UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Office of Prevention, Pesticides and Toxic Substances TXR#: 0050926 November 6, 2002 MEMORANDUM SUBJECT: Molinate  Review of 60 Day Comments and Revised Human Health Risk Assessment DP Barcode: D286216 Submission: S618724 PC Code: 041402 FROM: Virginia A. Dobozy, VMD, MPH, Veterinary Medical Officer Reregistration Branch I, Health Effects Division ( 7509C)

THROUGH: Whang Phang, PhD, Branch Senior Scientist Reregistration Branch I, Health Effects Division ( 7509C)

TO: Robert McNally/ Wilhelmena Livingston Special Review and Reregistration Branch ( 7508C)

Action Requested: Review comments received as a result of the Molinate 60 day comment period for the preliminary risk assessment dated January 9, 2001.

Recommendation: RRB1 has considered comments from the following: Syngenta Crop Protection, USA Rice Federation, California Rice Commission and the Pesticide Action Network. The comments are summarized with RRB1' s response in the attached document. The attached Human Health Risk Assessment has been revised as follows: 1) the product chemistry data gaps have been deleted, except for the studies on stability to metals and metal ions ( GLN 830.6313) and UV/ visible absorption ( GLN 830.7050); 2) the irrigation crop study has been waived; 3) molinate metabolites to be included in water monitoring study have been revised based on EFED Memorandum ( D284308); 4) the section concerning taste and odor issues between Sacramento and West Sacramento in 4.2.2 Water Exposure has been deleted based on EFED data; 5) comments concerning inhalation exposure of California residents to molinate have been addressed in 4.4 Residential Exposure; and 6) editorial corrections have been made. 2 Comments Submitted and RRB1' s Response 1) Syngenta Crop Protection  " 60 Day Response to Draft Reregistration Eligibility Decision ( RED) for Molinate dated June 3, 2002"

Some of the comments are technical error corrections while others are challenges involving scientific interpretation of data. The registrant states that the company reserves the right to comment on the document titled " Molinate  review of the Registrant's Response to the Assessment of Molinate by the Mechanism of Toxicity SARC" dated January 6, 2002 because it was placed in the docket only shortly before the comment period expiration.

Toxicology and Report of the FQPA Safety Factor Committee Most of the comments deal with the mechanism of reproductive toxicity and HED's interpretation of increased sensitivity of offspring in the rat developmental and developmental neurotoxicity studies. Syngenta requests that the wording indicating molinate is a reproductive toxicant be changed to state that molinate is a reproductive toxicant in rats and that humans have been shown to be less sensitive. Mechanism of action data were reviewed by the Mechanism of Toxicity Science Assessment Review Committee on January 13, 2000. The registrant responded in a March 10, 2000 submission ( D266145; TXR # 0050457). RRB1' s review of this submission concluded that the available data do not provide sufficient evidence that reproductive effects observed in the rodent are not relevant to humans.

RRB1' s Response: RRB1 has considered similar proposed language revisions regarding reproductive toxicity from the California Rice Commission ( CRC) ( D278226; TXR # 0050244). It was concluded that the suggested revisions were not supported by currently available data.

Food Exposure The one food exposure comment requests waivers of the multi residue method testing for metabolites molinate acid and 4 hydroxy molinate and from the irrigation crop study which measures sulfoxide and sulfone.

RRB1 Response: A separate Memorandum from Christine Olinger to Wilhelmena Livingston dated September 5, 2002 ( D284879), with addendum dated November 6, 2002, addresses this waiver request. RRB1 recommended that a waiver be granted for the irrigation crop study only.

Exposure Assessment  Epidemiology Data Syngenta believes EPA misinterpreted several points from the epidemiology study, including conclusions about decrease in observed vs. expected number of children at parity 3 and 4+, participation rate, exposure timing and variability, within worker variability, confidence interval, chronic low level exposure, confounders and study power. 3 RRB1' s Response: HED has reviewed three separate submissions on this study. Each one has been an attempt to upgrade the study and address deficiencies. No additional data have been submitted with these comments that would alter HED's conclusions about the study.

Dietary Exposure  Risk Analysis Syngenta prepared acute and chronic dietary and aggregate risk assessments using the following deviations from the HED risk assessment:

° revised percentage crop treated ( 31.4% for both chronic and acute dietary exposure as compared to HED's values of 40% for chronic and 54% for acute exposures). The percent crop treated was calculated from the 1999 2001 Doane data for total base acres of rice treated at least once with molinate divided by total acres grown.

° used DEEM   version 7.76 vs. DEEM   version 6.76 used by HED The results from chronic, acute and lifetime exposure assessments were all < 100% of the RfD with the highest risk being in non nursing infants < 1 year, i. e., 24% and18.9% of the RfD for the acute and chronic dietary assessments, respectively. The percentage of the PAD for acute and chronic dietary risk assessments for infants < 1 year were 55% and 18%, respectively.

RRB1' s Response: The use of the 7.76 version of DEEM would have no impact on the dietary analyses. The same consumption data are used for both the 6.76 and 7.76 versions.

Aggregate Risk Assessment Syngenta questioned EPA's aggregate risk assessment which was based on worst case water exposure for children ( most sensitive group) and dietary ( food) for all infants, even though the most sensitive subgroup was non nursing infants. Syngenta questions aggregation of exposure to two different subgroups ( children and infants). Syngenta calculated an acute aggregate exposure for food and surface water of 92.3% of the PAD for most sensitive subgroups ( all infants). A chronic aggregate exposure of molinate in food and surface water of 83.0% of the PAD was calculated.

RRB1' s Response: As explained in section 5.0 Aggregate Risk Assessment and Risk Characterization, the calculations in Table 5 for the category " children" are based on food consumption for infants < 1 year. This is a worst case scenario for all children, regardless of age. 4 Toxicology Chapter Page 6  Dermal Toxicity Study in Rabbits should be in rats. Syngenta disputes EPA's classification of this study as unacceptable because plasma and brain cholinesterase ( ChE) were not measured. Syngenta argues that plasma ChE was measured. RBC ChE was only slightly decreased ( mean activity did not exceed 20%). The registrant thinks the NOAEL should be 10 mg/ kg/ day based on slight acanthosis at 25 mg/ kg/ day.

RRB1' s Response: This comment was addressed in the review of the registrant's 30 day response to the risk assessment ( D265730). RRB1 acknowledged that the heading was an error; the study was conducted in rats. Plasma cholinesterase measurements were conducted; therefore, the basis for concluding that the study was unacceptable was the lack of brain cholinesterase measurements. The Toxicology Chapter will not be revised; changes in the toxicology data will be reflected in the risk assessment. This study was not discussed in the body of the risk assessment but Appendix Table 1 of the risk assessment will be revised to indicate that the species in the 21 day dermal study ( MRID 40990601) was rats.

Page 7  Chronic Toxicology in Dogs EPA concluded that no NOAEL for neurotoxic effects was observed based on demyelination of the sciatic nerve and several regions of the spinal cord. Syngenta disagrees based on the inconsistency between findings in some nerves at different levels. In addition, the finding of minimal demyelination in 2/ 4 dogs in the control group raises questions about fixation and processing of the tissue.

RRB1' s Response: The NOAEL/ LOAEL in the Data Evaluation Report ( DER) were found acceptable by a HED peer review committee [ October 30, 1998 Report of the Hazard Assessment Identification Review Committee ( HIARC)]. No additional data have been submitted with these comments that would alter HED's conclusions about the study.

Page 9  Developmental Study in Rats Syngenta believes that the NOAEL is 35 mg/ kg/ day. EPA set the LOAEL at 35 mg/ kg/ day based on increased incidence of runting. Syngenta thinks that occurrence of 4 runts, in the absence of any effect on fetal weight, is incidental to treatment.

RRB1' s Response: The conclusions of the DER were found acceptable by HED peer review committees ( October 30, 1998 Report of the HIARC and December 17, 1998 Report of the FQPA Safety Factor Committee). The significance of runting was also discussed in a review of the registrant's rebuttal ( D254376; April 19, 1999) and in an October 30, 2001 Review of California Rice Commission Submission ( D27226; TXR# 0050244). 5 Page 11  Reproduction Study in Rats HED concluded that the reproduction/ developmental NOAEL was not attained based on decreased brain weight in offspring. Syngenta thinks the reproduction NOAEL should be 10 ppm. Although there was a slight increase in the proportion of abnormal sperm at 10 ppm, this was not associated with any effects on fertility, suggesting there was no reproduction consequence. It is also Syngenta's position that the reproduction NOAEL for females is 50 ppm. Although there were changes in the incidence of ovarian lesions at this level, there were no effects on fertility. Regarding the decrease in the absolute weight of offspring brain weight, the registrant argues that this change reflects the body weight decrease.

RRB1' s Response: The conclusions of the DER were found acceptable by HED peer review committees ( October 30, 1998 Report of the HIARC and December 17, 1998 Report of the FQPA Safety Factor Committee).

Page 14  Developmental/ Reproductive Toxicity  Four part Investigative Study, Part 4 Syngenta thinks the NOAEL should be 0.26 mg/ kg as this was the actual dose. The 0.2 mg/ kg dose used by HED was the target dose.

RRB1' s Response: As stated in the May 11, 2000 review of the registrant's 30 day comments, RRB1 acknowledges that the actual dose was 0.26 mg/ kg/ day. The Toxicology Chapter will not be revised; changes in the toxicology data will be reflected in the risk assessment. This dose was used for the intermediate term dermal risk assessment. The Margins of Exposure ( MOEs) for most of the scenarios were very low and would not be significantly altered if the NOAEL was 0.26 mg/ kg/ day rather than 0.2 mg/ kg/ day.

Page 18  Neurotoxicity  Acute Delayed Neurotoxicity Study in Hens Syngenta states that the metabolite molinate sulfoxide inhibits neurotoxic esterase ( NTE) weakly while the parent does not. Many weak NTE inhibitors do not cause delayed neuropathy. The registrant cites a study by Moretto et al ( 2001) that shows molinate is protective against the onset of delayed neuropathy for the classical delayed neurotoxicants such as tri ortho cresyl phosphate ( TOCP). This study is not listed with the Delayed Neuropathy References at the end of the section.

Syngenta states that, in the study in question, the molinate treated hens did not show the characteristic brain and spinal cord changes seen with TOCP. TOCP treated hens had leg weakness and incoordination, whereas no clinical signs were observed with molinate treated hens.

RRB1' s Response: As stated in the January 9, 2001 Memorandum with the revised Human Health Risk Assessment ( D271384), Dr. Karl Jensen, a neurotoxicologist with EPA's National Health and Environmental Effects Research Laboratory, reviewed the study and concluded that 6 molinate produces delayed neurotoxicity in the hen.

The Moretto et al ( 2001) study was obtained and reviewed. The objective of the study was to determine if molinate would inhibit or promote organophosphate induced delayed polyneuropathy ( OPIDP) in hens receiving di n butyl dichlorovinyl phosphate ( DBDVP). Certain esterase inhibitors protect from OPIDP when given before an effective dose of an organophosphate ( OP); however, when given after the OP, they cause exacerbation of OPIDP. Both initiation and protection from OPIDP are related to interaction with neurotoxic esterase ( NTE). Inhibition of a phenyl valerate esterase named M200 has been associated with promotion. In the study, hens were protected from of DBDVP induced neuropathy ( 1 and 5 mg/ kg SQ) by 100 or 180 mg/ kg molinate SQ when given prior to DBDVP. A dose of 45 mg/ kg molinate SQ offered only partial protection. When 180 mg/ kg molinate SQ was given after a 0.4 mg/ kg dose of DBDVP, there was an increased severity of clinical effects and histopathology in the spinal cord and peripheral nerves. Lower doses of molinate did not promote OPIDP or else produced a milder effect. The study authors concluded that protection of DBDVP neuropathy by molinate is correlated with inhibition of NTE whereas promotion DBDVP neuropathy is associated with > 50% M200 inhibition.

Hens were initially treated with 100 180 mg/ kg molinate SQ. NTE and M200 were irreversibly inhibited (> 78%) in the brain and peripheral nerve. No clinical or morphological signs of neuropathy developed in these animals. In the hen study submitted to EPA ( MRIDs 00133502 and 43136601), effects ( axonal degeneration in brain and spinal cord) were observed at higher doses ( LOAEL = 630 mg/ kg). The NOAEL in this study was 200 mg/ kg.

RRB1 concludes that the findings of the Moretto et al study do not alter the conclusion that molinate is a delayed neurotoxicant.

Page 21  Developmental Neurotoxicity Study Syngenta thinks the NOAEL should be 20 ppm because of the variability in startle amplitude, the parameter HED used to establish the developmental neurotoxicity LOAEL at this dose.

RRB1' s Response: The conclusions of the DER were found acceptable by HED peer review committees ( October 30, 1998 Report of the HIARC and December 17, 1998 Report of the FQPA Safety Factor Committee). The registrant's rebuttal was also previously reviewed ( D254376; April 19, 1999) and in the Review of the CRC's submission ( D278226, TXR # 0050244).

Occupational Exposure Pages 3 and 4  Syngenta points out that the short and intermediate term exposure periods have been changed since the risk assessment was completed. The intermediate term is now 30 days to several months. Since molinate exposures do not exceed 30 days per year, Syngenta thinks all 7 intermediate term assessments should be removed from the risk assessment.

RRB1' s Response: The occupational exposure assessment was based on 27 application days/ year for aerial applicators of granular and liquid molinate from data supplied by Syngenta at the September 23, 1998 SMART meeting. Pilots making multiple applications treating a number of farms and working over the entire planting/ early growth season could be exposed over 30 days. There was no information on the number of application days/ year for ground based applications for liquid and granular formulations so HED assumed 30 days per year. RRB1 maintains that intermediate exposure assessments are required for molinate.

Page 4  HED used the oral LOAEL of 1.8 mg/ kg/ day from the developmental neurotoxicity study. Both Syngenta and the California Department of Pesticide Regulation interpret the dose of 1.8 mg/ kg/ day as the NOAEL. Using the 1.8 mg/ kg/ day as the NOAEL would require a 100 fold safety factor instead of a 300 fold safety factor. Therefore, the risks for mixers/ loaders and applicators for all but one use pattern would be acceptable.

RRB1' s Response: As stated above, the conclusions of the DER which set the LOAEL at 1.8 mg/ kg/ day were reviewed and accepted by HED peer review committees.

Page 4  Syngenta disagrees with the 40% absorption rate used by HED. They state that additional data comparing absorption in rat in vivo/ in vitro and in human in vitro indicate that a 10% is a realistic figure for absorption through the human epidermis. Using a 10% value and a NOAEL of 1.8 mg/ kg/ day results in acceptable risks to pilots applying Ordram 15G or Ordram 15GM by air as well as acceptable risk to pilots applying Ordram 8E or Arrosolo by air.

RRB1' s Response: Syngenta has not submitted the data they used to calculate the 10% absorption value; therefore, RRB1 cannot comment.

Page 4  Syngenta points out that quantification of carcinogenic risk is no longer required RRB1' s Response: The quantification of carcinogenic risk was deleted from the January 9, 2001 Human Health Risk Assessment.

Page 12  HED normalized the handler's exposure to mg ai/ lb handled and used default body weight and anticipated application rates for handlers to estimate a daily dose. Syngenta believes that the actual weight of workers in studies should have been used in the normalization process. The workers weighed substantially more than the default 70 kg. Using the actual weights will result in larger margins of exposure ( MOE) for aerial mixers/ loaders handling both granular and liquid formulations.

RRB1' s Response: The March 3, 2000 ORE assessment ( D263662) calculated short and intermediate term MOEs using both actual body weight from the biomonitoring studies and the default value of 70 kg for comparison. Tables comparing the findings are on page 37 and 38 of 8 the assessment. While using the actual weights did result in larger MOEs, they still exceeded HED's level of concern ( short and intermediate term MOEs of 300 and 100, respectively), except for drivers and loaders wearing carbon coveralls. In addition, the actual mean weights of the men in the biomonitoring study loading granulars were so large ( 81 95 kg) that they are not representative of the population doing this activity.

Page 13  Concerning three biological monitoring scenarios, Syngenta says the conclusions on page 13 contradict page 3 and Tables 12 and 13 regarding short term MOEs > 300 and intermediate term MOE> 100 being below the Agency's level of concern.

RRB1' s Response: Without some more detailed information citing specific scenarios in Tables 12 and 13, RRB1 cannot respond to the comment at this time.

General Comments ° Syngenta will be phasing out Ordram 15G at the end of 2002; only Ordram 15GM will be manufactured after that.

° Ordram is no longer available in 50 lb bags. Ordram 15G comes in 500 and 1200 lb bulk bags. Ordram 15GM is available in 500 and 1500 lb bags.

° Liquid applications of Ordram 8E and Arrosolo by air are prohibited in CA. The only use for liquid formulations in CA is via chemigation.

° It is now rare for aerial applicators to use flaggers. Therefore, Syngenta thinks the flagger exposures should be removed from the risk assessment.

RRB1' s Response: As long as products are currently registered, they will be included in the risk asssessment. RRB1 acknowledges that Global Positioning Systems ( GPS) are commonly used for aerial application; however, flaggers are still used in some locations.

MARC Memorandum on Water Degradates ( November 3, 2000)

The MARC concluded that all degradates with an intact thiocarbamate moiety should be included in the drinking water risk assessment. Syngenta argues that molinate sulfone has not been found in any of the soil or water metabolism studies. It is also unstable and therefore not appropriate for monitoring. Syngenta assumes that the reference to the 2 hydroxy molinate is the side chain hydroxy degradate identified in the anerobic aquatic metabolism study. This degradate was only found at very low levels and only detected at three time points in the study. It is a transition product and undergoes oxidation to form molinate acid which is found at higher levels. In any surface water monitoring, Syngenta proposes monitoring for molinate sulfoxide, 3 keto and 4 keto molinate, 3 hydroxy and 4 hydroxy molinate, molinate acid and S ethyl 5 carboxypentyl thiocarbamate. 9 RRB1' s Response: These comments were addressed in the October 7, 2002 Memorandum ( D284308) from James Breithaupt, Environmental Fate and Effects Division ( EFED). EFED agrees that monitoring for minor metabolites or unstable transition products will not provide useful information on the extent of exposure to total toxic molinate residues in drinking water. It would be more productive to focus on residues of molinate sulfoxide, 3 and 4 keto molinate, 3 and 4 hydroxy molinate, molinate acid ( carboxymethyl molinate), and S ethyl 5 carboxypentyl thiocarbamate in drinking water.

Mechanism of Toxicity SARC Report These arguments will be considered when the registrant submits comments on the January 6, 2002 HED review titled " Molinate  review of the Registrant's Response to the Assessment of Molinate by the Mechanism of Toxicity SARC".

Revised Drinking Water Assessment EPA recommended that Syngenta collects monitoring data for the parent and all residues in the tolerance at locations with estimated concentrations that are similar to Drinking Water Level of Comparisons. Syngenta agrees to collect monitoring data from water treatment plants measuring the metabolites proposed under the MARC section of this review. However, they reserve the right to not conduct the studies if the toxicology endpoints change so that the need to conduct the study is negated.

RRB1' s Response: The toxicology endpoints have not changed. The October 7, 2002 Memorandum ( D284308) from James Breithaupt, EFED, recommends that a monitoring protocol be developed and submitted to the Agency prior to initiation. EFED also recommends that any monitoring protocol be submitted to the appropriate personnel at Sacramento and West Sacramento for their comment.

Product and Residue Chemistry A separate Memorandum from Christine Olinger to Wilhelmena Livingston dated September 5, 2002 ( D284879), with addendum dated November 6, 2002, addresses the product and residue chemistry comments. All of the outstanding product chemistry requirements have been satisfied, except for the studies on stability to metals and metal ions ( GLN 830.6313) and UV/ visible absorption ( GLN 830.7050).

2) USA Rice Federation This submission contains the following papers which has been previously submitted under DP Barcode D266985:

° Analysis of Carcinogenic Potential of Molinate dated May 31, 2000 10 ° Molinate Does Not Cause Delayed Neurotoxicity dated May 31, 2000 Also included is a previously submitted paper on worker risk and one on environmental fate and effects of molinate in the rice belt.

RRB1' s Response: These papers were considered when comparing the HED and California EPA risk assessments ( D272593; February 7, 2001) and in revising the Human Health Risk Assessment ( January 9, 2001).

3) CA Rice Commission ( CRC) dated May 31, 2002 Developmental Toxicity The CRC makes some of the same arguments as the registrant, including: 1) the NOAEL in the rat developmental study should be 35 mg/ kg/ day, not 2.2 mg/ kg/ day; 2) in the developmental neurotoxicity study, the changes in brain morphometrics and decreased startle response at 6.9 mg/ kg/ day in pups are transient and unlikely to be of biological significance ( HED concluded that the LOAEL was 1.8 mg/ kg/ day based on changes in startle response); 3) in the developmental neurotoxicity study, it cannot be concluded that offspring are more susceptible than dams because the two were not compared using the same endpoints ( i. e., startle amplitude and brain morphometrics).

Toxicology Paper  " Comments on Selected Toxicology Issues Relating to the U. S. EPA's Reregistration Eligibility Evaluation of Molinate", dated May 19, 2000.

Review of Developmental and Reproduction Studies  CRC has submitted their rebuttals to HED's conclusions on various developmental and reproduction studies.

Other Reviews  " Further Comments on Reproduction Toxicity of Molinate", dated May 25, 2002, includes detailed reviews of multiple studies prepared by Dr. Chris Wilkinson of Jellinek, Schwartz & Connolly, Inc. Dr. Wilkinson's arguments on the following are identical to those of the registrant: endpoints of the developmental studies and the developmental neurotoxicity study; the lack of a need for a 10x FQPA Safety Factor; rodent specific reproductive toxicity ; and a mechanism of reproductive toxicity in rodents that is consonant with the current state of science.

" Comments on the Reproductive Toxicity of Molinate", dated November 5, 2000, was also prepared by Dr. Wilkinson.

Literature Articles Included are two literature articles on the mechanism of molinate's reproductive toxicity which were previously reviewed by HED along with a manuscript prepared for publication.

Summary of Research Projects  A summary of the projects sponsored by the CRC 1995 through 11 2000 is submitted.

Benefits Information  Information on benefits of molinate to US and CA rice production is submitted.

RRB1' s Response: All of the above, except for the paper titled " Further Comments on Reproduction Toxicity of Molinate", May 25, 2002, have been previously submitted and considered by RRB1. OPP is awaiting the results of a mechanistic study in primates conducted by Dr. Marion Miller and supported by the CRC. The mechanism of reproductive toxicity and the relevance to humans will be reevaluated based on the data from this study.

4) Pesticide Action Network The Pesticide Action Network submitted comments concerning the failure to consider exposure to molinate via inhalation. These comments have been considered in a separate Memorandum from Jeff Dawson to Wilhelmena Livingston dated August 22, 2002 ( D284305). HUMAN HEALTH RISK ASSESSMENT Molinate U. S. Enviro nmental Protection Agency Office of Pesticide Programs Health Effects Division ( 7509C) Virginia A. Dobozy, VMD, MPH, Risk Assessor Revision Date: November 6, 2002 2 TABLE OF CONTENTS 1.0 Executive Summary 4 2.0 Physical/ Chemical Properties Characterization 8 3.0 Hazard Characterization 3.1 Hazard Profile 9 3.2 FQPA Considerations 11 3.3 Dose Response Assessment and Hazard Endpoint Selection 12 4.0 Exposure Assessment 4.1 Summary of Registered Uses 15 4.2 Dietary Exposure 4.2.1 Food Exposure 15 4.2.2. Water Exposure 18 4.3 Occupational Exposure 4.3.1 Handler 26 4.3.2 Postapplication 31 4.4 Residential Exposure 31 4.5 Epidemiology Data 32 4.6 Incident Data 35 5.0 Aggregate Risk Assessment and Risk Characterization 37 6.0 Data Needs 40 3 APPENDIX Table 1: Toxicology Profile of Molinate 42 Table 2: Exposure and Risk Assessment for Workers Loading Granulars into Airplane Hoppers from Biomonitoring Study 48 Table 3: Exposure and Risk Assessment for Workers Loading Liquids into Airplane Hoppers from Biomonitoring Study 49 Table 4: Numerical Inputs from PHED Version 1.1 Used for Molinate Handler Exposure Assessment 51 Table 5: Non cancer Risks For Occupational Molinate Handlers at Baseline Clothing Scenario ( Unit Exposures from PHED) 54 Table 6: Non cancer Risks For Occupational Molinate Handlers Using Additional Protective Clothing and PPE to Mitigate Exposures ( Unit Exposures from PHED) 56 Table 7: Non cancer Risks For Occupational Molinate Handlers Using Engineering Controls to Mitigate Exposures ( Unit Exposures from PHED 58 4 1.0 EXECUTIVE SUMMARY The Health Effects Division ( HED) of EPA's Office of Pesticide Programs has evaluated the molinate data base and conducted a human health risk assessment for the reregistration of the chemical. Molinate is a list B reregistration chemical. It was the subject of a Phase 4 Review dated February 21, 1991. Risk reduction mitigation occurred in 1996 because of concern about the health risks of workers exposed to molinate. Beginning with the 1997 growing season, the use of activated carbon impregnated body suits was required. In addition, the amount of emulsifiable concentrate used by workers in a single growing season was restricted.

Molinate ( s ethyl hexahydro 1H azepine 1 carbothiate) is a herbicide registered for use primarily for the control of watergrass in rice. Rice is grown in California and the south central/ south eastern states of Arkansas, Louisiana, Missouri, Texas and Tennessee. There are four active enduse products ( EPs) with food/ feed uses registered to Zeneca Ag Products under the trade names Ordram ® or Arrosolo ® ( combination of molinate and propanil). Emulsifiable concentrate ( 33.1% 90.9% a. i.) and granular ( 15% a. i.) formulations may be applied to rice preemergence and/ or postemergence using ground and aerial equipment. Another registrant, RICECO, recently registered a molinate technical and two end use products, a granular ( 15% a. i.) and an emulsifiable concentrate ( combination of molinate and propanil) formulation.

Tolerances are presently established ( 40 CFR § 180.228) for residues of molinate per se in/ on rice and rice straw each at 0.1 ppm. However, HED is recommending that the tolerances for residues in/ on rice grain be increased to 0.75 ppm. The tolerances for residues in/ on rice straw should be increased to 7.0 ppm. Tolerances for hulls and bran processed from molinate treated rice grain should be 3.0 and 2.0 ppm, respectively. HED is also recommending that residues to be regulated in plants include molinate and its metabolites 4 hydroxy molinate and molinate acid. Residues of molinate and its metabolites of concern are not expected to transfer to edible livestock commodities at the maximum dietary burden based on current uses.

Molinate is a thiocarbamate. In general, thiocarbamates are less potent cholinesterase ( ChE) inhibitors than other carbamates. Multiple studies in various species indicate that molinate produces ChE inhibition ( plasma, red blood cell and brain) via multiple routes of exposure. Molinate also inhibits neurotoxic esterase ( NTE) and is positive for delayed neurotoxicity in the hen. The findings in multiple studies demonstrate that molinate is a neurotoxin after single and multiple doses via the oral, dermal and inhalation routes of exposure and across species ( rat, dog, mouse). In neurotoxicity studies of varying durations, clinical signs indicative of nervous system effects, ChE and NTE inhibition and neuropathology were observed. In the subchronic neurotoxicity study, the Lowest Observed Adverse Effect Level ( LOAEL) was 4.0 mg/ kg/ day in males and 4.5 mg/ kg/ day in females based on decreased red blood cell and brain cholinesterase and neurotoxic esterase in both sexes; a No Observed Adverse Effect Level ( NOAEL) was not established.

In the developmental neurotoxicity study, pups born to molinate treated dams exhibited 5 treatment related functional and anatomical nervous system effects. Evidence of reproductive toxicity was found in studies in rats, mice, rabbits and dogs; however, the male rat appeared to be the most sensitive species/ sex. A wide range of male reproductive parameters have been altered adversely in the studies with both oral and inhalation exposures, including testes weight, sperm number and morphology, fertility and testicular histopathology. Reproduction studies in both rats and mice demonstrated treatment related effects on fertility and gestation. In a special five week fertility study, a dose of 0.5 mg/ kg/ day in males produced adverse effects on sperm parameters; a NOAEL was not established. There was also evidence that molinate causes increased sensitivity to offspring following prenatal exposure in rats.

Special mechanistic studies have been conducted to demonstrate a proposed mechanism of toxicity for the male reproductive effects. The registrant position's is that the reproductive effects of molinate require the production of molinate sulfoxide and the dependence of the enzyme cholesterol ester hydrolase for steroid sex hormone production. The registrant also concludes this mechanism is specific to rodents and not relevant to humans. The currently available mechanistic studies have been reviewed by the HED Mechanism of Toxicity Assessment Review Committee, which concluded that the data are not adequate to demonstrate the proposed mechanism. Some of the reasons for this conclusion include the following: lack of concordance between dose levels where effects on testosterone and precursor hormone levels are observed and dose levels where fertility/ sperm effects are observed; lack of data to show that sulfoxidation is occurring at the dose levels where fertility/ sperm effects are observed in the rat; and lack of data demonstrating an inhibition of n CEH in vivo at dose levels where fertility/ sperm effects occur.

In the rat combined chronic toxicity/ carcinogenicity study, there was an increase in kidney tumors in males at the high dose level. Molinate was reviewed by the HED Cancer Assessment Review Committee ( CARC) on November 1, 2000, and based on the kidney tumors, was classified as Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential using the 1999 draft Guidelines for Carcinogen Risk Assessment. Dose response assessments are not recommended for chemicals in this classification.

Molinate was negative in a Salmonella tymphimurium assay and for aberrations in cultured human lymphocytes. Because suggestive increases were found for mutations, aberrations, and sister chromatid exchange [ SCE] in mouse lymphoma cells, and there was conflicting data in two mouse micronucleus assays, a dominant lethal test was requested. Subsequently, molinate was shown to be negative in this assay.

The metabolism data indicate that molinate is well absorbed and extensively metabolized following both oral and intravenous exposure and is rapidly excreted, mainly in the urine. Data indicate that the metabolism of molinate in mammals is primarily via three routes: carbon oxidation, sulfur oxidation, and thiocarbamate cleavage. The data also suggest that carbon oxidation predominates at low doses and sulfur oxidation at high doses of molinate in both rodents and humans. It is not known at what dose level the predominate pathway becomes saturated. The only toxicology studies with any metabolites are mechanistic studies conducted to 6 demonstrate the mechanism of molinate toxicity on the male reproductive system. Based on a study in the rat with radiolabeled molinate, dermal absorption was determined to be 40%.

The 10x FQPA Safety Factor has been retained based on the following: increased fetal susceptibility observed in the prenatal developmental study in rats; increased fetal susceptibility in the developmental neurotoxicity study in rats; reproductive effects in mice and rats; and uncertainty associated with the molinate surface water exposure in some rice growing areas.

The toxicology profile for molinate is presented in Table 1 of the Appendix.

The results of the acute and chronic dietary assessments showed that, for all population subgroups ( general population, females 13 50, infants < 1 year, children 1 6 years and children 7 12 years), risk estimates were below HED's level of concern [< 100% of the Population Adjusted Dose ( PAD)]. The most highly exposed subgroup was infants (< 1 year) for both assessments consuming 18% of the chronic PAD ( cPAD) and 21% of the acute PAD ( aPAD) at the 95th percentile of exposure. Even at the 99.9th percentile, the acute risk estimate was approximately 55% of the aPAD.

Exposure to molinate in drinking water is based on monitoring data in rice growing areas where the chemical is used. Raw water data were used for exposure to ground and surface water for risk assessment purposes. The exposure values were increased by a factor of 1.56 to account for the lack of analyses for molinate metabolites in the monitoring studies.

Aggregate risk assessments using percentage of the PAD calculations were quantitated for dietary exposure to food and water ( ground and surface water) for three separate subpopulations ( adult males, adult females and children) for acute and chronic exposures. There are no residential uses to be considered in this aggregate assessment. The aggregate risk assessment of acute exposure to food and surface water in children ( 110% of the aPAD) exceeded HED's level of concern (> 100% of aPAD). However, HED thinks that this assessment may overestimate the risk and that refinement of either the food or water exposure may bring the risks into an acceptable range. The anticipated residues in food were based on field trial residues. Monitoring studies closer to the point of consumption or cooking studies would refine exposure.

HED has determined that there is a potential for exposure from handling molinate products during the application process ( i. e., mixer/ loaders, applicators, flaggers, mixer/ loader/ applicators) and from entering agricultural areas previously treated with molinate. Occupational postapplication exposures, however, are expected to be minimal because of the nature of the activities associated with rice cultivation ( e. g., scouting and water management) and the protective equipment that is commonly used during these activities ( e. g., waterproof rubber boots for walking through rice paddies). The exposure and risk for three mixer/ loader scenarios were assessed using biomonitoring exposure data. The exposure and risk of another eight scenarios involving mixing/ loading, flagging and applying granular and liquid formulations using aerial and groundbased equipment were assessed using PHED data. The short term and intermediate term risks 7 were calculated using the biomonitoring data.

With the PHED data, individual short and intermediate term dermal and inhalation risks were calculated and then combined. HED determined that the dermal and inhalation exposures could be combined due to the common endpoints for short term ( neurotoxicity) and intermediate term ( reproductive effects) exposures. Assessing short term and intermediate term exposure using biomonitoring data, the risks exceeded the Agency's level of concern for liquid and granular mixer/ loaders at the baseline level of personal protective equipment ( PPE) and for additional PPE. Assessing short term dermal risks using PHED data, risks exceeded the Agency's level of concern for all eight scenarios at the baseline level of personal PPE and for additional PPE. With engineering controls, the risks still exceeded the level of concern for five of the scenarios. Shortterm inhalation risks using PHED data did not exceed the level of concern for the eight scenarios at the baseline level of PPE. When the short term dermal and inhalation exposures and risks were combined, the risks exceeded the level of concern for all scenarios at the baseline level and when additional protective clothing/ PPE were added. When engineering controls were added, the risks still exceeded the level of concern for pilots applying granular and liquid formulations and for handlers mixing/ loading liquids for ground based application and applying liquids using groundbased equipment.

Intermediate term dermal risks data estimated for eight handler scenarios using PHED data all exceeded the Agency's level of concern at the baseline clothing and additional levels of PPE. With the addition of engineering controls, the risks of six scenarios still exceeded the level of concern. Intermediate term inhalation MOEs all exceeded the level of concern at the baseline PPE level. The addition of a full face respirator resulted in intermediate term inhalation risks above the level of concern for all the scenarios. Risks for pilots applying liquids and granulars were only assessed with engineering controls; both exceeded the Agency's level of concern. When intermediate term dermal and inhalation risks were combined, the risks exceeded the Agency's level of concern for all scenarios at baseline and with added protective clothing/ PPE. When engineering controls are added, the risks still exceed the level of concern for pilots applying both granular and liquid formulations and for handlers applying both granular and liquid formulations using ground based equipment and for handlers mixing/ loading liquids for ground based application.

The toxicology data base is adequate, except the 21 day dermal toxicity study and the acute neurotoxicity study were both unacceptable and not upgradeable. Repeating these studies would complete the data requirements; however, the results may not alter the endpoints and doses selected for risk assessment. Outstanding residue chemistry studies include a multiresidue method testing for molinate, 4 hydroxy molinate and molinate acid. A waiver from conducting a crop irrigation study ( GLN 860.1400) has been granted. Outstanding product chemistry requirements are detailed in the October 28, 1999 Product and Residue Chemistry Chapter and updated in a September 5, 2002 Memorandum, with addendum dated November 6, 2002, from Christine Olinger to Wilhelmena Livingston ( D284879). 8 N S O CH 3 N S O CH 3 O H N S O OH O 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION Molinate [ S ethyl hexahydro 1H azepine 1 carbothioate] is a selective thiocarbamate herbicide. The chemical name and structures of molinate and its metabolites of concern are depicted in Figure A.

Figure A. Chemical names and molecular structures of molinate and its metabolites of concern in plants.

Chemical Name Common Name Structure s ethyl hexahydro 1H azepine 1 carbothioate Molinate s ethyl hexahydro 4 hydroxy 1H azepine 1 carbothioate 4 Hydroxy molinate s( carboxymethyl) hexahydro 1H azepine 1 carbothioate Molinate acid 9 A. Physical Properties of Molinate Physical state: Liquid Boiling point: 136.50C at 10 torr Solubility: soluble in water at 970 mg/ L at 250C, miscible with acetone, chlorobenzene, ethanol, kerosene, n octanol and xylenes Vapor pressure: 5.3 X 10 3mm Hg at 250C Specific gravity: 1.0663 at 200C Octanol/ water partition coefficient ( K ow): 756 at 250C B. Other Identifying Characteristics and Codes for Molinate Empirical Formula: C9H17NOS Molecular Weight: 187.3 CAS Registry No.: 2212 67 1 Shaughnessy No.: 041402 3.0 HAZARD CHARACTERIZATION 3.1 Hazard Profile The Toxicology Chapter of the RED was prepared by Dr. Linda Taylor ( D249717 dated January 4, 1999). Molinate is a thiocarbamate. In general, thiocarbamates are less potent cholinesterase ( ChE) inhibitors than other carbamates. Multiple studies in various species indicate that molinate produces ChE inhibition ( plasma, red blood cell and brain) via multiple routes of exposure. Molinate also inhibits neurotoxic esterase ( NTE) and is positive for delayed neurotoxicity in the hen. In addition, molinate is a reproductive and developmental toxicant and a suggestive human carcinogen.

The toxicological data base on molinate is adequate, except the 21 day dermal toxicity study and the acute neurotoxicity study were both unacceptable and not upgradeable. Repeating these studies would complete the data requirements; however, the results may not alter the endpoints and doses selected for risk assessment. The existing data base supports reregistration eligibility. The quality of the data from the toxicology studies is generally good; however, a NOAEL was not established in several guideline studies, including the subchronic inhalation study, 21 day dermal toxicity study ( systemic effects), chronic dog study, combined chronic toxicity/ carcinogenicity study in the rat and reproduction study ( brain weight effect). In general, molinate was not acutely toxic via the oral, dermal, and inhalation routes of exposure in the acute studies required for labeling. It was a mild skin and a moderate eye irritant, but not a dermal 1The hen study ( MRIDs 00133562 and 43136601) was evaluated by Dr. Karl Jensen, a neurotoxicologist at EPA's National Health and Environmental Effects Research Laboratory ( NHEERL). He concluded that molinate produces delayed neurotoxicity in the hen.

10 sensitizer. Molinate produced delayed neurotoxicity in the hen [ axonal degeneration]. 1 Acute and subchronic neurotoxicity studies in the rat demonstrated adverse effects of molinate on motor activity and various functional observational battery [ FOB] measurements, in addition to cholinesterase and neurotoxic esterase [ NTE] activity inhibition. In the subchronic neurotoxicity study, the Lowest Observed Adverse Effect Level ( LOAEL) was 4.0 mg/ kg/ day in males and 4.5 mg/ kg/ day in females based on decreased red blood cell and brain cholinesterase and neurotoxic esterase in both sexes; a No Observed Adverse Effect Level ( NOAEL) was not established. The subchronic and chronic toxicity studies demonstrated that molinate inhibits cholinesterase activity in plasma, red blood cell [ RBC], and brain in rats, dogs, monkeys, and rabbits in a doseresponsive manner. Clinical signs associated with cholinesterase activity inhibition were observed and included ataxia, tremors, salivation, reduced motor activity, splayed/ adducted hindlimbs, and abnormal gait.

Delayed fetal development was observed in the rabbit at the same dose level where maternal toxicity was observed. In the rat, developmental toxicity/ developmental neurotoxicity were observed [ increase in runting/ reduction in startle amplitude] at dose levels below the maternal NOAEL. Molinate is a reproductive toxicant, and the rat is the most sensitive species for this effect. Abnormal sperm, decreased percent motile sperm, decreased sperm numbers, decreased litter size, decreased percentage of pups born live, decreased pup viability, increased incidence of microscopic lesions in the ovary, testes, and adrenal, delayed vaginal opening, reproductive organ weight effects, and decreased brain weight were consistent findings in studies in the rat. In a special five week fertility study, a dose of 0.5 mg/ kg/ day in males produced adverse effects on sperm parameters; a NOAEL was not established.

It is the registrant's position that the reproductive effect of molinate " requires the production of molinate sulfoxide and the dependence on the enzyme cholesterol ester hydrolase ( CEH) for steroid sex hormone production." Additionally, the registrant concludes that the reproductive toxicity in the rat is induced by a mechanism that is specific to rodents. Special studies data submitted to establish the proposed mechanism of toxicity were reviewed and evaluated by the HED Mechanism of Toxicity Assessment Review Committee. The Committee concluded that the submitted studies are not adequate to demonstrate the proposed mechanism of toxicity. The details of the reasons for the Committee's conclusions are included in the memorandum of that meeting. Some of the reasons include the following: lack of concordance between dose levels where effects on testosterone and precursor hormone levels are observed and dose levels where fertility/ sperm effects are observed; lack of data to show that sulfoxidation is occurring at the dose levels where fertility/ sperm effects are observed in the rat; and lack of data demonstrating an inhibition of n CEH in vivo at dose levels where fertility/ sperm effects occur.

In the rat combined chronic toxicity/ carcinogenicity study, there was an increase in kidney tumors 11 in males at the high dose level. Molinate was reviewed by the HED Cancer Assessment Review Committee on November 1, 2000 and, based on the kidney tumors, was classified as Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential using the EPA's 1999 draft Guidelines for Carcinogen Risk Assessment. Dose response assessments are not recommended for chemicals in this classification. ( See December 14, 2000 CARC report.)

Molinate was negative in a Salmonella tymphimurium assay and for aberrations in cultured human lymphocytes. Because suggestive increases were found for mutations, aberrations, and sister chromatid exchange [ SCE] in mouse lymphoma cells, and there were conflicting data in two mouse micronucleus assays, a dominant lethal test was requested. Subsequently, molinate was shown to be negative in this assay.

The metabolism data indicate that molinate is well absorbed and extensively metabolized following both oral and intravenous exposure and is rapidly excreted, mainly in the urine. The data also indicate that the metabolism of molinate involves s oxidation to form the intermediate molinate sulfoxide, which is either hydrolyzed to hexamethyleneimine or conjugated with glutathione, ultimately forming molinate mercapturic acid; ring hydroxylation at the 3 and 4 positions followed by glucuronide conjugation is also a significant route of metabolism. More recent information indicates that the metabolism of molinate in mammals is primarily via three routes: carbon oxidation, sulfur oxidation, and thiocarbamate cleavage, and the proportion of metabolism through each of these pathways varies among the species, including man. The data also suggests that carbon oxidation predominates at low doses of molinate, and this pathway saturates on increasing dose. Then the metabolism switches to sulfur oxidation. It is not known at what dose level the predominate pathway becomes saturated. Based on a study in the rat with radiolabeled molinate, dermal absorption was determined to be 40%.

The toxicology profile for molinate is presented in Table 1 of the Appendix.

3.2 FQPA Considerations There is evidence of neurotoxicity in multiple studies with several species. Increased susceptibility of offspring was observed in the prenatal developmental toxicity study and the developmental neurotoxicity study in rats. The HED FQPA Safety Factor Committee evaluated the hazard and exposure data for molinate as the bases for making a recommendation on the magnitude of the FQPA Safety Factor. The FQPA Safety Factor Committee recommendation in the December 17, 1998 report of the October 30, 1998 meeting was that the FQPA Safety Factor be retained at 10X for molinate. The rationale for the retention of the 10X is:

$ Increased susceptibility observed in the prenatal developmental toxicity study in rats.

° Increased susceptibility observed in the developmental neurotoxicity study in rats.

$ Reproductive effects were seen in mice ( anti fertility study) and rats ( sperm 12 morphology study) following oral administration ( although there was no evidence of increased susceptibility in the 2 generation reproduction study).

$ Uncertainty associated with the lack of characterization for the surface water monitoring data used for drinking water exposure assessments. The environmental fate data base indicates that the parent molinate is persistent and expected to reach surface water. Monitoring data are available, however there is a lack of characterization of the exposure levels for localities downstream of rice fields in the Southeast.

The Committee determined that the 10x FQPA safety factor is applicable for the following:

Acute Dietary Assessment: The Committee determined that the FQPA Safety Factor should be retained ( 10x) for acute dietary risk assessment because the increased susceptibility was demonstrated in both the prenatal developmental toxicity and developmental neurotoxicity studies.

Chronic Dietary Assessment: The Committee determined that the FQPA Safety Factor should be retained ( 10x) for chronic dietary risk assessment because of the concern for the severe reproductive effects seen following repeated oral exposures in studies with rats and mice.

For dietary risk assessments, the target exposure level above which risk is considered to be of concern is referred to as the Population Adjusted Dose ( PAD). An acute PAD ( aPAD) and a chronic PAD ( cPAD) are calculated by dividing the respective acute and chronic RfDs ( aRfD and cRfD) by the FQPA Safety Factor ( see Table 2).

3.3 Dose Response Assessment and Hazard Endpoint Selection On October 1 and 7, 1998, the Health Effects Division's Hazard Identification Assessment Review Committee ( HIARC) evaluated the toxicology database for molinate, re assessed the existing reference dose, and selected the doses and toxicological endpoints for dietary and nondietary exposure risk assessments. Table 1 contains the acute toxicity endpoints, which are especially important for labeling purposes. Table 2 contains a summary of the doses and endpoints selected for use in the various human health risk assessments. 13 Table 1: Acute Toxicity of Molinate Guideline No. Study Type MRIDs # Results Toxicity Category 81 1 870.1100 Acute Oral  rat 40593301 LD50 = 730 mg/ kg ( 679 785) Males = 700 mg/ kg ( 620 791) Females III 81 2 870.1200 Acute Dermal  rabbit 40593301 LD50 > 2000 mg/ kg III 81 3 870.1300 Acute Inhalation  rat 00245675 LC50 = 2.9 mg/ L ( 2.5 3.3) Males = 2.4 mg/ L ( 2.2 2.6) Females IV 81 4 870.2400 Primary Eye Irritation 40593301 moderate irritant II 81 5 870.2500 Primary Skin Irritation 00247547 mild dermal irritant IV 81 6 870.2600 Dermal Sensitization 40593302 Negative 81 7 870.6100 Acute Delayed Neurotoxicity ( Hen) 00133562 43136601 NOAEL = 0.2 g/ kg, based on axonal degeneration in brain and cervical spinal cord; delayed neurotoxicant. N/ A 81 8 870.6200 Acute Neurotoxicity  rat 43188001

motor activity,  time to tail flick; NTE, ChE, GFAP activities were not assessed at appropriate times N/ A Unacceptable 14 Table 2: SUMMARY OF TOXICOLOGY ENDPOINT SELECTION EXPOSURE SCENARIO DOSE ( mg/ kg/ day) ENDPOINT STUDY Acute Dietary LOAEL = 1.8 Developmental neurotoxic effect ( reduction in startle amplitude) Developmental Neurotoxicity UF = 300 Acute RfD = 0.006 mg/ kg Acute PAD = 0.0006 mg/ kg Chronic Dietary non carcinogenic effects LOAEL= 0.3 Degeneration/ demyelination in sciatic nerve and atrophy/ reserve cell hyperplasia of muscle Rat Chronic Toxicity/ Carcinogenicity UF= 300 Chronic RfD = 0.001 mg/ kg/ day Chronic PAD = 0.0001 mg/ kg/ day Short Term* ( Dermal) Oral LOAEL = 1.8 Developmental neurotoxic effect ( reduction in startle amplitude) Developmental Neurotoxicity Intermediate Term* ( Dermal) Oral NOAEL = 0.2a Reproductive effects including decrease in following: % viable sperm, % motile sperm, % normal sperm, sperm counts, number of implants, number of viable fetuses; increase in implantation loss 5 week rat fertility Long Term ( Dermal / Non cancer) None The use pattern ( 1 2 applications per season to rice) does not indicate potential long term dermal exposure; risk assessment is NOT required.

Short Term ( Inhalation) NOAEL = 0.12 mg/ L Hindleg muscle weakness Acute inhalation  rat Intermediate Term ( Inhalation) NOAEL = 0.0003 mg/ mL Reproductive effects including decreased number of implants and increased % of abnormal sperm 4 week inhalation  rat Long Term ( Inhalation) None The use pattern ( 1 2 applications per season to rice) does not indicate potential long term inhalation exposure; risk assessment is NOT required.

* = Since an oral LOAEL was selected a dermal absorption factor of 40% should be used for dermal risk assessments. a Actual dose was 0.26 mg/ kg/ day; 0.2 mg/ kg/ day was the target dose.

NOTE: For Short term dermal risk assessments, an MOE of 300 is required because a NOAEL was not achieved in the developmental neurotoxicity study; an MOE of 100 is adequate for all other exposure ( dermal and inhalation) risks. 2Two Zenca products, Ordram 6E and Ordram 10 G, were recently canceled ( Federal Register, September 6, 2000, Volume 67, Number 173, page 54113 54128). The cancellation order permits the registrant to continue to sell and distribute existing stocks of the canceled products until January 15, 2001. Existing stocks already in the hands of dealers or users can generally be distributed, sold or used legally until they are exhausted.

3 Molinate Use Closure Memo from Lois Rossi to Margaret Stasikowski summarizing September 23, 1998 SMART meeting with registrant.

15 4.0 EXPOSURE ASSESSMENT 4.1 Summary of Registered Uses Molinate is currently registered for use on rice for grass weed control, including barnyard grass, springletop and broadleaf grass, as well as flatsedge, dayflower and other small seed broadleaf weeds. There are four active end use products ( EPs) with food/ feed uses registered to Zeneca Ag Products under the trade names Ordram ® or Arrosolo ® ( combination of molinate and propanil). 2 Emulsifiable concentrate ( 33.1% 90.9% a. i.) and granular ( 15% a. i.) formulations may be applied to rice preemergence and/ or postemergence using ground and aerial equipment. Another registrant, RICECO, recently registered a molinate technical and two end use products, a granular ( 15% a. i.) and an emulsifiable concentrate ( combination of molinate and propanil) formulation. Molinate products can be used at various intervals in rice production. The maximum per season application rate range is 6 to 9 lbs a. i./ acre. Products may be applied two to three times per growing season. 3 In the southern states, usual planting times typically range from early to mid April through late May. In California, most planting is completed during May.

4.2 Dietary Exposure 4.2.1 Food Exposure The Product and Residue Chemistry Chapter of the RED was prepared by Christine Olinger ( DP Barcode: D249755, dated October 28, 1999). The Acute and Chronic Dietary Exposure Risk Analyses were completed by Felicia Fort ( D262577 dated February 9, 2000).

Molinate Residues Most residue chemistry guideline studies have been submitted. All that are necessary for dietary exposure assessment are available. Tolerances are currently established for residues of molinate per se ( 40 CFR § 180.228). The HED Metabolism Committee ( Memoranda dated March 2, 1994 and April 25, 1994 from Christine Olinger) has determined that the residues to be regulated in plant commodities are molinate and the metabolites 4 hydroxy 16 molinate and molinate acid. Therefore, the tolerance definition in 40 CFR § 180.228 should be amended to include all residues to be regulated.

Sufficient data are available to ascertain the adequacy of the established tolerances for molinate residues in/ on rice grain and rice straw. The tolerance for residues in/ on rice grain should be increased to 0.75 ppm based on combined residues of < 0.73 ppm in/ on grain from field trials. The tolerance for residues in/ on rice straw should be increased to 7.0 ppm based on combined residues of < 6.27 ppm in/ on straw from field trials. Molinate per se was < 0.05 ppm (< LOQ) in/ on rice grain and straw from all field trials.

An adequate processing study indicated that residues concentrated in hulls and bran processed from molinate treated rice grain; tolerances of 3.0 and 2.0 ppm, respectively, are required.

The livestock metabolism studies indicate that molinate residues of concern are not present in tissues, milk, or eggs from animals dosed with molinate at levels greater than the theoretical maximum dietary exposure. These diets are exaggerated and represent the maximum dietary exposure assuming all rice is treated and bears residues at the tolerance level. Tolerances for molinate residues in livestock commodities are not required based on current uses.

Studies which are outstanding include multiresidue method testing for molinate, 4 hydroxy molinate, and molinate acid. A waiver from conducting a crop irrigation study ( GLN860.1400) was granted ( September 5, 2002 Memorandum, D284879).

Anticipated Residues In a March 31, 1999 Memorandum, the Biological and Economic Analysis Division provided information on the percent of rice treated with molinate. Anticipated residues for chronic and acute dietary exposures were generated based on field trial data for the raw agricultural commodity, rice grain. Anticipated residues generated from the grain are adjusted by a processing factor and include the combined residues of molinate, 4 hydroxy molinate, and molinate acid. USDA and FDA monitoring data are not available for molinate. Rice and its food forms are all considered to be blended; therefore an average residue was used for both the chronic and acute assessments. Although an average concentration was used for the anticipated residue, it is a higher level than that to which the consumer is likely to be exposed, since the levels are based on field trial residues. A more refined value could be estimated if the registrant were to conduct monitoring studies closer to the point of consumption or if cooking studies were submitted. 17 Dietary Risk Assessment The doses and endpoints for dietary risk assessment selected by the HED Hazard Identification Assessment Review Committee ( HIARC) were discussed previously and are summarized in Table 2.

Also previously discussed ( section 3.2), the HED FQPA Safety Factor Committee determined that the FQPA Safety Factor should be retained ( 10x) for both chronic and acute dietary risk assessment for all populations ( B. Tarplee, 12/ 17/ 98).

HED conducts dietary risk assessments using the Dietary Exposure Evaluation Model ( DEEMTM) which incorporates consumption data generated in USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII), 1989 1992. For acute dietary risk assessments, one day consumption data are summed and a food consumption distribution is calculated for each population subgroup of interest. The consumption distribution was multiplied by a residue point estimate for a deterministic ( Tier # I/ II type) exposure/ risk assessment. Exposure estimates are expressed in mg/ kg bw/ day and as a percent of the aPAD. For chronic risk assessments, residue estimates for foods ( e. g. apples) or foodforms ( e. g. apple juice) of interest are multiplied by the averaged consumption estimate of each food/ food form of each population subgroup. Exposure estimates are expressed in mg/ kg/ bw/ day and as a percent of the cPAD.

The results of both the chronic and acute exposure assessments showed that for all population subgroups, risk estimates were below HED's level of concern (< 100% cPAD or aPAD). The most highly exposed subgroup was infants (< 1 year) for both assessments consuming 18% of the cPAD and 21% of the aPAD at the 95th percentile of exposure. Even at the 99.9th percentile, the acute risk estimate was approximately 55% of the aPAD. The dietary risk estimates are presented in Table 3. 18 Table 3. Dietary Risk Estimates for Molinate.

Population Subgroup Chronic Acute ( 95th % ile) Acute ( 99.9th % ile)

Exposure % cPAD Exposure % aPAD Exposure % aPAD U. S. Population 0.000005 5 0.000039 7 0.000186 31 All Infants (< 1 years) 0.000018 18 0.000128 21 0.000328 55 Children ( 1 6 years) 0.000010 10 0.000083 14 0.000249 42 Children ( 7 12 years) 0.000006 6 0.000049 8 0.000193 32 Females ( 13 50 years) 0.000004 4 0.000033 6 0.000152 25 aPAD = 0.0006mg/ kg, cPAd = 0.0001 mg/ kg/ day 4.2.2 Water Exposure The Drinking Water Assessment for molinate was prepared by James Breithaupt of the Environmental Fate and Effects Division ( EFED) ( DP Barcode D252252 dated February 16, 1999, D253406 dated March 17, 1999, D254562 dated April 2, 1999, D259945 dated January 13, 2000, D262859 dated February 8, 2000 and D271004 dated December 7, 2000). Potential exposure to molinate in the drinking water is limited to those ricegrowing regions where the chemical is used.

To obtain both ground and surface water concentrations for the purpose of risk assessment, EFED received monitoring data from the U. S. Geological Survey ( USGS), the State of Arkansas Department of Pollution Control and Ecology, the City of Sacramento, CA, the State of California Department of Environmental Regulation, and the State of Texas. EFED used monitoring data for the drinking water assessment since the data were available for the areas where molinate was applied except for Tennessee, where only 3,000 5,000 acres of rice were grown in Lake County. EFED has conducted a stateby state regional assessment since molinate was applied only in California and in the south central/ south eastern states of Arkansas, Louisiana, Missouri, Texas, and Tennessee. EFED has no official models to generate estimated environmental concentrations ( EECs) from aquatic crops.

The effect of water treatment appears to be an important factor in removing molinate from finished water. EFED has reviewed laboratory studies on the efficiency of parent molinate removal simulating the city of Sacramento's water treatment process. If chlorination is the only oxidant chemical used in treatment, up to 80% of molinate has been shown to remain after treatment as the metabolite molinate sulfoxide, which still has the carbamate functional group. Further degradation is likely to be achieved only if more effective oxidants are used ( e. g., ozone, chlorine dioxide, KMnO 4). Potassium permanganate ( KMnO 4) appears to be a more effective oxidant for molinate, since it degrades > 98 % of 4 Domagalski, J. Pesticides and Pesticide Degradation Products in Stormwater Runoff: Sacramento River Basin, California, Water Resources Bulletin, Volume 32, Issue 5, October, 1996, pp. 953 964 19 parent molinate to a non carbamate degradate. However, since the extent of use of stronger oxidants than chlorine is uncertain, EFED recommended using the raw water concentrations.

Adjustment of parent molinate concentrations in ground water and surface water for molinate degradates was necessary since there was no monitoring for any degradates with the exception of the photoproduct 4 keto molinate. At an October 31, 2000 meeting, the HED Metabolism Assessment Review Committee concluded that the following molinate metabolites and degradation products should be included in the water assessment: molinate sulfoxide, molinate sulfone, 3 keto and 4 keto molinate, hydroxy molinate ( 2, 3, and 4), molinate acid ( carboxymethyl molinate), and ring opened molinate ( S ethyl 5 carboxypentyl thiocarbamate). EFED re evaluated the molinate metabolites to be included in water monitoring studies and concluded that residues of molinate sulfoxide, 3 and 4 keto molinate, 3 and 4 hydroxy molinate, molinate acid ( carboxymethyl molinate), and Sethyl 5 carboxypentyl thiocarbamate in drinking water should be focused on in these studies ( D284308 dated October 7, 2002).

Calculation of a factor to account for the lack of monitoring data on the molinate metabolites/ degradation products was based on data from laboratory studies and aquatic field dissipation studies for dry seeded rice ( MRID 41421803) and water seeded rice ( MRID 41421804). The field studies provided data on molinate acid and molinate sulfoxide degradates relative to parent. The average percent of parent molinate was 9.4 % for dry seeded rice and 11 % for water seeded rice, leading to adjustment factors of 1.094 and 1.11, respectively. To account for 2, 3, and 4 hydroxy molinate, the estimated environmental concentrations ( EECs) were increased by another 14.7 % ( average percent observed in an aerobic aquatic metabolism laboratory study, MRID 44956603). The use of a laboratory study was necessary because no metabolites other than molinate acid and molinate sulfoxide were analyzed for in the aquatic field dissipation studies.

EFED used a recent publication of a study by Joseph Domagalski to recommend increasing molinate exposures by 30% to account for the amount of 4 keto molinate. 4 Monitoring was conducted in the Sacramento Basin below the confluence of the Colusa Drain and the Sacramento River to downstream of the City of Sacramento. The metabolite 4 keto molinate was detected at 10 30 % ( one detection of 50 %) of parent molinate in every sample where molinate was detected in surface water from storm water runoff. In the Southern region of the U. S., 4 keto molinate levels in water of 10 50 % of detected parent molinate have also been observed.

To adjust for all molinate metabolites and degradates, EFED recommended using a 1.56 20 adjustment factor for both California and the Southern Region for both surface and ground estimates of parent molinate.

Drinking Water from Ground Water For estimates of dietary exposure from ground water used as drinking water, EFED recommended the use of 0.056 ug/ L for acute and chronic assessment for parent molinate and 0.087 ug/ L for total toxic residues of molinate ( molinate plus metabolites). The 0.056 ug/ L concentration was the maximum observed in recent USGS monitoring data from both California and the Southern Region ( Mississippi and Arkansas). Some of the wells in which detections were observed were drinking water wells.

EFED did not run the SCI GROW2 ground water model because it is inappropriate for rice. SCI GROW2 assumes vulnerable soils with a shallow water table, but rice fields require impermeable layers to hold the floodwater. Also, SCI GROW2 does not directly take into account the volatility of a given compound.

Drinking Water from Surface Water Table 4 provides the estimates of drinking water exposure levels from parent molinate and the residues of toxic concern recommended by EFED for the aggregate risk assessments.

The surface water intakes with the highest exposure are Sacramento and West Sacramento. Maximum concentrations of parent molinate in these areas ranged from 1.52 2.13 ug/ L, and the annual mean concentrations ranged from 0.29 0.41 ug/ L. The intakes on the Mississippi and Atchafalaya Rivers in Louisiana had similar maximum parent molinate concentrations of 0.109 0.117 ug/ L and annual mean concentrations of 0.014 0.018 ug/ L. Arkansas, Mississippi, Missouri, and Tennessee have no surface water intakes in rice production areas, and therefore no exposure in drinking water from surface water. The only intake in Texas found to receive molinate residues was Anahuac. Maximum and annual mean concentrations of molinate were 0.073 and 0.0029 ug/ L, respectively. 21 Table 4. Monitoring estimated environmental concentrations ( EECs) for parent molinate and residues of concern that may be used for acute and chronic risk assessment for molinate+

Location ( Source of Data)

[ Population] Frequency of Detection ( Range of detection limits) Parent Molinate Adjustment Factor for degradates of concern2 Parent + degradates of concern ( See Table 3 below)

Maximum Concentration ( ug/ L) Annual Means ( ug/ L) 1 Maximum Concentration ( ug/ L) Annual Means ( ug/ L)

Sacramento, California ( Upper 95th percentile of parent molinate levels in raw water from the Sacramento River after holding periods ( 1991 2000 data), [ 374,600 people] 65/ 117 ( 0.1 ug/ L) 1.52 0.29 1.56 2.37 0.45 West Sacramento, California ( Upper 95th percentile of parent molinate levels in raw water from the Sacramento River after holding periods ( 1991 2000 data) adjusted for the percent flow data at City of Sacramento, [ 30,000 people] 3 65/ 117 ( 0.1 ug/ L) 2.13 0.41 1.56 3.32 0.64 Arkansas, Mississippi, Missouri, and Tennessee ( no surface water intakes in rice production areas) Not Applicable 0 0 1.56 0 0 New Orleans Area ( Upper 95th percentile of parent molinate levels in raw water from 1996 1999 USGS data in the Mississippi River at St.

Francisville, LA),

[ 1.21 million people] 4 13/ 58 ( 0.004 ug/ L) 0.117 0.014 1.56 0.18 0.022 22 St. Mary Parish, Louisiana Intakes at Atchafalaya River ( Upper 95th percentile of parent molinate levels in raw water from 1996 1999 USGS data at Melville, LA), [ 61,374 people] 4 15/ 57 ( 0.004 ug/ L) 0.109 0.018 1.56 0.17 0.028 Lake Anahuac in Texas, ( from dilution calculations) [ 1,960 people] 5 20/ 20 ( 0.004 ug/ L) 0.073 0.00296 1.56 0.114 0.0057 + Drinking water exposure estimates from surface water.

1 Time weighted annual mean concentrations were requested by the Health Effects Division.

2 Based on a meeting between EFED and the HED MARC committee, EFED calculated an adjustment factor of 1.56 for the parent molinate monitoring data to account for degradates of concern ( See EFED Chapter).

3 The City of West Sacramento gets all of its water from the Sacramento River, while the City of Sacramento gets 71.4 % of its water from the Sacramento River and 28.6 %

from the American River. EFED divided the Sacramento concentrations by 71.4 % to estimate concentrations for West Sacramento. Even though West Sacramento gets more molinate in their water, they do not get taste and odor complaints. The two cities are investigating this discrepancy.

4 The intakes below the USGS sampling points at St. Francisville in the Mississippi River and at Melville in the Atchafalaya River are at diluted portions, and both rivers are channelized. There are no significant downstream sources of water to dilute the residues further. As a result, EFED expects concentrations similar to the estimates at these intakes. The annual means using zero for non detections for 1996, 1998, and 1999 were at or below the limit of detection, while the means calculated using the limit of detection were above the limit of detection, indicating high uncertainty in these estimates for these locations.

5 White's Bayou drains rice fields directly into Lake Anahuac, a drinking water supply for 1,960 people. However, there are other sources of water for this intake and EFED does not know the exact proportions. Also, rice production along White's Bayou has declined by approximately two thirds since the year the data were generated ( 1994).

6 These estimates have additional uncertainty because it is below the lowest detection limit of 0.004 ug/ L. 23 Assumptions, Certainties, Uncertainties, and Limitations 1) Water Treatment EFED assumed that drinking water facilities use only chlorination as an oxidative process, and therefore 80 % of parent molinate present in raw water would still be present as molinate sulfoxide after treatment. Potassium permanganate may be a more effective oxidant for molinate as it degraded > 98% of parent molinate to a non carbamate degradate in laboratory studies. However, the extent of the use of oxidants rather than chlorine is unknown.

The efficiency of water treatment practices varies from intake to intake. The studies dealing with water treatment were laboratory simulations of the water treatment practices at Sacramento, California. Other intakes may have different practices that may provide very different removal efficiencies. Variables such as spiking rates of oxidants, size of the distribution system, and storage/ treatment times may provide different pesticide removal efficiencies. Therefore, using the results of one intake's treatment may not be accurate for another intake.

The water treatment practices at the Mississippi and Atchafalaya River intakes was not provided by the registrant. EFED is assuming that chlorination is the only oxidative treatment at these intakes.

2) Use of Monitoring Data EFED is very certain about the drinking water conclusions for California, Missouri, Tennessee, and Arkansas for parent molinate. EFED is less certain about the Mississippi and Atchafalaya River intakes in Louisiana because of fewer years of monitoring data ( 4 years or less) compared to California ( 19 years). EFED is uncertain about the extent of exposure at Anahuac, Texas, because the amount of water from other sources and the number of days that Lake Anahuac receives rice drainage is unknown.

The amount of the degradate 4 keto molinate exposure in the use season is uncertain. The Domagalski article states that between 10 30 % of detected molinate was present in the Sacramento River in California. However, this study was conducted in January, and molinate is applied in May June primarily.

The use of monitoring data to assess dietary exposure creates uncertainties. Monitoring 24 data are not available everywhere for all uses of a given compound. In a given year, it is highly likely that peak concentrations are missed since sampling is not always conducted on a daily schedule or over the time necessary to detect peaks. Also, peak concentrations are not likely to be detected unless sampling is conducted in a stratified sampling pattern in highly vulnerable sites. Sampling is also not necessarily representative of the entire year unless sampling is conducted over a year. Since monitoring data are dependent on the weather in a particular year, data may not always be available for enough years to cover the range of weather in a given area of application. The associated information to interpret monitoring information, such as amount of use and the area treated in a watershed, the timing and amount of rainfall events that drive runoff events, and specific cultural practices are not always available. Inclusion of data from an area where no pesticide is applied tends to bias estimates of exposure downward when considered with data from use areas. In analyzing these data, efforts were made to only include data from areas where molinate was known to have been used.

3) Estimation of degradate concentrations based on field and laboratory studies Estimation of degradate concentrations in surface water based on laboratory and field studies introduces uncertainties because levels of degradates relative to parent compound vary with time. Degradate concentrations are lowest relative to parent compounds immediately following the application and increase with time. As a result, no single adjustment factor for monitoring data will perfectly represent the contribution of degradates to ecological and drinking water exposure. However, the 1.56 factor is an average number will reasonably represent the contribution of degradates for both ecological and drinking water exposure. Monitoring for all residues of concern is the only certain method to assess exposure.

4) Time weighting of monitoring data Time weighting of monitoring to provide annual exposure data from seasonal data introduces uncertainties because of extrapolation and censored data. Extrapolation introduces potential error because a concentration represents a point in time. Extrapolation of high concentrations increases the estimates. On the other hand, extrapolation of non detections ( censored data) decreases the estimates depending on the level of detection ( LOD).

5) Uncertainties of using dilution calculations 25 Dilution calculations were used to estimate dietary exposure at Lake Anahuac, Texas. At this location, White's Bayou drains rice fields into Lake Anahuac, which is a drinking water source for 1,960 people. However, other sources of water that do not receive rice drainage are used to supplement the lake. Also, rice production along White's Bayou has declined by approximately two thirds since the year the data were generated ( 1994). As a result, the predicted EEC's are probably higher than actual exposure. EFED has no information on the proportion of water from the other source and from rice fields and the number of days Lake Anahuac receives rice drainage so that the estimates of drinking water concentrations can be refined.

4.3 Occupational Exposure The Occupational/ Residential Exposure Assessment for the RED was prepared by Steven Weiss ( DP Barcode D249751 dated December 21, 1999 and D263662 dated March 3, 2000).

Molinate use on rice differs based on cultural practices ( e. g., wet versus dry seeding and water management). Application parameters are generally defined by the physical nature of the use site, by the equipment required to deliver the chemical to the use site, and by the application rate required to achieve efficacy. Molinate applications intended for weed control in rice are predominantly made by aircraft ( approximately 90 percent of total applied) while the remaining applications are completed by ground based equipment designed to apply granulars or by typical groundboom spray rigs. Most ground based applications occur by pre plant/ incorporation. Information obtained at the September 1998 SMART meeting indicates molinate is apparently sold mostly in bulk packaging. This is supported by the fact that the predominant applicators are pilots who would use larger quantities of molinate compared to a typical grower ( i. e., bulk packaging is easier to handle for larger quantity users).

The predominant rice producing states are Arkansas, California, Louisiana, Mississippi, Missouri, and Texas. Cropping time for rice ranges from approximately 120 to 140 days. In the southern states, usual planting times typically range from early to mid April through late May. In California, most planting is completed during May. Harvest in the southern states can range from the beginning of August through the end of October. Likewise, harvest in California essentially occurs throughout October. The occupational risk assessment does not differentiate risks to workers in the various rice growing areas.

4.3.1 Handler 26 HED has determined that there is a potential for exposure from handling molinate products during the application process ( i. e., mixer/ loaders, applicators, flaggers, mixer/ loader/ applicators) and from entering agricultural areas previously treated with molinate.

The non dietary exposure database that has been developed in support of the reregistration of molinate is extensive when compared to that for other similar chemicals. This database contains exposure monitoring data that have been developed using both passive dosimetry and biological monitoring techniques. A molinate specific epidemiology assessment has also been completed ( discussed under 4.5). HED policy dictates that chemical specific data be used in conjunction with other sources of exposure data commonly used by HED to complete risk assessments ( e. g., Pesticide Handlers Exposure Database). As such, several data sources were considered in this assessment including the Pesticide Handlers Exposure Database ( PHED) and the array of molinate specific data that have been submitted.

HED anticipates that occupational molinate exposures will only occur in a short term or intermediate term pattern. HED anticipates that occupational exposures will not be chronic because HED defines chronic exposures as use of the chemical for approximately 180 days per year and it is anticipated that molinate as with other typical pesticide compounds will not be used in this manner.

In October 1998, the Hazard Identification Assessment and Review Committee ( HIARC) reassessed toxicological endpoints for non dietary exposure to molinate. For details on the dose and endpoints selected for risk assessment, see Table 2. For short term dermal risk assessments, an MOE of 300 is required because a NOAEL was not achieved in the developmental neurotoxicity study; an MOE of 100 is adequate for all other exposure ( dermal and inhalation) risks.

Handler Risk Assessment Assumptions and Factors A series of assumptions and exposure factors served as the basis for completing the handler risk assessment. The following assumptions and factors were used to complete this assessment:

° Average body weight of an adult handler is 70 kg. This body weight is used in all assessments. 27 ° The number of application days/ year, the amount of ai/ handled per day by loaders and areas treated/ day were defined for each handler scenario.

For aerial applications, the following assumptions were used and are based on information provided to the HED during the SMART meeting on 9/ 23/ 98, subsequent conversations with Zeneca, and the best professional judgement of the HED.

* aerial applications of granulars: 27 application days/ year with average of 300 acres treated / day * aerial applications of liquids: 27 application days/ year with average of 300 acres treated / day * loading granulars for aerial applications: 1,680 lb ai handled/ day ( average in 1993 study MRID# 431656 02 was approximately 900 lb ai handled/ day)

* mixing/ loading liquids for aerial applications: 900 lb ai handled/ day ( average in 1996 study MRID# 442122 01 was approximately 300 lb ai handled/ day)

No information on the number of application days/ year for ground based applications was provided to HED. Therefore, HED assumed that ground based applications for liquid or granular formulations could occur for 30 application days/ year.

All short term and intermediate term handler calculations were completed at the maximum labeled application rate for each scenario.

There are three basic risk mitigation approaches considered appropriate for controlling occupational exposures. These include administrative controls, the use of personal protective equipment or PPE, and the use of engineering controls. Occupational handler exposure assessments are completed by HED using a baseline exposure scenario and, if required, increasing levels of risk mitigation ( PPE and engineering controls) to achieve an appropriate margin of exposure or cancer risk. [ Note: Administrative controls available generally involve altering application rates for handler exposure scenarios. These are typically not utilized for completing handler exposure assessments because of the negotiation requirements with registrants.] The baseline clothing/ PPE ensemble for occupational exposure scenarios is generally an individual wearing long pants, a longsleeved shirt, no chemical resistant gloves ( there are exceptions pertaining to the use of gloves and these are noted), and no respirator. The first level of mitigation generally applied is PPE. This involves the use of an additional layer of clothing, chemical resistant 28 gloves, and a respirator. The next level of mitigation considered in the risk assessment process is the use of appropriate engineering controls which, by design, attempt to eliminate the possibility of human exposure. Examples of commonly used engineering controls include closed tractor cabs, closed mixing/ loading/ transfer systems, and watersoluble packets.

Occupational Exposure Patterns The anticipated use patterns and current labeling indicate 11 major occupational exposure scenarios. These scenarios include:

( 1) loading granulars for aerial applications; ( 2) truck drivers supporting loading granulars for aerial applications; ( 3) pilots applying granulars using aerial equipment; ( 4) flagging during aerial application of granulars; ( 5) mixing/ loading liquids for aerial applications; ( 6) pilots applying liquids using aerial equipment; ( 7) flagging during aerial application of liquids; ( 8) loading granulars for ground based applications; ( 9) applying granulars using ground based equipment; ( 10) mixing/ loading liquids for ground based applications; ( 11) applying liquids using ground based equipment Estimating Exposure and Risk Using Biomonitoring Exposure Data Exposure and risk for the three mixer/ loading scenarios [( 1) loading granulars for aerial applications; ( 2) truck drivers supporting loading granulars for aerial applications; ( 5) mixing/ loading liquids for aerial applications] were evaluated using biomonitoring exposure data. Calculations of exposure ( combined dermal and inhalation) and risk were based on the assumption that loaders of granulars are using bulk bags and are wearing long sleeve shirts, long pants, coveralls ( Tyvek or carbon), and a full face respirator. Risks for truck drivers were calculated for those wearing carbon suits and those wearing no suits. For loaders of liquids for aerial applications, three levels of PPE were evaluated:

Level 1: Activated carbon suit worn underneath " Kleenguard" coveralls Level 2: " Kleenguard" coveralls worn over normal work clothing Level 3: Normal work clothing, recommended as long sleeved shirt and long pants Estimating Exposure and Risk Using Unit Exposures from PHED 29 Since adequate biomonitoring data were only usable for the three scenarios, the other eight scenarios [( 3) pilots applying granulars using aerial equipment; ( 4) flagging during aerial application of granulars; ( 6) pilots applying liquids using aerial equipment; ( 7) flagging during aerial application of liquids; ( 8) loading granulars for ground based applications; ( 9) applying granulars using ground based equipment; ( 10) mixing/ loading liquids for ground based applications; and ( 11) applying liquids using ground based equipment] were evaluated using the unit exposures from the Pesticide Surrogate Exposure Guide ( 8/ 98).

Short and intermediate term risks were calculated for dermal, inhalation and the combined dermal and inhalation exposures. It was concluded that the dermal and inhalation exposures could be combined due to the common endpoint for short term ( neurotoxicity) and intermediate term ( reproductive effects) exposures. Since the shortterm dermal endpoint was based on a LOAEL with an additional uncertainty factor of 3, the LOAEL was divided by 3 before calculating the combined short term dermal and inhalation MOEs. The intermediate term dermal and inhalation endpoints were both based on a NOAEL so this additional step was not necessary for the combined intermediate MOEs. The combined MOEs were calculated using the following equation:

1 1 + 1 ( Dermal MOE) ( Inhalation MOE) 3 A combined MOE of less than 100 exceeds the Agency's level of concern.

Summary of Risks to Occupational Handlers Using Biomonitoring Data ( Appendix Tables 2 3)

Short term MOE's estimated for liquid and granular mixers/ loaders using biomonitoring data are less than 300 at the baseline level of personal protective equipment ( i. e., long pants, long sleeved shirts, gloves) and for the additional PPE of coveralls over long pants, long sleeved shirts, chemical resistant gloves and full face respirators. Short term total MOEs estimated for truck drivers supporting loading of granulars for aerial applications are greater than 300.

Intermediate term MOEs estimated for liquid and granular mixer/ loaders using biomonitoring data are less than 100 at the baseline and additional levels of PPE ( MOEs ranged from 17 to 73). Intermediate term total MOEs for truck drivers supporting loading of granulars for aerial applications are greater than 100. 30 Summary of Risks to Occupational Handlers Using PHED Data ( Appendix Tables 4 7)

Short term dermal MOEs estimated for 8 handler scenarios using PHED data are all less than 300 at the baseline clothing and additional PPE levels ( MOEs ranged from 32 to 230). Engineering controls resulted in short term dermal MOEs above 300 for only 3 of the 8 scenarios.

Short term inhalation MOEs estimated for 8 handler scenarios using PHED data are above 100 at the baseline level of clothing/ PPE.

When the short term dermal and inhalation MOEs are combined, the MOEs were below 100 for all scenarios at the baseline level and when additional protective clothing/ PPE are added. When engineering controls are added, the MOEs are still below 100 for pilots applying both granular and liquid formulations and for handlers mixing/ loading liquids for ground based application and applying liquids using ground based equipment.

Intermediate term dermal MOEs estimated for 8 handler scenarios using PHED data are all less than 100 at the baseline clothing and additional levels of PPE ( MOEs ranged from 4 to 26). Engineering controls resulted in MOEs above 100 for only 2 of the 8 scenarios.

Intermediate term inhalation MOEs estimated for 8 handler scenarios using PHED data are all less than 100 at the baseline PPE level ( MOEs ranged from 8 to 31). The addition of a full face respirator resulted in intermediate term inhalation MOEs above 100 for 6 scenarios assessed using PHED data. Risks for pilots applying liquids and granulars were only assessed with engineering controls; the MOEs were 89 and 3, respectively.

When intermediate term dermal and inhalation risks are combined, the MOEs are less than 100 for all scenarios at baseline and when added protective clothing/ PPE are added. When engineering controls are added, the MOEs are still less than 100 for pilots applying both granular and liquid formulations and for handlers applying both granular and liquid formulations using ground based equipment and for handlers mixing/ loading liquids for ground based application.

The handler assessments are believed to be reasonable high end representations of molinate uses. There are, however, many uncertainties in these assessments. The uncertainties include but are not limited to the following: extrapolating exposure data by the amount of active ingredient handled or applied; not all of the exposure data are of high confidence because of the lack of replicates and/ or inadequate QA/ QC in the studies. 31 4.3.2 Postapplication Occupational postapplication exposures are expected to be minimal because of the nature of the activities associated with rice cultivation ( e. g., scouting and water management) and the protective equipment that is commonly used during these activities ( e. g., waterproof rubber boots for walking through rice paddies). Thus, a quantitative exposure and risk assessment for post application activities was not performed. Since the acute toxicity categories for the technical grade are III for oral and dermal, II for primary eye irritation, and IV for inhalation and primary skin irritation, the 24 hour restrictive entry interval ( REI) that appears on molinate product labels is in compliance with the Agency's Worker Protection Standard ( WPS).

4.4 Residential Exposure HED has not addressed any residential exposure scenarios because there are no residential uses of molinate. This assessment for molinate reflects the Agency's current approaches for completing residential exposure assessments based on the guidance provided in the Draft: Series 875 Occupational and Residential Exposure Test Guidelines, Group BPostapplication Exposure Monitoring Test Guidelines, the Draft: Standard Operating Procedures ( SOPs) for Residential Exposure Assessment, and the Overview of Issues Related to the Standard Operating Procedures for Residential Exposure Assessment presented at the September 1999 meeting of the FIFRA Scientific Advisory Panel ( SAP). The Agency is, however, currently in the process of revising its guidance for completing these types of assessments. Modifications to this assessment shall be incorporated as updated guidance becomes available. This will include expanding the scope of the residential exposure assessments by developing guidance for characterizing exposures from other sources already not addressed such as from spray drift; residential residue track in; exposures to farmworker children; and exposures to children in schools.

OPP received comments from the Pesticide Action Network North America ( PANNA) concerning inhalation exposure of people in California that live in close proximity to molinate treated rice fields. A study conducted in the early 1990s by the California Air Resources Board was used by PANNA to calculate risk estimates for varying durations of exposure. OPP concurred with the use of this study. However, OPP does not concur, with a number of the values and approaches used by PANNA, such as route to route extrapolation and use of data presented in a California Air Resources Board ( CARB) study in some cases. A detailed discussion is contained in a August 22, 2002 Memorandum from Jeff Dawson to Wilhelmena Livingston ( D284305). 5 The 1999 review dated December 16, 1999 ( D249804 and D260965) provides a summary of the study protocol and results.

6 Tomenson JA et al ( 1999) An assessment of fertility in male workers exposed to molinate. J Occup Environ Med 41( 9): 771 87.

32 4.5 Epidemiology Data A molinate epidemiology study of exposed male workers, begun in the early 1980s, has been reviewed three times by Dr. Ruth Allen ( 1991, 1993 and 1999). 5 The purpose of the registrant sponsored study was to determine whether workers in molinate production and formulation plants showed any adverse reproductive effects, changes in sperm parameters, or reduced fertility. Each successive submission to EPA has been an attempt to upgrade the study report and address deficiencies in previous reviews. The study was published in a peer reviewed journal in 1999 after a reanalysis of the statistical data. 6 A total of 225 male workers donated at least two semen samples between 1980 and 1982 at a molinate production plant in Cold Creek, Alabama, and two molinate formulation plants in Richmond, California and in North Little Rock, Arkansas. A total of 43 employees provided semen samples at a single period. Male workers were known by job title and duties to be exposed to molinate in manufacturing and formulating at one of the three facilities.

The study was conducted over four distinct time periods with and without chemical production or formulation. Due to seasonal and individual variation in sperm parameters, each worker served as his own control. Measurements were made on such reproductive structure and function indicators as: sperm concentration, motility score, percent normal morphology, percent non motility, percent live, serum FSH, LH and testosterone. Questionnaire data were also collected on fertility and infertility from 222 wives of workers.

Exposure assessment was based on 660 personal and 335 area air monitoring samples that were collected the year before or during the study period.

The study author concluded " the reanalysis of the study data has provided no evidence of a real molinate exposure effect on sperm or serum hormone parameters despite the use of a wide range of statistical approaches and characterizations of exposure and effect. Supplemental analyses of the fertility or the wives of employees and seasonality patterns of births also provided no indication of a molinate exposure effect." 33 HED concluded that there was a small decrease in the observed compared to expected number of children at parity 3 and 4+, especially for the high exposure classification, both between production cycles and during peak production exposure. These results are suggestive of a possible effect for the high exposure group, and a number of subtle questions and issues remain to be clarified. Those issues are as follows:

$ Participation Rate. At 49%, the study participation rate is low, and this could introduce error/ bias. Study participation rates are needed by population strata, including more highly exposed workers and families at higher parity. A participation rate above 85% is desired. The lower response rate precludes total reliance on this one molinate epidemiology study to make any sweeping health and safety claims. In addition, there was a difference in the demographics of the three plants. At Richmond and Cold Creek, the workers were 75 and 78% white, respectively, whereas those at North Little Rock were 62% black and 10 years younger.

$ Exposure Timing and Variability. Job title is an imprecise but commonly used surrogate for actual exposure measurements. The same job title may be associated with different levels of exposure depending on personal hygiene practices and proximity to other concurrent exposures. In addition, molinate was not the only chemical produced or formulated at the various plants.

Within worker variability is not fully examined. The study design is reasonable for the 1980' s with multiple testing of the same person. The study does not address timing of exposure adequately and changes in biomarkers, such as increases in FSH via feedback in shorter intervals than 4 6 months. These would not be detected in the intermittent screening of the current design.

$ Confidence Intervals. There should be a shift in presentation of results to measure effects of molinate with characterization of the precision of estimates with confidence intervals not significance testing of patterns and coefficients.

$ Chronic Low Level Exposure. Estimates of exposure for each area/ job are given. The highest exposure for an area/ job was 633

g/ M3 ( geometric mean TWA), and at each site at least one value reached 250

g/ M3. The highest cumulative exposure for a single period of study was 230,000

g/ M3.

The current results do not differentiate workers with changing exposure and a possible better outcome compared to chronic low level exposure.

$ Confounders. No explanation is given for the marked variability in responses in workers in formulation plants compared production plants.

$ Study Power. Study power for analysis is weak for Cold Creek and North Little River plants which raises concerns about the Generalized Estimating Equation ( GEE) statistical 34 analysis.

Additional comments regarding the study report can be found in the December 16, 1999 review.

HED recommendations based on review of the epidemiology study:

Molinate is used for weed control in rice fields world wide ( India, Iran, Japan, China, Philippines, Australia, Hungary, Italy, Spain) in addition to various U. S. rice growing regions. In these other countries, use of protective equipment and label compliance are unpredictable and cannot be assured. Any adverse male reproductive health effects could go unreported or under reported. Therefore, prudent public health measures are advised, including labeling products with the National Pesticide Telecommunications Network international phone number or equivalent poison control center in country number to facilitate the use of existing health surveillance and disease reporting system for pesticide poisoning prevention. Reporting of incidents to a central organization would serve as an international biomonitoring of workers exposed to molinate.

Moreover, pesticide poisoning surveillance reporting on adverse health effects is very uneven globally, and efficacy of multi lingual translations of worker protection label precautionary measures world wide is uncertain. Therefore, publication of all human health findings from the molinate epidemiology study in the open epidemiologic literature is recommended as a normal part of prudent public health practice and good product stewardship. Given the worldwide use of this chemical, such precautional measures are one responsible way to demonstrate a commitment to public health.

4.6 Incident Data A review of the incidents of human adverse effects reported with molinate exposure was prepared by Dr. Ruth Allen ( D262407, January 14, 2000). Four separate data bases were consulted with the following results:

1) OPP Incident Data System ( IDS)  reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. Reports submitted to the Incident Data System represent anecdotal reports or allegations only, unless otherwise stated. Typically no conclusions can be drawn implicating the pesticide as a cause of any of the reported health effects. Nevertheless, sometimes with enough cases and/ or enough documentation risk mitigation measures may be suggested.

There were 11 incidents in IDS. Two involved ecological ( aquatic) effects. Four reported molinate detections in water in California. One was for molinate residues on rice. Two were summaries of incident reports involving multiple pesticides; no details were provided. In an incident from 1999, according to pesticide industry reports, molinate was reportedly 35 associated with 7 individual incidents, including eye irritation and swelling, hives, second degree burns, kidney problems, and ear infections. In another 1999 incident, after molinate was sprayed on rice fields next to a house, dizziness in the whole family was reported due to over spraying.

2) Poison Control Centers  as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1996 for all pesticides. Most of the national Poison Control Centers ( PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System which obtains data from about 65 70 centers at hospitals and universities. PCCs provide telephone consultation for individuals and health care providers on suspected poisonings, involving drugs, household products, pesticides, etc.

A total of 2 exposures were reported to the Toxic Exposure Surveillance System of the American Association of Poison Control Centers. Both cases were in adults. One case did not receive follow up but potentially had moderately toxic effects and the other had symptoms judged unrelated to their exposure. This is too few cases to permit meaningful comparisons with other pesticides.

3) California Department of Food and Agriculture ( replaced by the Department of Pesticide Regulation in 1991)  California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required, by statute, to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides. The majority of the incidents involve workers. Information on exposure ( worker activity), type of illness ( systemic, eye, skin, eye/ skin and respiratory), likelihood of a causal relationship, and number of days off work and in the hospital are provided.

There are 13 total reported incidents for molinate. This includes 10 incidents for molinate alone, and 3 incidents for molinate with combinations, including copper sulfate, thiobencarb, and/ or bensulfuron methyl.

Eye irritation, burning pain, and/ or blurred vision were reported in 1 molinate and two molinate mixture cases. Skin irritation, including rash on contact with dust were reported in 2 molinate and 1 molinate mixture case. These cases were mainly in workers, including flaggers and applicators.

Systemic and respiratory symptoms were reported for 5 molinate cases, including coughing, dizziness, vomiting, nausea, and/ or mild perspiration.

In 1991, a case included non occupational exposure to molinate when store merchandise was delivered on molinate contaminated pallets and 3000 people were evacuated by the fire dept. from the store with a few being seen by doctors. Also in 1991, a non employee doing a demonstration at a store developed mild nausea, headaches and dizziness when exposed to the odor of molinate. 36 In 1992 a shop worker exposed to molinate fumes from a mixer/ loader 150 feet away became ill with shortness of breath, headaches and nausea.

In1996, a worker loading a crop duster with molinate experienced eye problems and pain, sought medical help two days later, but the ophthalmologist could not determine the cause of the eye injury, pain and redness in both eyes.

A total of 13 days off work and 0 days hospitalized were reported.

4) National Pesticide Telecommunications Network ( NPTN)  NPTN is a toll free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984 1991, inclusive has been prepared. The total number of calls was tabulated for the categories human incidents, animal incidents, calls for information, and others.

On the list of the top 200 chemicals for which NPTN received calls from 1984 1991 inclusively, molinate was not reported to be involved in human incidents.

In summary, the only data base which would provide an accurate gauge of poisoning incidents in workers exposed to molinate is the one from California. Although the number of incidents was small, there were reports of both local and systemic effects. Also, there was no assessment of the number of incidents in relation to the amount of molinate used in the state. No appropriate data bases assess worker incidents in the southern U. S. where rice is also grown.

5.0 AGGREGATE RISK ASSESSMENT AND RISK CHARACTERIZATION An aggregate exposure risk assessment was prepared for dietary exposure to food and water. These assessments apply only to rice growing areas. EFED has determined that the monitoring data are suitable for quantification of drinking water risks. Using the suggested raw water concentrations for both ground and surface water and the dietary exposure from DEEMJ, HED calculated the percentage of the Population Adjusted Dose ( PAD) for acute and chronic risk assessments. The following equations were used:

Adult Males Water Exposure = Concentration of water ( ug/ L) x 10 3 ( mg/ ug) x 2 L/ day ( mg/ kg/ day) 70 kg Adult Females Water Exposure = Concentration of water ( ug/ L) x 10 3 ( mg/ ug) x 2 L/ day ( mg/ kg/ day) 60 kg 37 Children Water Exposure = Concentration of water ( ug/ L) x 10 3 ( mg/ ug) x 1 L/ day ( mg/ kg/ day) 10 kg Percentage of PAD = Aggregate Exposure ( Food + Water) ( mg/ kg/ day) x 100 PAD ( mg/ kg/ day)

For ground water, EFED determined that 0.087 ug/ L ( 0.056 x 1.56) should be used as an estimate of total residues of molinate in drinking water for acute and chronic aggregate risk assessments. For surface water, HED performed the risk assessment calculations using the data from West Sacramento, California as a worse case [ 3.32 ug/ mL ( 2.13 x 1.56) for acute exposure and 0.64 ug/ mL ( 0.41 x 1.56) for chronic exposure)].

For food exposure, separate calculations were done for adult males ( using general population food exposure), adult females ( using females 13 50 food exposure) and children ( using infants < 1 year food exposure) for acute ( using the 99.9 percentile) and chronic risk assessments.

Greater than 100% of the PAD for the aggregate exceeds the Agency's level of concern. The data are presented in Table 5.

The percentage of the aPAD for acute aggregate exposure to molinate in food and surface water for children ( 110%) exceeded the Agency's level of concern. However, HED believes this assessment may overestimate the risk and that refinement of the exposure to either food or water exposure may bring the risks into an acceptable range. The anticipated residues of food were based on field trial residues. Monitoring studies closer to the point of consumption or cooking studies would refine exposure. Better monitoring data for molinate and its metabolites and degradates in water would also refine the risks. 38 Table 5: Percentage of Population Adjusted Dose ( PAD) for Aggregate Dietary ( Food and Water) Exposure Water Exposure ( mg/ kg/ day) Food Exposure ( mg/ kg/ day) aPAD/ cPAD ( mg/ kg/ day) Percentage of PAD Molinate Molinate + Metabolitesa Molinate Molinate + Metabolitesa Acute Risk Assessment  Surface Water Adult Males 0.000061 0.000095 0.000186 0.0006 41% 47%

Adult Females 0.000071 0.00011 0.000152 0.0006 37% 44%

Children 0.00021 0.00033 0.000328 0.0006 90% 110%*

Acute Risk Assessment  Ground Water Adult Males 0.0000016 0.0000025 0.000186 0.0006 31% 31%

Adult Females 0.0000019 0.0000030 0.000152 0.0006 26% 26%

Children 0.0000056 0.000087 0.000328 0.0006 56% 56%

Chronic Risk Assessment  Surface Water Adult Males 0.000012 0.000019 0.000005 0.0001 17% 24%

Adult Females 0.000014 0.000022 0.000004 0.0001 18% 26%

Children 0.000041 0.000064 0.000018 0.0001 59% 82%

Chronic Risk Assessment  Ground Water Adult Males 0.0000016 0.0000025 0.000005 0.0001 7% 8%

Adult Females 0.0000013 0.0000029 0.000004 0.0001 5% 7%

Children 0.0000056 0.0000087 0.000018 0.0001 24% 27%

a Water exposure values were increased by 56% to account for metabolites not included in the monitoring data.

* > 100% exceeds the Agency's level of concern. 39 6.0 DATA NEEDS Product Chemisty: the registrant must submit additional studies as described below before all guideline requirements can be considered fulfilled.

$ Studies on stability to metals and metal ions ( GLN 830.6313) and UV/ visible absorption ( GLN 830.7050).

. Residue Chemistry: Studies which are outstanding include multiresidue method testing for molinate, 4 hydroxy molinate, and molinate acid. A waiver from conducting a crop irrigation study ( GLN860.1400) was granted ( September 5, 2002 Memorandum, D284879), with addendum dated November 6, 2002. 40 APPENDIX 41 Table 1. Toxicology Profile of Molinate Guideline [ § / OPPTS] Study Type MRID # NOAEL/ LOAEL 81 1/ 870.1100 acute oral  rats 40593301 see Table 1: Acute Toxicity of Molinate 81 2/ 870.1200 acute dermal  rabbits 40593301 see Table 1: Acute Toxicity of Molinate 81 3/ 870.1300 acute inhalation  rats [ 0.06, 0.12, 0.28, 0.83, 0.9, 1.6, 2.2, 2.4, 2.8, 4.0, & 4.9 mg/ L]

mouse ( 0.034, 0.09, 0.23, 1.1, 1.8, 2.0, 2.3, & 3.2 mg/ L) 00245675 NOAEL hindleg weakness = 0.12 mg/ L LOAEL hindleg weakness = 0.28 mg/ L.

NOAEL ataxia = 2.4 mg/ L LOAEL ataxia = 2.8 mg/ L NOAEL aggression/ hyperexcitability = 0.83 mg/ L LOAEL aggression/ hyperexcitability = 0.9 mg/ L no NOAEL for depression/ leg weakness.

NOAEL decreased testes weight = 1.8 mg/ L LOAEL decreased testes weight = 2.0 mg/ L NOAEL microscopic lesions of testes = 1.1 mg/ L LOAEL microscopic lesions of testes = 1.8 mg/ L 81 4/ 870.2400 primary eye irritation 40593301 see Table 1: Acute Toxicity of Molinate 81 5/ 870.2500 primary dermal irritation 00247547 see Table 1: Acute Toxicity of Molinate 81 6/ 870.2600 dermal sensitization 40593302 see Table 1: Acute Toxicity of Molinate 81 7/ 870.6100 acute delayed neurotoxicity  hen 00133562 43136601 NOAEL = 200 mg/ kg LOAEL = 630 mg/ kg, based on axonal degeneration in brain & spinal cord [ delayed neurotoxicant]

81 8/ 870.6200 acute neurotoxicity  rat 43188001 no NOAEL; LOAEL = 25 mg/ kg, based on decreased motor activity & increased time to tail flick; ChE activity, NTE, & GFAP were not assessed at appropriate times immediately after dosing 82 1/ 870.3100 subchronic feeding  rats

82 1/ 870.3150 subchronic feeding  dog 12 week fertility  male monkey [ 0.2, 10, 50 mg/ kg/ day]

00246520 42361302

NOAEL = 10 mg/ kg/ day LOAEL = 50 mg/ kg/ day, based on decreased plasma ChE activity [ brain ChE not measured]. Repeat study NOAEL 0.2 mg/ kg/ day LOAEL 10 mg/ kg/ day, based on decreased RBC ChE [ brain ChE not affected] Table 1. Toxicology Profile of Molinate Guideline [ § / OPPTS] Study Type MRID # NOAEL/ LOAEL 42 82 2/ 870.3200 21 day dermal  rats [ 10, 25, 50 mg/ kg/ day] 40990601 no NOAEL for RBC ChE inhibition.

NOAEL skin effects = 10 mg/ kg/ day LOAEL skin effects = 25 mg/ kg/ day, based on skin irritation & acanthosis 82 4/ 870.3465 90 day inhalation  rodent [ 2, 10, 50 mg/ m3]

4 week inhalation [ 0.1, 0.2, 0.4, 0.8, 1.6 mg/ m3] 00241965 41589203 no NOAEL; LOAEL = 0.002 mg/ L, based on testicular degeneration & abnormal spermatoza, a dose related decrease in mean number of implantations & mean number of fetuses NOAEL = 0.0003 mg/ L; LOAEL = 0.0006 mg/ L, based on decreased number of implants & increased % abnormal sperm 82 5/ 870.6200 subchronic neurotoxicity  rats [ 50, 150, 450 ppm; males 4, 11.7, 35.5/ females 4.5, 13.9, 41 mg/ kg/ day] 43270701 43965901 no NOAEL; LOAEL = males 4/ females 4.5 mg/ kg/ day, based on decreased brain & RBC ChE activity and decreased NTE in both sexes at all dose levels 83 1( a)/ 870.4100 chronic toxicity  rats [ 7, 40, 300 ppm ( males: 0.3, 1.8, 13/ females 0.4, 2, 15 mg/ kg/ day] for 24 months; 600 ppm [

30 mg/ kg/ day] for 12 months 41815101 no NOAEL for neurotoxic effects;

NOAEL = 7 ppm [ males 0.3/ females 0.4 mg/ kg/ day]

LOAEL = 40 ppm [ males 1.8/ females 2.0 mg/ kg/ day], based on ovarian lesions; at HDT [ 300 ppm ( males 13/ females 15 mg/ kg/ day)] degeneration w/ atrophy of testes & decreased testes weight 83 1( b)/ 870.4100 chronic toxicity  dog [ 1, 10, 50 mg/ kg/ day for 1 year; 100 mg/ kg/ day for 14 weeks] 41781101 no NOAEL for neurotoxic effects;

NOAEL = 10 mg/ kg/ day LOAEL = 50 mg/ kg/ day, based on decreased BWG, anemia, decreased ejaculate volume & decreased % mobile sperm & increased adrenal weight [ both sexes]

83 2/ 870.4200 carcinogenicity  mice [ 10, 100, 1000, 2000 ppm [ males 1, 10.4, 105, 200 mg/ kg/ day,/

females 1.3, 13.9, 133, 249 mg/ kg/ day] 41809201 NOAEL [ testicular effects] = 10 ppm [ 1.0 mg/ kg/ day]; LOAEL [ testicular effects] = 100 ppm [ 10.4 mg/ kg/ day], based on testicular degeneration NOAEL [ other effects] = 100 ppm [ males 10.4/ females 13.9 mg/ kg/ day]

LOAEL [ other effects] = 1000 ppm [ males 105/ females 133 mg/ kg/ day, based on decreased survival, BW/ BWG/ FC, increased incidence of non neoplastic lesions in brain, spinal cord, sciatic nerve & ovaries Table 1. Toxicology Profile of Molinate Guideline [ § / OPPTS] Study Type MRID # NOAEL/ LOAEL 43 83 3( a)/ 870.3700 developmental toxicity  rat [ 2.2, 35, 140 mg/ kg/ day] 41473401 maternal NOAEL = 35 mg/ kg/ day maternal LOAEL = 140 mg/ kg/ day, based on decreased BW/ BWG/ FC, increased salivation & dehydration, RBC ChE inhibition.

developmental NOAEL = 2.2 mg/ kg/ day developmental LOAEL = 35 mg/ kg/ day, based on increase in runting 83 3( b)/ 870.3700 developmental toxicity  rabbits [ 0, 2, 20, 200 mg/ kg/ day]

13 week oral  male rabbit [ 40, 80, 160/ 120 mg/ kg/ day 8 week oral  male rabbit [ 10, 100 for 49 days, 200 mg/ kg/ day for 16 days]

12 week oral  male rabbit [ 10, 100, 200 mg/ kg/ day]

28 day oral  male rabbit 2 range finding studies [ 100, 200, 300 mg/ kg/ day]

[ 40, 100, 250 mg/ lg/ day] 14021015 42361301 42361304 42361305 42361306 42361307 maternal NOAEL = 20 mg/ kg/ day maternal LOAEL = 200 mg/ kg/ day, based on increased abortions, decreased [ negative] BWG during days 14 21, & increased liver weight.

developmental NOAEL = 20 mg/ kg/ day developmental LOAEL = 200 mg/ kg/ day, based on a delay in fetal development as evidenced by reduced ossification of sternebrae.

male fertility NOAEL = 40 mg/ kg/ day male fertility LOAEL = 80 mg/ kg/ day, based on sperm effects [ increased incidence of atypically stained heads in ejaculated & epididymal sperm samples]

deaths at 100 & 200 mg/ kg/ day [ fertility assessed only during week 4; limited data at 100 mg/ kg/ day suggest a reduction in male fertility associated w/ an increased incidence of sperm abnormalities [ total & midpiece] & increase in preimplantation loss & decrease in # live fetuses at week 4 due to poor survival, no definitive statement possible w/ respect to male rabbit fertility no deaths at  250 mg/ kg/ day; no NOAEL for RBC ChEI LOAEL = 300 mg/ kg/ day , based on deaths Table 1. Toxicology Profile of Molinate Guideline [ § / OPPTS] Study Type MRID # NOAEL/ LOAEL 44 83 4/ 870.3800 2 generation reproduction  rats [ both sexes dosed]

[

5, 10, 15 ppm ( 0.4, 0.8, 1.3 mg/ kg/ day/  20, 50, 300 ppm ( 1.9, 4.7, 28.8 mg/ kg/ day)]

[ only females dosed]

[ 6, 50, 450 PPM] 44403201 41333402 no NOAEL for decreased brain weight LOAEL for decreased brain weight = 5 ppm/ 20 ppm [ males 0.4/ females 1.9 mg/ kg/ day]

paternal NOAEL = 5 ppm [ 0.4 mg/ kg/ day]

paternal LOAEL = 10 ppm [ 0.8 mg/ kg/ day], based on increased incidence of abnormal sperm & decreased right cauda weight in F0 males.

maternal NOAEL = 20 ppm [ 1.9 mg/ kg/ day]

maternal NOAEL = 50 ppm [ 4.7 mg/ kg/ day], based on microscopic lesions in the ovary & adrenal.

neonatal NOAEL = 5 ppm/ 20 ppm [ males 0.4/ females 1.9 mg/ kg/ day]

neonatal LOAEL = 10 ppm/ 50 ppm [ males 0.8/ females 4.7 mg/ kg/ day], based on decreased brain weight in F2B females, decreased testes & spleen weights in F1A males, & delayed vaginal opening in females.

reproductive NOAEL = 5 ppm/ 20 ppm [ males 0.4/ females 1.9 mg/ kg/ day]

reproductive LOAEL = 10 ppm/ 50 ppm [ males 0.8/ females 4.7 mg/ kg/ day], based on microscopic lesions in ovary, increased incidence of abnormal sperm morphology [ both generations], decreased absolute right cauda weight [ F0 males], decreased % pups born live [ F1A & F2B], decreased F2B survival & decreased litter size [ F1A, F2A, F2B]

maternal NOAEL = 6 ppm [ 0.34 mg/ kg/ day]

maternal LOAEL = 50 ppm [ 2.9 mg/ kg/ day], based on decreased fecundity [ F1], increased incidence of vacuolation/ hypertrophy of ovary, decreased brain weight [ F1 females].

reproductive NOAEL = 6 ppm [ 0.34 mg/ kg/ day]

reproductive LOAEL = 50 ppm [ 2.9 mg/ kg/ day], based on occurrence of vacuolation/ hypertrophy of ovary.

neonatal NOAEL = 6 ppm [ 0.34 mg/ kg/ day]

neonatal LOAEL = 50 ppm [ 2.9 mg/ kg/ day], based on ovarian lesions.

83 5/ 870.4300 chronic toxicity/ carcinogenicity  rat 41815101 see under chronic rat Table 1. Toxicology Profile of Molinate Guideline [ § / OPPTS] Study Type MRID # NOAEL/ LOAEL 45 83 6/ 870.6300 developmental neurotoxicity  rat [ 0, 20, 75, and 300 ppm ( 0, 1.8, 6.9, and 26.1 mg/ kg/ day] 44079201 maternal toxicity NOAEL = 75 ppm [ 6.9 mg/ kg/ day]

maternal toxicity LOAEL = 300 ppm [ 26.1 mg/ kg/ day], based on decreased BW/ BWG/ FC.

no NOAEL for developmental neurotoxicity developmental neurotoxicity LOAEL* = 20 ppm [ 1.8 mg/ kg/ day], based on a reduction in startle amplitude in auditory startle test in females on day 23 84 2/ 870.5100 gene mutation 40918301

84 2/ 870.5375 chromosomal aberration 40946701

84 2/ 870.5300 in vitro mammalian cell gene mutation 00163790

84 2/ 870.5550 unscheduled DNA synthesis 41052701 43192301

84 2/ 870.5450 dominant lethal assay 43986701 44562201

85 1/ 870.7485 metabolism 41781801 41781805

85 2/ 870.7600 dermal penetration 43284101

86 1\ 870.7200 domestic animal safety

none 5 week fertility [ males]

[ 0.2, 4, 12, 30, 60 mg/ kg/ day]

7 week gavage [ males]

[ 2, 20, 100, 200 mg/ kg/ day] 00245675 NOAEL = 0.2 mg/ kg/ daya LOAEL = 4 mg/ kg/ day, based on decreased % viable sperm % normal sperm, sperm counts, # implants, # viable fetuses, increased resorptions & pre implantation loss NOAEL = 20 mg/ kg/ day LOAEL = 100 mg/ kg/ day, based on decreased male fertility, # implants, # fetuses/ pregnancy none vaginal opening [ day 7 gestation til day 22 post partum]

[ 300 ppm] 44373601 no NOAEL [ only one dose]

LOAEL = 300 ppm, based on delayed vaginal opening.

none male fertility [ 5 weeks]

[ 0.5, 1, 2, 3, 4, 8 mg/ kg/ day] 43158202 no NOAEL LOAEL 0.5 mg/ kg/ day, based on increased incidence of headless sperm, midpiece abnormality, tail abnormality, total abnormal sperm Table 1. Toxicology Profile of Molinate Guideline [ § / OPPTS] Study Type MRID # NOAEL/ LOAEL 46 none mechanistic study  female [ gestation days 7 10]

[ 75, 135, 200 mg/ kg/ day] 42361308 no NOAEL for microscopic lesions in adrenal cortex & ovary; no evidence of effect on ability to maintain a pregnancy, no deaths at 75 mg/ kg/ day.

 there is a chronic study available;  ChEI was not monitored;  only females were administered Molinate;

 a 28 day hen study is not available;  NTE, ChE, GFAP activities were not assessed at appropriate times * altered by HIARC and Toxicology Science Assessment Committee from original Data Evaluation Record a Actual dose was 0.26 mg/ kg/ day; target dose was 0.2 mg/ kg/ day. 47 Table 2. Exposure and Risk Assessment for Workers Loading Granulars into Airplane Hoppers from Biomonitoring Study Using actual exposure from biomonitoring study ( MRID 43165602)

Task PPE lb ai handled/

3 days ( mean) mean body wt ( kg) mg/ lb ai handled ( geometric mean) Daily Dose 1 mg/ kg/ day ( geometric mean) Short term MOE2 Intermediate term MOE3 Dir Lo Tyvek 2797 95.0 0.000676 0.0062 290 33 Carbon 1927 94.7 0.000469 0.0028 660 73 Both Tyvek 2462 90.9 0.000839 0.0065 280 31 Carbon 3264 85.7 0.000948 0.0116 160 17 Driver none  82.7  0.00081 2,200 250 carbon  81.0  0.00059 3,000 340 1 see Tables 1 through 4 of Appendix C of Occupational/ Residential Exposure Chapter 2 Short term MOE = Oral LOAEL ( 1.8 mg/ kg/ day)/ Daily Dose ( mg/ kg/ day)

3 Intermediate term MOE = Oral LOAEL ( 0.2 mg/ kg/ day)/ Daily Dose ( mg/ kg/ day)

Using default body weight of 70 kg and unit exposures normalized to mg/ lb ai handled Task PPE lb ai handled/

day mg/ lb ai handled Default body wt ( kg) Daily Dose1 mg/ kg/ day Short term MOE2 Intermediateterm MOE3 Max Avg w\ Max lb ai/ day w\ Avg lb ai/ day Dir Lo Tyvek 1,680 900 0.000676 70 0.0162 0.0087 110 12 Dir Lo Carbon 1,680 900 0.000469 70 0.0113 0.0060 160 18 Both Tyvek 1,680 900 0.000839 70 0.0201 0.0108 90 10 Both Carbon 1,680 900 0.000948 70 0.0227 0.0122 80 9 1 Daily Dose ( mg/ kg/ day) = [ Max use rate ( lb ai handheld/ day) x Unit exposure ( mg/ lb ai handled)] / Body weight 2 Short term MOE = Oral LOAEL ( 1.8 mg/ kg/ day)/ Daily Dose ( mg/ kg/ day)

3 Intermediate term MOE = Oral LOAEL ( 0.2 mg/ kg/ day)/ Daily Dose ( mg/ kg/ day) 48 Table 3. Exposure and Risk Assessment for Workers Loading Liquids into Airplane Hoppers from Biomonitoring Study Using actual exposures from biomonitoring study ( MRID 44212201)

Work Task PPE lb ai 1 handled/

3 days Body weight 1 ( mean) Unit exposure 1 mg/ lb ai handled ( geometric mean) Daily Dose 1 mg/ kg/ day ( geometric mean) Short term MOE2 Intermediate term MOE3 Loading Arrosolo ( liquid) Level 1: Activated carbon suit worn underneath ' Kleenguard'

coveralls 839 83 0.00076 0.0072 250 28 Level 2: ' Kleenguard' coveralls worn over normal work clothing 857 82 0.00117 0.0111 162 18 Level 3: Normal work clothing,

recommended as long sleeved shirt and long pants 750 82 0.00340 0.0284 63 7 1 see Tables 1 through 4 of Appendix D of the Occupational/ Residential Exposure Chapter 2 Short term MOE = Oral LOAEL ( 1.8 mg/ kg/ day)/ Daily Dose ( mg/ kg/ day)

3 Intermediate term MOE = Oral LOAEL ( 0.2 mg/ kg/ day)/ Daily Dose ( mg/ kg/ day) 49 Using default body weight of 70 kg, loading rate of 900 lb ai/ day, and unit exposures normalized to mg/ lb ai handled Work Task PPE lb ai/

day body wt ( kg) Unit exposure mg/ lb ai handled ( geometric mean) Daily Dose1 mg/ kg/ day Short term MOE2 Intermediateterm MOE3 Max Avg w\ Max lb ai/ day w\ Avg lb ai/ day Loading Arrosolo ( liquid) Level 1: Activated carbon suit worn underneath ' Kleenguard'

coveralls 900 300 70 0.00076 0.0098 0.0033 184 20 Level 2: ' Kleenguard' coveralls worn over normal work clothing 900 300 70 0.00117 0.0150 0.0050 120 13 Level 3: Normal work clothing,

recommended as long sleeved shirt and long pants 900 300 70 0.00340 0.0437 0.0146 41 5 1 Daily Dose ( mg/ kg/ day) = [ Use rate ( lb ai handheld/ day) x Unit exposure ( mg/ lb ai handled)] / Body weight 2 Short term MOE = Oral LOAEL ( 1.8 mg/ kg/ day)/ Daily Dose ( mg/ kg/ day)

3 Intermediate term MOE = Oral LOAEL ( 0.2 mg/ kg/ day)/ Daily Dose ( mg/ kg/ day) 50 Table 4: Numerical Inputs from PHED Version 1.1 Used for Molinate Handler Exposure Assessment No. Exposure Scenario Unit Exposures from Pesticide Surrogate Exposure Guide ( 8/ 98) Application Parameters Baselinea Additional PPEb Engineering Controlsc Dermal (

g/ lb ai) Inhalation (

g/ lb ai) Dermal (

g/ lb ai) Inhalation (

g/ lb ai) Dermal (

g/ lb ai) Inhalation (

g/ lb ai) Application Rate ( lb ai/ A) d Area Treated ( acre/ day) e Application Days/ year Maximum Typical Aerial Applications  Granulars:

3 pilots applying granulars using aerial equipment na na na na 1.7 1.3 5 4 300 27 4 flagging during aerial application of granulars 2.75 ( single layer,

no gloves) 0.15 ( single layer,

no gloves) 1.17 ( additional layer, no gloves) 0.0075 ( full face resp) 0.0462 ( enclosed truck cab) 0.003 ( enclosed truck cab) 5 4 300 27 Aerial Applications Liquids:

6 pilots applying liquids using aerial equipment na na na na 5.0 ( single layer,

no gloves,

close cab) 0.068 ( single layer,

no gloves,

close cab) 3 3 300 25 7 flagging during aerial application of liquids 11.0 ( single layer,

no gloves) 0.35 ( single layer,

no gloves) 10.22 ( additional layer, no gloves) 0.018 ( full face resp) 0.22 ( single layer,

no gloves,