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performed. For the proposed uses of imidacloprid, all potential occupational 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 Safety 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utilized two outdated assessments for imidacloprid (1997 and 1998) in formulating her opinion.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 assessments. In 2002, the HED Hazard Identification 

Assessment Review Committee (HIARC) re-examined the FQPA SF and the potential for 

increased susceptibility of infants 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 qualitative evidence of increased susceptibility of rat fetuses to 

in utero exposure in developmental studies. 

 There is no quantitative or qualitative evidence of increased susceptibility of rabbit 

fetuses to in utero exposure in developmental studies. 

 There is no quantitative or qualitative 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 effects in pups are wellcharacterized with clear NOAELs; 2) any pup effects occur in the presence of maternal 

toxicity with the same NOAEL for effects in both pups and dams; and 3) the doses and 

endpoints selected for regulatory purposes are 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 imidacloprid 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 conclusion 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 caudate/putamen width at the mid dose in females 

would be any different from control values, since this measurement was unaffected in males and 

there is no evidence in the study that females are more sensitive than males; since the change in 
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caudate/putamen width at the high dose in females was very small (only 2%); and since there 

was no effect on brain weight or on any other morphometric 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 neurotoxicity study) that had a LOAEL but no 

NOAEL; however, she incorrectly states that the Agency failed to apply a conventional 3X 

adjustment: “EPA has conventionally applied an additional 3X adjustment factor when it relies 

on a study in which a no-effect level cannot be established... In this case, however, EPA did not 

follow convention....” In fact, the Agency did apply a conventional 3X adjustment factor to this 

point of departure. Specifically, a 3X FQPA SF was applied in the form of a LOAEL-toNOAEL extrapolation factor (UFL) for this exposure scenario. This decision was based not only 

on convention but primarily on the following scientific observations that took the entire 

toxicological database into consideration: 

1) the LOAEL in the study (42 mg/kg) is comparable 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)] and 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 confident 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 observed at doses that were approximately 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 possible adverse impacts are not tested for or 

considered by EPA." EPA disagrees with this statement. Current law for food-use pesticides, 

such as imidacloprid, requires a complete battery 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 damage. In addition, with the implementation 

of the endocrine disruptor screening program, possible interactions of a given compound with the 

estrogen, androgen, and thyroid hormone systems are also being tested. All of the required 

toxicity studies, which are performed in 4 species, assess effects in all of the many organs and 

organ systems that are possible targets of toxicity in both adult and young animals, thereby 

providing a full picture of the hazard potential of each pesticide. In the case of imidacloprid, 
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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 regarding human health risks for imidacloprid.