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National Research Council (US) Committee on Acute Exposure Guideline Levels; National Research Council (US) Committee on Toxicology. Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington (DC): National Academies Press (US); 2011.

Cover of Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A

Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A.

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At its meeting held on October 26-29, 2010, the committee reviewed TSD on benzonitrile. A presentation on the TSD was made by Gary Diamond, of Syracuse Research Corporation. The following is excerpted from the Executive Summary of the TSD:

Benzonitrile is a colorless liquid at ambient temperature and pressure and has an odor of volatile oil of almonds. The liquid is irritating to the skin and eyes, and the vapor is irritating to the eyes, nose, and throat…. AEGL-1 values are not recommended for benzonitrile because of insufficient data…. The AEGL-2 was based on labored breathing and poor coordination in rats exposed to 900 ppm for 3 hours…. The exposure of mice to 890 ppm for 2 hours resulting in 1/7 deaths was used as the basis of AEGL-3.

A revised document should be submitted to the committee for review.

AEGL-Specific Comments


Page 6, lines 6-9 (also see page 8, lines 5-8): “Symptoms of acute poisoning with benzonitrile are similar to those produced by other uncoupling agents, such as pentachlorophenol and dinitrophenol, and include fatigue, excessive sweating, thirst, pyrexia, anxiety, tachycardia, and hyperventilation. Symptoms may resolve on cessation of exposure. (HSDB 2003).” If these symptoms have been observed in humans, many of which are consistent with the AEGL-1 defintions, why do the authors state on page 15 that “no human data consistent with the definition of AEGL-1 were available.” HSDB is a secondary source. The authors should evaluate the primary source for these data and reassess whether the AEGL-1 value can be derived. If human data are in fact unavailable, the authors should consider whether data from “other uncoupling agents” could be used to derive AEGL-1 values for benzonitrile if acute effects are indeed similar across these agents.


Page 9, lines 28-39 (also see page 10, lines 29-42): In addition to poor coordination and labored breathing that occurred in rats and mice in the MacEwen and Vernot (1974) study described in Section 3.1, the authors reported the progression to prostration with an additional 30 min of exposure; that is, for 3.5 h at 900 ppm in rats and for 2.5 h in mice presumably at 700 ppm. Poor coordination and prostration data are pertinent to the derivation of AEGL-2 and should be added to the toxicity description in this section and in Table 2. However, is labored breathing an AEGL-2 end point? The TSD notes that, in mice exposed at 700 ppm for 4 h, “Congestion accompanied by edema was noted in the lungs of both exposure groups at necropsy.” In humans, labored breathing may equate to respiratory failure, which in cases, depending on the severity, may not be reversible without medical intervention. Please discuss whether labored breathing may be a more appropriate end point for AEGL-3

Page 15, line 29-30 states that a 2-fold modifying factor is used to “account for the sparse data base and potential delayed hepatic effects….” Although these are pertinent reasons for using a modifying factor, other crucial considerations are missing in this discussion. It is important to note that poor coordination is an end point to be prevented at the AEGL-2 because it can impair escape. The progression into prostration with only an additional 30 min of exposure lends further support for escape impairment (see details in Other Comments below). Thus, the use of a modifying factor should be sufficient for ensuring that these overt effects will not be likely to occur. To achieve sufficiency, at least two additional factors should be considered. One factor is the incidence of poor coordination at 900 ppm. Although the frequency of occurrence is not given in the study report, it appears to be prevalent for both rats and mice under the study conditions. The other factor is the extremely steep time-response relationship, showing progression into prostration with only an additional 30 min of exposure. Taken together, the modifying factor of 2 is probably not adequate. The authors should consider a modifying factor of 3 instead.


In selecting the POD at 890 ppm for 2 h that resulted in 14% fatality in mice (MacEwen and Vernot 1974), it should be noted that all 10 mice died at 700 ppm for 4 h. Of these, one died at 3.5 h of exposure. Thus, the default time-dose adjustment that brings the POD for 4 h at 445 ppm does not appear to be sufficiently low, as it is only 1.6-fold [=700/445] below a level that resulted in 100% death.

Other Comments

Cover page: Please provide the chemical structure on the title page.

The reference HSDB (2003) is cited repeatedly in the Executive Summary and throughout the document (For example, page 8, lines 5, 8, and 17). Instead of citing the summary data, it is preferable that the original literature be reviewed and cited. Use of summary data gives the false impression that research was conducted more recently than in actuality.

Page 7, Table S 1: Please indicate the exposure duration for the POD in the AEGL summary table when its concentration is mentioned

Page 9, line 38-39: The sentence “However, multifocal areas of lymphoid hyperplasia.…” is incomplete. Please revise it.

Page 12, Table 2: The following items need to be revised in Table 2:

  • Inhalation Section—In the rat exposure study (1900ppm) by Industrial Bio-Test (1970), the “Effect” cell should include the following sentence “two died at 2 h after exposure, one died on day 6 postexposure” in order to clarify that two post-exposure time points are included in “30% Mortality (3/10).”
  • Inhalation section—Provide information on mice effects from the MacEwen and Vernot (1974) study at the same level of detail as done for the rats, that is, indicate the irritation of extremities at the first hour of exposure, poor coordination, and labored breathing after 60-90 min. Also indicate that the one death at 890 ppm occurred on day 2.
  • Oral section—Unify all entries of dose in the unit of mg/kg.

Page 10, lines 12-13: “Agaev (1977) reported the following ‘lethal concentrations for one-time exposure’ of benzonitrile in white rats: LC84 = 1,071 ppm, LC50 = 929 ppm, and LC16 = 738 ppm.” Please specify that the duration of exposure for the lethal concentrations was given.

Comment References

  • Agaev, F.B. 1977. Experimental substantiation of the maximum allowable concentration of benzonitrile for the air of the workplace [in Russian]. Gig. Tr. Prof. Zabol. 6:34-37. [PubMed: 892542]
  • HSDB (Hazardous Substances Data Bank). 2003. Benzonitrile (CASRN 100 -47-0). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD: [online]. Available: http://toxnet​.nlm.nih​.gov/cgi-bin/sis/htmlgen?HSDB [accessed Dec. 8, 2010].
  • Industrial Bio-Test. 1970. Acute Toxicity Studies on Benzonitrile. Report to Velsicol Chemical Co. OTS 0571101.
  • MacEwen, J.D. and E.H. Vernot. 1974. Acute inhalation toxicity of benzonitrile. Pp. 77-80in Toxic Hazards Research Unit Annual Technical Report: 1974. AMRL-TR-74-78. Aerospace Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force Base, OH.
Copyright 2011 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK209460
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