGL Values for Acrylonitrile Reviewed by the Committee

Classification 10 min 30 min 1 h 4 h 8 h End Point, Derivation Factors
AEGL-1 (nondisabling) 1.5 ppm (3.3 mg/m3) 1.5 ppm (3.3 mg/m3) 1.5 ppm (3.3 mg/m3) 1.5 ppm (3.3 mg/m3) 1.5 ppm (3.3 mg/m3) No-effect level for notable discomfort (eye irritation) in human subjects (4.6 ppm, 8 h); UF = 3
AEGL-2 (disabling) 81 ppm (180 mg/m3) 30 ppm (65 mg/m3) 16 ppm (35 mg/m3) 4.5 ppm (9.8 mg/m3) 2.4 ppm (5.2 mg/m3) No-effect level for impairment of escape (tremors, convulsion) in rats (305 ppm, 2 h); UF = 36; n = 1.1 for time scaling
AEGL-3 (lethality) 130 ppm (280 mg/m3) 50 ppm (110 mg/m3) 28 ppm (61 mg/m3) 9.7 ppm (21 mg/m3) 5.2 ppm (11 mg/m3) No-effect level for lethality (30-min, 1-h, and 8-h BMCL05) in rats; UF = 36; n = 1.1 for time scaling

Abbreviations: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response; UF, uncertainty factor.



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