Page 2 of 4 performed. For the proposed uses of imidaclopr id, all potential occupa tional exposure scenarios

will be assessed in the risk assessment document.

FQPA Safety Factor and DNT Study

I. In a recent submission to the Agency, Ms. Quirindongo of the Natural Resources Defense Council argued that the FQPA Safe ty Factor (SF) for imidacloprid should be 10X rather than the values determined by the Agency. In her statement on p. 9, it appears that Ms. Quirindongo utilized two outdated assessments for imidaclopr id (1997 and 1998) in formulating her opinion. However, two peer reviews of the toxicological database for imidacloprid took place after 1998 and these supersede any previous assessmen ts. In 2002, the HED Hazard Identification Assessment Review Committee (HIARC) re-exa mined the FQPA SF and the potential for increased susceptibility of in fants and children from exposure to imidacloprid. The peer-review committee concluded that the FQPA SF could be reduced to 1X based on several toxicological

considerations. These include the following:

 There is no quantitative or qualita tive evidence of increased sus ceptibility of rat fetuses to in utero exposure in developmental studies.

 There is no quantitative or qua litative evidence of increased susceptibility of rabbit fetuses to in utero exposure in developmental studies.

 There is no quantitative or qual itative evidence of increased susceptibility of rat offspring in the multi-generation reproduction study.

 There is evidence of increased qualitative susceptibility in the rat developmental neurotoxicity study. However, the concern is low since 1) any e ffects in pups are wellcharacterized with clear NOAELs; 2) any pup e ffects occur in the pr esence of maternal toxicity with the same NOA EL for effects in both pups and dams; and 3) the doses and endpoints selected for regulatory purposes ar e protective of the pup effects noted at higher doses in the developmental neurotoxicity study.

 There are no residual uncertainties for pre- /post-natal toxicity in the toxicological database for imidacloprid.

II. On p. 10 of her submission, Ms. Quirindongo correctly states that a developmental neurotoxicity (DNT) study was submitted for imidacl oprid and that the results should be highly regarded. In fact, the results of the DNT study were utilized by the HIARC in 2002 to arrive at

the committee’s scientific conclu sion that the FQPA SF should be reduced to 1X. In the study, toxicity was observed in both maternal animals and offspring at the same dose (the high dose), and clear NOAELs were obtained for both offspring and maternal animals. Measurement of the caudate/putamen at the mid dose was requested by the Agency for females only; however, there

is no scientific reason to believe that the ca udate/putamen width at the mid dose in females would be any different from control values, sin ce this measurement was unaffected in males and there is no evidence in the study th at females are more sensitive than males; since the change inPage 3 of 4 caudate/putamen width at the hi gh dose in females was very small (only 2%); and since there was no effect on brain weight or on any other mor phometric or structural measurement in either sex. Because the biological significance of such a small change is equivocal, its use as an endpoint to set the LOAEL in the study is considered highly conservative.

III. On p. 12 of her submission, Ms. Quirindongo correctly noted that the acute dietary exposure endpoint was based on a study (acute ne urotoxicity study) that had a LOAEL but no NOAEL; however, she incorrectly states that th e Agency failed to a pply a conventional 3X adjustment: “EPA has conventionally applied an a dditional 3X adjustment factor when it relies on a study in which a no-effect level cannot be es tablished... In this cas e, however, EPA did not follow convention....” In fact, the Agency did appl y a conventional 3X adjust ment factor to this point of departure. Specifically, a 3X FQPA SF was applied in the form of a LOAEL-toNOAEL extrapolation factor (UF L ) for this exposure scenario. This decision was based not only on convention but primarily on the following scie ntific observations th at took the entire toxicological database into consideration:

1) the LOAEL in the study (42 mg/kg) is comparab le to or lower than the LOAELs seen in adults in the developmental toxicity study in rat (30 mg/kg/d) and the two-generation reproductive toxicity study [47/ 52 mg/kg/d (male/female)] an d in offspring in the DNT study (55 mg/kg/d).

2) the extrapolated NOAEL of 14 mg/kg (42/3X = 14) is lower than the NOAEL of 20 mg/kg/d established in offspring in the DNT study and therefore protective of any offspring toxicity observed at higher doses in the DNT study.

3) the effects in this study showed a good dose response which resulted in minimal and statistically non-significant effects on motor activity and locomotor activity in one sex at

the LOAEL.

For these reasons, therefore, the Agency is confiden t that the 3X uncertainty factor applied to the acute dietary exposure endpoint results in an acute reference dose that is protective of the offspring toxicity that was obs erved at doses that were appr oximately 400 times higher in the DNT study. It is also noted that the chronic reference dose is also protective of the offspring toxicity that was observed at doses that were approximately 1000 times higher in the DNT study.

IV. On p. 14, Ms. Quirindongo states "many possi ble adverse impacts ar e not tested for or considered by EPA." EPA disagrees with this statement. Current law for food-use pesticides, such as imidacloprid, requires a complete batter y of at least 22 GLP studies in animals that assess a full range of potential toxicities, These include acute, subchronic, chronic, developmental, and reproductive toxicities, as well as neurotoxicity, immunotoxicity, carcinogenicity, mutagenicity, and chromosomal da mage. In addition, with the implementation of the endocrine disrupto r screening program, possible interac tions of a given compound with the estrogen, androgen, and thyroid horm one systems are also being tested. All of the required toxicity studies, which are perf ormed in 4 species, assess effect s in all of the many organs and organ systems that are possible targets of toxicity in both ad ult and young animals, thereby providing a full picture of the hazar d potential of each pesticide. In the case of imidacloprid,Page 4 of 4 such a comprehensive assessment of toxicity has allowed EPA to assess with confidence that there is a reasonable certainty of no harm to humans following its use on vegetable, bulb, and cereal grain.

II. ACTION REQUESTED Please address the comments made by NRDC rega rding human health risks for imidacloprid.