UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON D.C., 20460



### MEMORANDUM

Date: May 28, 2014 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Dichlorvos (DDVP): Re-examination of the Toxicity Study, Endpoint and Point of Departure Selected for Short- and Intermediate-term Risk Assessments

PC Code: 084001


### Decision No.: 491158


### Petition No.: N/ A
Risk Assessment Type: N/ A

TXR 

### No.: 0056973
MRID 

### No.: N/A DP Barcode: 420277 

### Registration No.: Regulatory Action:
Case No.: NA


### CAS No.: 62-73-7
40 

### CFR: NA

FROM: Ray Kent, Senior Scientist 

# a**t~** Health Effects Division (7509P) 

# 1'

THROUGH: Jess Rowland, Deputy Director

## ~~ Health Effects Division (7509P)



### TO: Garland Waleko, Risk Manager Reviewer
Risk Management and Implementation Branch 2
Pesticide Re-Evaluation Division (7508P)



### I. Introduction

EPA has agreed to re-examine the Reference Doses (RIDs) and Population-Adjusted Doses (PADs) for DDVP in the 1996 DDVP RED to the extent that the RIDs/PADs relied upon a human study, Gledhill, A. J. (1997) Dichlorvos: A Single-Blind, Placebo Controlled, Randomised Study to Investigate the Effects of Multiple Oral Dosing on Erythrocyte Cholinesterase Inhibition in Healthy
Male Volunteers (MRID 44248801) ("Gledhill study"). EPA agreed to revise these RIDs/PADs if
it determines that revision is appropriate and to rescind any existing RID/PAD for which there are

no longer existing pesticide uses. EPA further agreed issue a memorandum explaining the results
of its re-examination ofthe DDVP RID/PADs by May 31,2014. This agreement was memorialized
in a Settlement Agreement between EPA and NRDC in connection with NRDC'sjudicial challenge

to EPA's denial ofNRDC's petition to revoke DDVP tolerances [Settlement Agreement, NRDC v. EPA, No. 12-3671-ag (2013)].


### 12 EPA specifically agreed to re-examine the fo llowing risk assessment scenarios that relied upon the Gledhill study: short-term incidental or al exposure; short-term, intermediate-term, and long-term dermal exposures; and short-term a nd intermediate-term inhalation exposure. EPA defines a Level of Concern for non-dietary scenarios such as these by using an approach referred to as the target Margin of Exposure (MOE), whereas EPA defines the Level of Concern for dietary exposure using RfDs and PADs. As EPA has explained previously, “the RfD/PAD and MOE approaches are fundamentally equivalent.” 73 FR 42683, 42688 (July 23, 2008). Both approaches choose a Point of Departure (PoD) from a relevant toxicity study and take in to account appropriate uncertainty/safety factors in calculating the Level of Concern. Most importantly, “[f]or a given risk and given exposure to a pesticide, if exposur e were found to be acceptable under an RfD/PAD analysis it would also pass under the MOE approach, and vice-versa.” Id. For the risk assessment scenarios named above, EPA in the DDVP RED assesse d the risk posed by the scenarios using the target MOE approach, just as it does ge nerally with other non -dietary risks.

To be consistent with general Agency pract ice and EPA’s prior asse ssment of DDVP risk,
HED has re-examined the above risk assessment s cenarios using the Level of Concern approach referred to as the target MOE. Just as was done in the DDVP RED, HED has identified a PoD and target MOE for each risk assessment scenario.

This memorandum contains HED’s recommendations as to the appropriate study for the risk assessment scenarios mentioned above and the associated PoDs and target MOEs for the affected
scenarios. 1 As discussed below, HED has concluded th at the Gledhill study is not appropriate for regulatory use, and thus HED ha s concentrated in this memorandum on what alternative study or studies should be relied upon for endpoint and PoD selection and how selection of an alternative study or studies affect the target MOE. On a separate track, HED is undertaking a comprehensive review of the organophosphate (O P) pesticides, including dichlor vos, as part of Registration Review. For the OPs during Registration Review , acetylcholinesterase inhibition will be reevaluated in the toxicology database in multiple species, durations, lifestages, and routes. The temporal pattern of acetylcholines terase inhibition from single dos ing and repeated dosing studies in laboratory animals will also be evaluated. Typically, OPs exhibit a phenomenon known as steady state acetylcholinesterase i nhibition, which is characterized as acetylcholinesterase inhibition coming into equilibrium with the synthesis of ne w, uninhibited enzyme afte r repeated dosing with the same concentration of the OP. Thus, the de gree of acetylcholinesterase inhibition at a given dose remains consistent across duration. In genera l, OPs reach steady state within 2- 3 weeks but this varies among OPs. This comprehensive re-evalu ation may result in revisi ons to the selection of endpoints of concern, PoDs, and Levels of C oncern (RfD/PADs and target MOEs), for OPs generally as well as DDVP specifically.

1 If NRDC wishes to know what a “R fD/PAD” would be for these risk assessment scenarios, such a number can be calculated by dividing the PoD for the scenario by the target MOE.3 II. Decision on Use of the Gledhill study.

HED conducted a refined statisti cal reanalysis of the underlyi ng data in the Gledhill study (D420275). Based on this analysis, HED recommends that EPA no longer rely on the Gledhill study for risk assessment, and to instead use another study or studies to pr ovide points of departure for the
aforementioned risk assessment scenarios. This new statistical analysis is briefly summarized in the following paragraphs].

A total of 9 male subjects were enrolled in the Gledhill study. At the beginning of the study each subject had blood drawn every few days over a 2-week period to establish a baseline of red blood cell acetylcholinesterase (RBC c holinesterase) activity. Followi ng the pre-dosing period, on day 0 of the dosing phase of the study, 6 of the 9 subjec ts were selected to receive 0.1 mg/kg of DDVP via capsule on a daily basis for 3 weeks. The re maining 3 subjects served as controls and were given a placebo. The study is “single-blind” in that none of the subjects knew whether he was receiving DDVP or a placebo. The baseline for comparison of RBC cholinesterase activity during the 3-week dosing period was the mean of the pr etreatment and 0-day baseline RBC cholinesterase measurements. Using the pooled predose measurem ents as a reference point, there was a clear indication that dosing of the male subjects with DDVP resulted in up to 16% inhibition of RBC cholinesterase activity (See Figure 1).

Figure 1. Apparent Effect of DDVP Administrati on on RBC Acetylcholinesterase in Male
Volunteers4 There is a key assumption in the original anal ysis – that the pre-dos ing measurements of RBC cholinesterase activity are independent of e ach other and randomly distributed. HED did not make such an assumption in the follow-up anal ysis. Instead each subject was followed throughout the study commencing with the firs t pre-dosing measurement of c holinesterase activity to the termination of dosing. When the individual pre- treatment measurements of RBC cholinesterase activity are taken into account ra ther than averaged, the distribu tion of RBC cholinesterase in the pre-dosing period was not random, but declined over the two-week duration of pre-dosing in those subjects who were later select ed to receive DDVP. As shown in Figure 2, the slope of RBC cholinesterase activity in the pl acebo group is essentially flat ove r the entire study while the slope
of the RBC cholinesterase activ ity for the treatment group dec lines over the study, including the pre-treatment period. Moreover, th e statistical analysis showed that the slopes of the two groups were significantly different from one another in the pre-treatment period (p-value < 0.001). No explanation was provided in the Gle dhill study either for the differences in cholinesterase activity in the two groups or why this difference was not taken into account. Once the pretreatment
differences in cholinesterase activ ity in the two groups is incorporated into th e statistical analysis that analysis shows that there is no statistically significant eff ect of dosing with 0.1 mg/kg DDVP on either the slope or intercept of th e treated group mean response.

Figure 2. Lack of Effect of DDVP Administ ration on RBC Acetyl cholinesterase in
Male Volunteers5 Based on this statistical analysis there are at least two reasons for re jecting reliance on the Gledhill study. First, the unexplainable non-random responses in the treated subjects (i.e., the decline in RBC cholinesterase activity that began pre-dosing), create a fundamental uncertainty as to whether the study examined essentially equivale nt groups of subjects (other than due to DDVP treatment), and thus render the data unreliable. S econd, even putting this flaw to one side, the study
included insufficient dose levels to show what the analysis now purports to indicate – that 0.1 mg/kg/day is a no observed adverse effect le vel (NOAEL) for DDVP. Generally, to show a NOAEL, a study would need multiple dose levels so that the study could bot h detect the NOAEL as
well as a dose that does cause adverse effects. In the absence of a dose that causes adverse effects, it is uncertain that the study was cap able of ascertaining adverse effect s, if they were present. The Gledhill study is not usable for regulatory purposes.

III. Risk Assessment Scenarios under Considera tion/Rescission of Unnecessary PoDs

As noted, EPA is re-examining its prior choi ce of the target MOE and associated PoD forthe following risk assessment scenarios that all used the Gledhill study for risk assessment: shortterm incidental oral exposure; short-term, interm ediate-term, and long-term dermal exposure; and short-term and intermediate-term inhalation exposure . HED has determined that there are no longer any registered uses that result in long-term dermal exposure. Prior pet-collar uses th at do result in such exposure have been canceled. 72 FR 35235 (June 27, 2007). Accordingly, HED recommends that the target MOE and PoD for long-term de rmal exposure is no longer required. HED’s reexamination addresses all of the other named scenarios.

IV. Selection of Alternative Study and Po int of Departure to Assess Relevant Risk
Assessment Scenarios

Because the Gledhill study will not be used for risk assessment, an alternative study (or studies) must be identified for asse ssing risks associated w ith exposures over short (up to 1 month) and intermediate (up to 6 months) time frames. HED reviewed the DDVP toxicology data base and selected the following studies most relevant to these time frames: 1) the 13-week subchronic toxicity study in rats (MRID 41004701); 2) the 90-day subchronic neurotoxicity study in rats (MRID 42958101): 3) the repeated dose component of the comparative cholinesterase assay in young and adult rats (MRID 46153304); and the 1-y ear chronic toxicity study in dogs (MRID 41593101). Each of the studies wi ll be briefly discussed.

1. Subchronic Toxicity Study in Rats: In an acceptable 13-week subchronic study (Kleeman, 1998, MRID 41004701), Crl:CD R (SD)BR rats, 10/sex/group, were gavaged with 0, 0.1, 1.5 or 15 mg DDVP/kg/day, 5 days/week, for 13-weeks. Effects noted during th e 13-week dosing period
included instances of salivation and/or urine stains in some high-dose males and females at approximately 30 to 60 minutes post- dosing; and generalized retinal atrophy at terminal sacrifice was noted in 2/10 high-dose and 1/10 low-dose females (but no control females. Increased liver/body weight ratio seen in high dose male s was not accompanied by any body weight or enzyme changes.6 Plasma and RBC cholinesterase activity were reduced in mid and high dose animals, and RBC cholinesterase activity was reduced in 0.1 mg/kg/day females at 14 weeks; however, the reduction was less than ten percen t below control and such a small change in RBC cholinesterase activity is not considered an adverse effect. The reduction of brain cholinesterase activity in high dose male and female rats at study termination was biologically significant. No other changes were
seen in the test animals which could be attrib uted to administration of the test compound.

The data presented support a NOAEL of 0.1 mg/kg/day and a LOAEL of 1.5 mg/kg/day
based on cholinesterase inhibiti on (plasma and RBC in males and RBC in females at week 7 and RBC only in males and females at week 14). For br ain cholinesterase inhibition, the NOAEL is 1.5 mg/kg/day based on decreased brain cholinesterase activity in both sexes at the high dose only. Subsequent to the initial review, the dose-response data were analyzed by benchmark dose analysis. Whenever possible and appropria te EPA prefers to use Benchm ark Dose (BMD) analysis for determining PoDs, because such an analysis uti lizes the whole dose-response curve and provides a more quantitative alternative to the first step in dose-response assessment than the NOAEL/LOAEL process. The results of the BMD analysis ar e summarized in the following table (Table 1):

Table 1. BMD Analysis of the 13-Week Subchronic Study in Rats

DDVP inhibitory concentration (mg/kg/day)

Test group RBC Brain

BMD 10 BMDL 10 BMD 10 BMDL 10 49day - (Male) 0.57 0.41 -- -- 49day - (Female) 0.65 0.45 -- -- 98day - (Male) 0.60 0.49 1.81 0.43 98day - (Female) 0.65 0.54 2.35 1.83

2. Subchronic Neurotoxicity Study in Rats. In a subchronic oral neurotoxicity study (Lamb, 1993, MRID 42958101), DDVP was administered in deionized water to 15 Sprague-Dawley rats/sex/group at gavage doses of 0, 0.1, 7.5, or 15.0 mg/kg/day for 90 days. Within each dose group, 10 rats/sex were allocated for brain cholinesterase determ ination and 5 rats/sex were allocated for neuropathology evaluation. Additionally, blood samples were collected for cholinesterase measurements pre-study and on study weeks 3, 7, and 13. Five rats/sex/dose from the cholinesterase group and 5/sex/dose from the neuropathology group were evaluated with the Functional Observational Battery (FOB) and moto r activity tests pretes t and on study weeks 3, 7, and 12. Body weight and food consumption were measured weekly.

There was no treatment-related mortality. Mean body weight in high-dose females was consistently lower than the control (11-21%) throughout the st udy. No body weight effects were observed in any other animals, and there was no treatment-related eff ect on food consumption. Tremors, salivation, exophthalmos, lacrimation, a nd clear material on the forelimbs were observed in high-dose males and females approximately 15 minutes post-dosing. Rales, chromodacryorrhea, and red/yellow/orange material around the nose a nd mouth were also seen in high-dose rats.
Tremors were observed in three mid-dose males and nine mid-dose females. Generally, the clinical7 signs occurred during the third week of treatment in the mid-dos e animals and as early as the first week of dosing and throughout the study in th e high-dose rats. Cholinesterase activity was decreased in mid- and high-dose male and female rats as follows: plasma 30-58%; erythrocyte 8- 35%; brainstem and brain cortex 10-16%. There were no treatment -related effects in the FOB or motor activity tests. No treatment-related neurohist opathological lesions and no apparent changes in brain weight or size were observed. The NOA EL is 0.1 mg/kg/day and the LOAEL is 7.5 mg/kg/day based on decreased cholinesterase activity and clinical cholinergic signs.

EPA used benchmark dose analysis where feasible to refine points of departure from the subchronic neurotoxicity study. Ma ny useful analyses of brain substructures were performed, but analyses of RBC and plasma cholinesterase were not useful primarily becau se of poor fit of the
BMD models to the data.

3. Comparative Cholinesterase Assay in rats. In a series of special comparative cholinesterase inhibition (ChEI) assay, DDVP was ad ministered by gavage to groups of either Sprague-Dawley or Wistar rats. In the repeated dosing phase of the studies, seven daily doses of 0, 0.1, 7.5, or 15 mg/kg/day were given to groups of 5 rats/sex beginning on either post-natal day 12 (pre-weaning) or 42 (young adult). Animals were sacrificed on e hour after the last dose. RBC and brain ChE
activities were measured in all animals. Plas ma enzyme activity was not measured (Moxon, 2003, MRID 46153304),

In pre-weaning rats, tremors were observed in 5/5 males a nd 5/5 females at 15 mg/kg/day on 3-5 days of the dosing interval . In young adult rats at 15 mg/ kg/day, tremors were observed in 3/5 males and 5/5 females on one to four days of th e dosing interval. In ad dition, tremors were seen in one young adult male after the last dose of 7.5 mg /kg/day. No clinical si gns of toxicity were observed in the remaining groups.

Dose-related inhibition of RBC and brain ChE activities was apparent in both adult and pre-weaning rats. Biologically significant inhibi tion of RBC enzyme activity (>50%) occurred at doses of 7.5 and 15 mg/kg/day in both sexes of adults and pre-weaning and at 0.1 mg/kg/day for adult animals (11-17%). Brain enzyme activity was statistically and biologically inhibited in both sexes at doses of 7.5 and 15 mg/kg/day for a dults (>50%) and at all doses for pups (>20%).

The dose-response data for cholinesterase inhibition were subsequently analyzed by benchmark dose modeling. The following table (Table 2) briefly summarizes the results of the analysis:8 Table 2. BMD Analysis of Repeated Do se Comparative Cholinesterase Data

DDVP inhibitory concentration (mg/kg/day)

Test group RBC Brain

BMD 10 BMDL 10 BMD 10 BMDL 10 Pre-weaning (M) 1.66 1.41 1.50 1.40
Pre-weaning (F) 1.47 0.83 1.46 0.76
Young adults (M 1.63 1.31 2.02 1.80
Young adults (F) 1.55 1.26 1.55 1.26

4. One-year Chronic Toxicity Study in Dogs. Generally chronic studies are used in selecting a PoD for chronic exposures and for evaluating po tential carcinogenic effects. However, for DDVP, the chronic dog study is relevant to shor ter than chronic exposure periods because plasma and RBC cholinesterase activity measurem ents were recorded at 5 intermediate time points during the study, and, for the mid- and high-dose groups, statis tically significant
cholinesterase inhibition was seen within a few weeks of the onset of the study.

In the chronic feeding study (Markiew icz, 1990, MRID 41593101), groups of beagle dogs were administered DDVP by capsule for 52 weeks at dose levels of 0, 0.1, 1.0 and 3.0 mg/kg/day. The 0.1 mg/kg/day dose was lowe red to 0.05 mg/kg/day on day 22 due to the inhibition of plasma cholinesterase noted after 12 days (plasma cholinesterase was decreased in males (21.1%) and females (25.7%) at week 2 in the 0.1 mg/kg/day group). At time points after week 2, plasma cholinesterase activity was only significantly reduced in the mid- and high-dose groups. With one exception, RBC cholinesterase ac tivity was not decreased at any point in the study at the low dose (either the initial 0.1 mg/k g/day dose or the 0.05 mg/kg/day dose). The one exception occurred at week 6. At that time point, reported RBC cholinesterase activity was reduced in males (23.6%) and females (50.1%). HE D’s initial review of the study suggested that this reported RBC cholinesterase activity might be an effect on RBC cholinesterase of the higher dose of 0.1 mg/kg/day that had been administer ed earlier. RBC cholinesterase activity was significantly decreased in the mid- and high-dose gr oups starting at week 2. Brain cholinesterase activity was significantly reduced in males in the mid-dose group and in both sexes in the high dose group. However, the brain cholinesterase measurement was only made at the end of the study and thus has limited relevance for evaluating the effects of short- or intermediate-term exposure. The NOAEL was 0.05 mg/kg/day a nd the LOAEL was 1.0 mg/kg/day based on plasma, RBC and brain cholinesterase inhibition in males and females.

Further analysis of the RBC cholinesterase inhibition at 6 weeks in the 0.05 mg/kg/day dose group indicates that it is un likely to be due to “an effect on RBC cholinesterase of the higher dose of 0.1 mg/kg/day” for several reasons. First, all dose groups exhibited a higher than expected increase in RBC inhibiti on at 6 weeks. Second, the in crease in RBC cholinesterase inhibition did not occur until approximately 20 days after the low dose was decreased. Finally, the 6-week “bump-up” in RBC cholinesterase inhibition was not seem with plasma9 cholinesterase activity measurements. Plasma c holinesterase did not sh ow significant inhibition once the dose was reduced at day 22. The most likely cause of the 6-week RBC inhibition increase is a mistake in analysis of all of th e RBC 6-week samples. Therefore, data from the 6- week measurement was not used for endpoint selection.

Brain and RBC cholinesterase data were anal yzed by benchmark dose methods, and the results
are summarized in Table 3.

Table 3. BMD Analysis of the 1-Year Oral Subchronic Study in Dogs

DDVP inhibitory concentration (mg/kg/day)

Test group RBC Brain

BMD 10 BMDL 10 BMD 10 BMDL 10 13wk - (Male) 0.14 0.13 -- -- 13wk - (Female) 0.13 0.09 -- -- 53wk - (Male) 0.11 0.09 0.54 0.41 53wk - (Female) 0.21 0.18 0.84 0.58

V. Selection of the Appropriate Study.

HED determined that the chronic toxicity study in dogs is the appropriate study for selecting an endpoint and PoD for short- and intermediate-term risk assessments. Compared to the other considered studies, both the NOAEL for RBC cholinesterase inhibition and the BMDL 10 for that effect were lowest in the chronic dog study. Further, RBC cholinesterase inhibition was
observed within a few weeks of the start of dos ing and generally remained at the same level throughout the study. Thus, the study is relevant to short- and intermediate-term exposure. RBC, not brain, cholinesterase in hibition is recommended as the e ndpoint of concern because the benchmark dose analysis shows that RBC cholin esterase is more sensitive than brain
cholinesterase to the inhib itory effects of DDVP (Table 3). Although HED has previously indicated (77 FR 54402, 54418; September 5, 2012), that the subchronic rat study would be the proper study for selecting an endpoint and PoD fo r short- and intermediate-risk assessment of dichlorvos in the absence of the Gledhill study, that determination was made prior to full
consideration of the relevance of the chronic dog study and a BMD analysis of that study.
Reliance on oral studies to assess risk from exposure under the dermal and inhalation routes is an issue being comprehensively examined as part of Registration Review for OPs, including
dichlorvos.

VI. Selection of Point of Departure

The RBC BMDL 10 values at study week 13 are 0.09 mg/kg/day in females and 0.13 mg/kg/day in males. Since there is no indica tion in the study data of a sex difference in sensitivity to RBC cholinestera se inhibition, HED has selected 0.1 mg/kg/day, an average of these values, as the PoD for risk assessment.10 This PoD is lower than any other for repe ated dose studies analyzed by benchmark dose methods, but all such studies had PoDs close to the recommended one. The PoD should be used to assess short-term incidental oral risk; short- term and intermediate-term dermal risk; and shortterm and intermediate-term inhalation risk. As explained earlier, HED has determined that there are no longer any registered uses that result in long-term derm al exposure and thus no PoD for long-term dermal risk assessment is required.

VII. Uncertainty/Safety Factors

In the 1996 RED, a 3X FQPA Safety Factor was retained due to a lack of a NOAEL in the human study (Gledhill, 1997) that was used for assessing risk via short-term incidental oral; short-,intermediate-, and long-term dermal; short- and intermediate-term inhalation of vapors; and shortand intermediate-term inhalation exposure scenarios.

In this re-examination, the FQPA Safety Factor is not required (i.e ., 1X) since an animal study with a NOAEL has replaced the human study with a LOAEL and also due to the completeness of the DDVP toxicity database, the lack of residual uncertainties for pre- and/or postnatal toxicity, and the fact that the DDVP fo od, drinking water, and residential assessments are not expected to underestimate exposure. Fo r more details on the DDVP FQPA Safety Factor, refer to the Human Health Risk Assessment, dated June 22, 2006, and to the comprehensive analysis of the need for a FQPA safety factor fo r dichlorvos in response to the petition seeking
revocation of dichlorvos tolerances. See 72 FR 68662

, 68694-68695 (December 5, 2007); 73 FR
42683

, 42696 (July 23, 2008); 77 FR 54402, 54412-54419 (September 5, 2012).

Therefore, the Agency’s Level of Concern in a target Margin of Exposure of 100 which include the conventional 100 uncertainty factors. The default interspe cies factor of 10x for
uncertainties related to the ex trapolation of toxicokinetic a nd toxicodynamic properties of a chemical in a test species to an average human is appropriate; as well as the default intraspecies
factor of 10x for uncertainties rela ted to the variation in susceptibility in th e human population to the toxicity of individual chemi cals should be applied to the sele cted PoD to derive a level of

concern

VIII. Conclusion

HED recommends a PoD of 0.1 mg /kg/day with a Level of Concern of 100 for short-term incidental oral exposure; short-term and interm ediate-term dermal exposure; and short-term and intermediate-term inhalation exposure. Further, as explained earlier, HED has determined that there are no longer any registered uses that result in long-term dermal exposure and thus the designated PoD and target MOE for long-term dermal exposure should be rescinded.

As mentioned above, organophosphates, including dichlorvos, are presently undergoing a comprehensive reevaluation as part of Registra tion Review. Conclusions in this memorandum may change based on that comprehensive reevaluation.11 IX. Bibliography

Kleeman, J. (1988) 13-Week Gavage Toxicity St udy with DDVP in Rats: Final Report: Project ID: HLA 6274-102. Unpublished study pre- pared by Hazleton Laboratories America, Inc. 294 p.
MRID 41004701.

Lamb, I. (1993) A Subchronic (13 Week) Neurot oxicity Study of Dichlo rvos in Rats: Final Report: Lab Project Number: WIL-188004. Unpublished study prepared by WIL Research Labs, Inc. 1199 p. MRID 42958101.

Markiewicz, V. (1990) A 52-Week Chronic T oxicity Study on DDVP in Dogs: Lab Project Number: 2534/102. Unpublished study prepared by Hazleton Laboratories America, Inc. 431 p.
MRID 41593101

Moxon, M.E. (2003) Dichlorvos: Re peat dose cholinesterase inhi bition study in pre-weaning and young adult rats. Central Toxico logy Laboratory, Cheshire, UK SK104TJ. Laboratory report number CTL/KR1490/Regulator y/Report; Study No. KR1490, 24-OCT-2002. MRID 46153304. Unpublished.

Nguyen, (2014). Statistical Report: Dichlo rvos - A Single Blind, Placebo Controlled, Randomized Study to Investigate the Effects of Multiple Oral Dosing on Erythrocyte Cholinesterase Inhibition in Healthy Ma le Volunteers. Memorandum dated May 28, 2014, (D420275)