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Comment: MGK Insect Control Solutions. With respect to the uncertainty factor of 

1000 for the short-term and intermediate-term inhalation endpoints related to respiratory 

tract lesions, we disagree with the Agency’s position on metaplasia. A number of 

research studies on the respiratory tract provide evidence that a wide variety of factors 

(including chemical exposure) can bring about the histopathological transformation of 

squamous metaplasia of the larynx. Other factors that suggest squamous metaplasia in 

the larynx of rats should not be viewed as a toxicological response, but rather an 

adaptive one. We provided more detail information during the Reregistration process 

and plan to revisit this issue during the Registration Review process. 

HED Response: With respect to the short-term inhalation endpoint, HED points out that 

it is based on tremors, labored breathing, hyperactivity, secretory signs, matted coat, and 

decreased body weight/body weight gain, which were observed during the first few 

weeks of the subchronic inhalation study. The intermediate-term inhalation endpoint is 

not based solely on metaplasia. The LOAEL in the subchronic inhalation study is based 

on hypertrophy/hyperplasia in the mucosal seromucous glands of the larynx, 

pseudostratified ciliated/nonciliated columnar epithelial hyperkeratosis of the larynx 

(both sexes), goblet cell hyperplasia in the nasopharynx and nasoturbinates (males), and 

epithelial intracytoplasmic eosinophilic material in the nasoturbinates, which were 

observed at all dose levels at the end of the study.

Comment: MGK Insect Control Solutions. Under Hazard Characterization, second 

bullet. EPA has made a gross error in this document and quoted the incorrect cancer 

classification for pyrethrins. After review of the mechanism of action data of the PJV, in 

the EPA HED report “PYRETHRINS: Fourth Report of the Cancer Assessment Review 

Committee”, TXR No.: 0054822, dated February 14, 2008, HED reclassified pyrethrins 

as “Not Likely to be Carcinogenic to Humans” at doses that do not cause a mitogenic 

response in the liver/cell proliferation.

HED Response: The Agency acknowledges this error. MGK Insect Control Solutions is 

correct in pointing out that the cancer classification for pyrethrins is “Not Likely to be 

Carcinogenic to Humans” at doses that do not cause a mitogenic response in the liver/cell 

proliferation. 

Comment: MGK Insect Control Solutions. In addition, as a member of the Residential 

Exposure Joint Venture (REJV), the original survey database, and the new one just 

getting underway, will provide highly refined use and usage information for consumer 

products containing pyrethrins. We strongly urge the Agency to use the Surveys not only 

for Human Health risk assessments, but also the surveys can be mined for detailed 

information that can refine ecological risk assessments for outdoor products. 

HED Response: HED looks forward to reviewing revised REJV survey to inform 

residential human health exposure and risk assessment when that survey data is submitted 

to the Agency. That data is anticipated to be useful for assessing residential exposure, 

from a deterministic and probabilistic perspective.
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Comment: MGK Insect Control Solutions. The large number of incidents reported in 

the time period of 2006 to 2011, is misleading with respect to products containing 

pyrethrins. Many of the products with pyrethrins also contain more toxic residual 

pyrethroids which are more likely to have caused effects, if they were attributable to the 

pesticide exposure (many reportable incidents are deemed unrelated to exposure to the 

product.) The PJV is mid way through a 5 year product stewardship program with the 

Agency providing information to clarify any role pyrethrins may have in adverse effects, 

particularly possible allergic reactions. So far, the results indicate many fewer effects 

directly related to pyrethrins exposure. This program is further described in bullet three 

in the EPA document. 

HED Response: EPA acknowledges that when an incident involves more than one 

pesticide, it is difficult to determine which effects are attributed to the pesticide being 

considered. However, because pyrethrins are usually co-formulated with other active 

ingredients, and because there is about a 50-fold difference between the frequency of 

incidents involving pyrethrins alone versus pyrethrins and other chemicals, it is important 

to attend to the incidents involving multiple chemicals. Consequently, based on the 

frequency of exposures and the potential for exposures to result in high severity 

outcomes, these incident data warrant further analysis in the preliminary risk assessment 

phase of Registration Review. EPA agrees it will be important to consider Pyrethrins 

Joint Venture (PJV) product stewardship program during the preliminary risk assessment 

phase of Registration Review.

Comment: MGK Insect Control Solutions. With respect to the Immunotoxicity study 

requirement, MGK points EPA to the ongoing effort between CropLife America and EPA 

OPP’s Health Effects Division review of all of the existing immunotoxicity data submitted 

to date. This effort brings out the fact that no toxicological endpoints have changed or 

been further informed by this data requirement. We look forward to EPA’s review and 

further dialog in hopes that clear criteria for waiving out of the data requirement can be 

identified to prevent the unnecessary sacrifice of animals from unnecessary studies.

HED Response: OPP is conducting an independent retrospective analysis of more than 

150 immunotoxicity studies submitted to Agency. Preliminary findings of OPP’s 

retrospective analysis suggest that immunotoxicity studies have not yet provided lower 

PoDs than are selected from other guideline experimental toxicology studies and thus, so 

far, immunotoxicity studies would not have impacted the Agency’s risk assessments. The 

OPP retrospective analysis is anticipated to be completed in the summer of 2012. In the 

interim, HED recommends that the immunotoxicity continue to be required for 

registration and registration review chemicals.

Comment: PCRM. The Physician’s Committee for Responsible Medicine raised two 

studies that may be relevant for bridging pyrethroid (and in this case, pyrethrins) data in 

regard to immunotoxicology. The two citations for the two studies are as follows: 

• Zhang Y et al. 2010. Immunotoxicity of pyrethroid metabolites in an in vitro model. Environ 

Toxicol Chem. Nov;29(11):2505-10. 
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• Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of 

Health. and Human Services. EPA Toxicological Profile for Pyrethrins and Pyrethroids. Pg. 77. 

September 2003. 

HED Response: HED will investigate these studies as part of the toxicological 

evaluation of pyrethrins conducted for Registration Review.