# Pyrethrins and Developmental Neurotoxicity Meeting Between the Pyrethrins Joint Venture (PJV) and the EPA July 24, 2008Science Strategies & PJV 

# Agenda  

### Thank you ...  

### IntroductionScience Strategies & PJV 

## The Bases for Requiring a DNT  Are there sufficient “ triggers ” in the current database that suggest the potential for developmental neurotoxicity?  Are there reports in public literature that raise the concern for developmental neurotoxicity of pyrethrins?  Will the new data be likely to alter the regulation of pyrethrins in any significant way?Science Strategies & PJV 

# Science Triggers? Is there ...  E vidence of significant neuropathological effects observed in toxicology studies on adult animals;  Clear indication of behavioral alteration in studies at doses close to or less than those producing clear systemic toxicity, and/or;  Indication from developmental or reproduction/fertility studies that suggests there may be increased sensitivity in prenatal or juvenile animals.Science Strategies & PJV 

# Science Triggers? Pyrethrins  

### “ The developmental neurotoxicity study is an upper tier study which would only be required if effects observed (e.g. lesions of the CNS) in the acute and 90- day neurotoxicity studies indicate concerns for potential increased sensitivity of the infant or neonate. ” - HED Revised Risk Assessment for PyrethrinsScience Strategies & PJV 

# Science Triggers? Pyrethrins

 

### “ Based on the finding of neuropathy in the acute neurotoxicity study in rats, a developmental neurotoxicity study is required (for pyrethrins). ” - HED Revised Risk Assessment for PyrethrinsScience Strategies & PJV 

### E vidence of significant neuropathological effects observed in toxicology studies on adult animals? No  Reread of slides from original neurotoxicity study

 Confirmed original finding of mild-moderate peripheral axonopathy in only 3/10 high dose females - 200 mg/kg)  Sporadic degeneration in other groups as well (including controls)  No axonopathy in central fiber tracts, nerve somata, nor neuronopathy or myelinopathyScience Strategies & PJV 

### E vidence of significant neuropathological effects observed in toxicology studies on adult animals? No  

### Reread, continued  Myelin vacuolation - unequivocally artifactual  No central nervous system (CNS) effectsScience Strategies & PJV 

## Indications of Behavioral Alterations? No  Functional observational battery (FOB) and motor activity (MA) data

 Correlation of 2 high-dose female rats showing behavioral changes with the more pronounced axonopathy (still only mild-to-moderate)  Only after 1st post dosing interval (3-4 hr)  Clinical observations - animals prostrate - inability to perform FOB to be expected  Animals completely recovered - no other effectsScience Strategies & PJV 

## Indications from Developmental or Reproductive/Fertility Studies? No  

### No evidence of persistent gross or behavioral effects on successive generations after in utero exposure even at the highest dose testedScience Strategies & PJV 

# Science Triggers? NoScience Strategies & PJV 

## Published Reports Relevant to the DNT Requirement? Yes
 Extensive review by Shafer et al, (2005)  More research is needed  No clear and consistent pattern of post-natal effects from prenatal/perinatal exposure to compounds that target VSSCs  Data suggest that Type II pyrethroids (like deltamethrin) are significantly more lethal in young animals that adults (Sheets et al. 1994)Science Strategies & PJV 

## Published Reports Relevant to the DNT Requirement? Yes

 Two Type I pyrethroids (cismethrin and permethrin; pyrethrins are also Type I) did not have any age-dependent toxicity ( Sheets (2000)  No age-dependent differences in the behavioral toxicity of either Type I or Type II pyrethroids at doses below those causing overt toxicity ( Sheets (2000)Science Strategies & PJV 

## Likely Importance of the DNT to Regulation of Pyrethrins? Not likely

 NOAEL for neuropathology -  63 mg/kg females, 125 mg/kg males  RED Endpoints for risk assessments  4.3-20 mg/kg - EPA Assessment assumes NOAEL from DNT to be 6.3 mg/kg/day  Work on other pyrethroids  Unlikely that a DNT study will provide any revelations about increased susceptibility or persistent effects on nervous system developmentScience Strategies & PJV 

## The Bases for Requiring a DNT
 Are there sufficient “ triggers ” in the current database that suggest the potential for developmental neurotoxicity? No.  Are there reports in public literature that raise the concern for developmental neurotoxicity of pyrethrins? No.  Will the new data be likely to alter the regulation of pyrethrins in any significant way? Not likely.Science Strategies & PJV 

# Conclusion  

### Threshold for the DNT requirement has not been met for pyrethrins and that such a requirement should be waived.Science Strategies & PJV 

# Discussion