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Incident Report

Subform I: General Information

1. Report Type.

New incident report

Incident Report Number: 2011-6171

2. Registrant Information.

Registrant Reference Number: TKI201112

Registrant Name (Full Legal Name no abbreviations): Tessenderlo Kenley Inc

Address: 2255 N. 44th Street, Suite 300

City: Phonenix

Prov / State: AZ

Country: USA

Postal Code: 85008

3. Select the appropriate subform(s) for the incident.

Scientific Study

4. Date registrant was first informed of the incident.

5. Location of incident.

6. Date incident was first observed.

Product Description

7. a) Provide the active ingredient and, if available, the registration number and product name (include all tank mixes). If the product is not registered provide a submission number.

PMRA Registration No. 19696      PMRA Submission No.       EPA Registration No. 61842-24

Product Name: Linuron

• Active Ingredient(s)
  • LINURON

7. b) Type of formulation.

Application Information

8. Product was applied?

Unknown

9. Application Rate.

10. Site pesticide was applied to (select all that apply).

11. Provide any additional information regarding application (how it was applied, amount applied, the size of the area treated etc).

To be determined by Registrant

12. In your opinion, was the product used according to the label instructions?

Unknown

Subform VII: Scientific Study

1. Study Reference

Title Linuron: Human Recombinant Aromatase Assay

Date 07-DEC-11

2. a) Is an extension needed to translate the document?

No

3. Type of incident identified in the study

New health or environmental hazard

4. Describe the incident identified in the study (e.g. study demonstrates an increased risk to non-Hodgkin's Lymphoma after exposure to pesticide X)

Linuron was found to be equivocal for inhibition of the aromatase enzyme in the Human Recombinant Aromatase Assay (OCSPP 890.1200). The equivocal finding in this study is not supported by other scientifically relevant data available which demonstrate that linuron is not an aromatase inhibitor.

5. a) Was the study discontinued before completion?

No

5. b) Provide the reason for discontinuation

6. If the study is ongoing, what is the expected completion date?

For Registrant use only

7. Provide supplemental information here

The weight-of-evidence from the publically available peer-reviewed literature and ToxCastTM cell-free HTP provide scientifically defensible Other Scientificatlly Relevant Information (OSRO) that are functionally equivalent and consistent with the guidance recommended in OPPTS 890.1200-Aromatase (Human Recombinant). Overall, these data are direct evidence to indicate that linuron is not an aromatase inhibitor. Additional indirect evidence is provided by the fact that linuron administration to rats resulted in an increase in estradiol, which is consistent the absence of aromatase inhibition in vivo. Accordingly there is no need to conduct this assay. Linuron has been tested for its effects on this enzyme in human placental microsomes, an assay which has been pre-validated by EPA and an assay which has been in common use for measuring aromatase and aromatase inhibition because of its reliability, reproducibility, and ease of use (EPA, 2005b). Although human placental microsomes do not contain the same level of aromatase activity as the human recombinant microsomes, they do have sufficient activity to detect inhibitors of this enzyme such as fenarimol. In addition, propiconazole, triadimefon and triadimenol were identified as weak inhibitors of aromatase activity and the positive control, androstendione, was shown to be a very effective inhibitor of aromatase (74%) at 1¿¿M (Vinggaard, et al., 2000). In this study linuron was at least 50 times less potent compared to the positive control at the concentration tested and was clearly negative in this assay at 50 ¿¿M which is only 20 times lower than highest concentration (10-3 ¿¿M) recommended for testing in the EPA guidance. Linuron was also tested in the ToxCast cell-free HTS aromatase assay and was negative. The range of concentrations used were narrower than those recommended by EPA but should be adequate along with the results obtained by Vinggaard, et al. (2000) to conclude that linuron has been adequately tested in, not one, but two different systems for any potential effect on the human aromatase enzyme. In summary, the OSRI does not support the equivocal finding in the Human Recombinant Aromatase Assay. References Cook, J. 1990. Investigation of a mechanism for Leydig cell tumorigenesis by Linuron in rats. DuPont HLR 494-90. MRID 416301-01 U.S. EPA 2005a http://www.epa.gov/endo/pubs/aromatase_prevalidation.pdf. U.S. EPA 2005b http://www.epa.gov/endo/pubs/edmvs/aromatase_drp_final_3_30_05.pdf . U.S. EPA,ToxCastTM 2009 http://www.epa.gov/ncct/toxcast. Vinggaard, A., Hnida, C., Breinholt, V., and Larsen, J. 2000. Screening of selected pesticides for inhibition of Cyp19 aromatase activity in vitro. Toxicology in Vitro 14:227-234.