Section 211(b) Research Group Response to Independent Peer Reviewer Comments On: 

Gasoline DIPE Vapor Condensate: 

Embryo-Fetal Toxicity Study in Rats by Inhalation Exposure 

HLS Study No. 05-4287

In the 211(b) testing program, the draft final reports of all developmental toxicity studies on vapor 

condensates of gasoline + oxygenates were reviewed by two independent peer reviewers: Dr. Thomas 

Goldsworthy, Consultant, and Dr. Richard Schlesinger, Pace University (formerly of New York 

University School of Medicine). 

The reviewers concur that the study was properly conducted and scientifically sound. None of the 

reviewers’ comments or recommendations invalidates the study. Both of the reviewers questioned the 

selection/justification of the developmental NOAEL. 

The 211(b) Working Group (WG) responses are organized by reviewer. 

Dr. Goldsworthy

Dr. Goldsworthy recommended that the analysis of data for developmental effects be made more robust 

by examining related studies for value in interpretation of fetal body weight differences and incidence of 

14th ribs, as well as examination of the original study [with partial data compromise on internal 

observations] for concordance. 

The WG will provide the original study (EMBSI Study No. 171734, 2008) to the HLS study 

director for review and consideration. In the previous study at EMBSI, administration of the test 

substance was not associated with statistically significant changes in mean fetal body weight or any 

statistically significant skeletal anomalies (Appendix K, Statistician’s Report). 

 The WG will request that appropriate historical control information on relevant developmental 

endpoints be included as an appendix to the report. 

 The WG will request that the study director review the overall 211b developmental toxicity 

program findings for possible consideration in the interpretation of the results of this study. The study 

director was a co-author on a presentation of the results of this study and others in the 211b 

developmental toxicity testing program in rats (Roberts, et. al, 2009). In this poster presentation, the 

study was interpreted to have a maternal NOEL of 2000 mg/m3

/day based upon reductions in gestation 

body weight change and food consumption at the higher exposure levels, and a developmental NOEL of 

10,000 mg/m3

/day based upon lowered fetal body weight at 20,000 mg/m3/day. The higher, but not 

statistically significant, incidence of rudimentary lumbar ribs was noted in the poster but not defined as 

attributed to exposure. 

Dr. Goldsworthy observed that the results for gravid uterine weight (Table 8) were not stated in the 

Results section of the report. 

 The WG will request that gravid uterine weight be included in the text of the Results section. 

Dr. Goldsworthy recommended the following two editorial changes: 
(a) Remove the word, “marginal,” when presenting body weight gain deficits in the Summary, 

Conclusions (Section 3.3.3) 

a. The WG will request this deletion in the Summary, Results (section 3.3.3), and 

Conclusion (section 4) 

(b) Correct the incomplete (last) sentence in the Introduction that begins, “Because the 

potential...” 

a. The WG will request that the first word, “Because,” be removed from the final 

sentence in the Introduction. 

Dr. Schlesinger

Dr. Schlesinger commented that there should be no particles in the chamber air if it is properly filtered, 

whereas particulates were measured in the chambers (0.0036 – 0.0063 mg/m3

). 

Appropriate filters were in place, but some particles are invariably present in chamber 

atmospheres, representing background air. The primary purpose of particulate measurements in a 

study utilizing high vapor concentrations is to make certain that vapor condensation is not 

occurring, and to preclude the possibility of aerosol formation. We believe that the particles in 

the chambers reflect ambient background levels. 

Dr. Schlesinger agreed with the conclusions in the draft report, but commented that the differences in fetal 

weight noted for the high exposure group, which were not considered to be an effect of exposure since the 

difference from control was very small, should not be summarily discounted. 

This comment is similar to a suggestion from Dr. Goldsworthy. The lab will be asked to review 

their interpretation in light of typical variability within their historical control data as well as to 

consider whether the slight but statistically significant differences noted for fetal body weight, 3-

4% of control values, are truly considered not to represent an effect of the exposures, as the report 

is currently written, or not to represent a biologically or toxicologically relevant difference. Fetal 

body weight was a consideration in the selection of the developmental NOEL, 10,000 mg/m3

. 

Dr. Schlesinger commented that error bars should appear on Figures 1 and 2. 

 Figures 1 and 2 represent gestation body weights and food consumption. The WG will ask the 

study director to include error bars if this is possible within the program that generates the 

figures. If the program is unable to do this, we will not pursue this request further, since Tables 4 

and 5 provide standard deviations and statistical significance.