Reviewer Comments January 31, 2006 

Thomas L. Goldsworthy 

RE: Gasoline DIPE Vapor Condensate: Embryo-Fetal Toxicity Study in Rats by Inhalation 

Exposures 

 A well written report that is complete and comprehensive. Study conduct was 

appropriate; protocol deviations did not impact data interpretations or study outcomes. Test 

substance analysis and chamber monitoring demonstrated the appropriateness of the atmospheric 

generation techniques and stability of test substance. Exposure concentrations were reasonably 

close to target, and study exposures allowed for suitable testing of test substance for embryofetal toxicity assessments. 

 Some reductions were seen in maternal body weight changes and food consumption 

during the exposure period. Body weight changes were statistically significant at all doses and 

generally exposure-dose related (most severe reductions in high does group). Similarly, red 

nasal discharge was observed in exposed animals at all dose levels. Given the relatively minor 

changes observed in the low dose exposure group for these endpoints, I concur that a NOAEL of 

2,000 mg/m3

 for maternal effects is appropriate. 

[editorial: remove ‘marginal’ when presenting body weight gains deficit in summary, conclusion 

and section 3.3.3] 

 The report states no effect of exposures at any level on pregnancy, including pre- or postimplantation loss, fetal weights or the incidence of fetal abnormalities and thus establishes a 

NOAEL for embryo fetal effects at 20,000 mg/m3. Fetal body weights in females and for the 

litter were decreased in the high exposure group. Text (page 29; 3.4.1) noted that this statistical 

significant finding was interpreted to not represent an effect of exposure since other signs of 

effects on pregnancy outcome were not observed. However, it seems possible to have decreased 

weight loss without always having accompanying adverse pregnancy outcomes. I suggest to 

examine related studies to determine if rejection or acceptance of this finding is based on a 

consistent basis. The incidence of 14th (supernumerary, rudimentary) ribs was noted as being 

increased, non-statistically significantly, in the high exposure group. Data show the finding 

increased in both fetal and litter analysis, and an increased bilateral effect was also observed. 

Text notes that this increased level is “closer to the upper range seen previously in a single 

group”. It would be useful to present the historical data of non-exposed animals for the 

laboratory as well as to comment within the context of all API-sponsored gasoline studies. I 

would also suggest a trend-test of raw data in the current study. These suggestions for a more 

robust analysis would aid in understanding if the NOAEL for embryo should be established at 

10,000 mg/m3, or as stated in the text, 20,000 mg/m3 (and would result in modifying text, 

including summary and conclusions). 

 Text acknowledges that this study was essentially a re-run of a previous study. If 

analysis were completed on the earlier study, text should state if differences between the two 

studies were noted in any of the assessed endpoints. Concordance may provide the ‘robustness’ 

for placing various findings in the proper context. It would also be useful to know if study 

design and/or test parameters were changed from the original study and if so, why? 

 Results were not stated in the Results Section for the data shown in Table 8 on gravid 

uterine weight. 

[editorial: Page 10, Introduction. Last sentence, “Because the potential...” is not complete.]