Page 1 of 17 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D. C., 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES TXR No. 0053990 MEMORANDUM DATE: March 20, 2006 SUBJECT: Human Studies Review Board: Final Weight of Evidence Comparison of Human and Animal Toxicology Studies and Endpoints for DDVP Human Health Risk Assessment and Discussion of Interspecies Extrapolation in the Organophosphate Cumulative Risk Assessment.

DP Barcode: 327499 Reregistration Case#: 0310 PC Code: 084001 MRID #: several FROM: Ray Kent, Ph. D., Chief Reregistration Branch 4 Health Effects Division ( 7509C)

William Dykstra, Ph. D., Toxicologist Reregistration Branch 4 Health Effects Division ( 7509C)

TO: Tina E. Levine, Ph. D., Director Health Effects Division ( 7509C)

This weight of evidence ( WOE) document for dichlorvos ( DDVP) describes the Agency's rationale for selecting a repeated dose human toxicity study ( MRID 44248801) to assess risks from short and intermediate term residential and occupational exposure to DDVP. In addition, the WOE document also discusses why an acute human toxicity study ( MRID 44248802) was not considered appropriate to assess risks from a single exposure to DDVP. The WOE document also discusses the Agency's conclusions regarding the usefulness of this study in the cumulative risk assessment for the OPs. Page 2 of 17 Background. Dichlorvos is an organophosphate insecticide that is toxic to mammals, including humans, through inhibition of the acetylcholinesterase( s) of the peripheral and/ or central nervous system. The technical registrant for dichlorvos has submitted a number of toxicity studies involving direct dosing of humans to support their contention that humans are no more or less sensitive to the effects of dichlorvos than rats, dogs or other experimental animals. In this document, HED scientists compare the strengths and weaknesses of the human and animal toxicity studies and present how the human studies compare with the animal studies, i. e., are the human data consistent with animal data in terms of types of effects and effect levels or are there notable differences between animals and humans.

This document focuses on two human studies in which humans were intentionally dosed with dichlorvos; a single dose oral study ( MRID 44248802) and a repeated dose oral study ( MRID 44248801). The human data are compared with animal data from similar studies, and recommendations for endpoint selection are made based on the most appropriate studies and uncertainty factors. All of the studies are discussed in summary form and then the weight of evidence discussion of endpoint selection follows.

Chemical and Hazard Characterization of Dichlorvos Dichlorvos is a phosphate triester with a molecular formula of C4H7O4PCl2 and a molecular weight of 221. It is a liquid at room temperature with a relatively high vapor pressure of 0.032 mm ( 30 C).

The high vapor pressure of dichlorvos is the basis for its use as a fumigant for processed food commodities, food warehouses and food handling establishments. Because of its volatility, dichlorvos is also incorporated into resin strips for use at many sites including family homes.

Like most other cholinesterase inhibiting phosphotriesters, dichlorvos is asymmetrical with respect to the ester substituents, with two relatively difficult to hydrolyze methyl groups and a dichlorovinyl " leaving group" which is more readily hydrolyzed and is the group displaced when dichlorvos reacts at the active site of cholinesterases. Many sulfur containing organophosphate cholinesterase inhibitors require metabolic activation to convert an unsubstituted phosphorous sulfur ( P= S) group to a phosphorus oxygen oxon ( P= O) group before inhibition of cholinesterase can occur; however, dichlorvos already exists in the oxon form and needs no activation to inhibit cholinesterases.

Dichlorvos is well absorbed by all routes of exposure and extensively metabolized with excretion of metabolic products occurring mostly in the urine and through exhalation as CO2. Absorbed dichlorvos is initially inactivated by an esterase found in plasma and liver. The esterase catalyzes the hydrolysis of dichlorvos to dimethyl phosphate and dichlorovinyl alcohol which Page 3 of 17 spontaneously rearranges to 2,2, dichloroacetaldehyde which is then metabolized further. Dichlorvos may also be inactivated by a glutathione dependent reaction to form desmethyl dichlorvos. The half life of dichlorvos in the blood is very short, 15 minutes or less.

Dichlorvos inhibits plasma, erythrocyte, and brain cholinesterase in a variety of species, but does not cause organophosphate induced delayed neurotoxicity ( OPIDN) in the hen ( MRID 43433501). In acute and 90 day neurotoxicity studies in rats ( MRIDs 42497901, 41004101, there was no neuropathology associated with changes in FOB and motor activity. Subchronic and chronic oral exposures in rats and dogs ( MRIDs 41004701, 41593101) as well as chronic inhalation exposure in rats ( MRIDs 00057695, 00532569) resulted in significant decreases in plasma, red blood cell and/ or brain cholinesterase activity. Animal toxicity studies do not show evidence of gender susceptibility. Repeated, oral subchronic exposure in male humans was associated with statistically and biologically significant decreases in red blood cell cholinesterase activity ( MRID 44248801).

There was no evidence of increased susceptibility following in utero exposure to rats and rabbits as well as pre/ post natal exposure to rats in developmental and reproduction studies ( MRIDs 41802401, 41951501, 42483901). However, increased sensitivity to dichlorvos induced inhibition of brain cholinesterase activity was observed in repeated gavage studies in preweaning rats in comparison to young adult rats ( MRID 46153304). These findings necessitated that a special Food Quality Protection Act ( FQPA) 3x safety factor be retained for assessment of risks ( other than risks from acute exposure) where the endpoint is based on RBC cholinesterase inhibition as a result of repeated exposure. A factor of 3x is considered appropriate since the differences in brain cholinesterase inhibition were minimal. The factor of 3x is not needed for assessing acute risks, since there was no increased sensitivity in brain cholinesterase activity in preweaning rats in comparison to young adults following a single gavage dose of dichlorvos.

Specific Toxicity Studies Single Dose Oral Studies:

A. Human In a single dose human study with DDVP ( MRID 44248802), the NOAEL for RBC cholinesterase depression is 1.0 mg/ kg bw based on the absence of statistically significant ChE depression in 6 fasted young healthy male volunteers administered a 70 mg oral dose of DDVP. In this study, the first cholinesterase measurement was recorded 24 hours after dosing. In another study ( MRID 46153303) on the measurement of RBC and brain ChE activity in preweaning and adult female rats treated with a single dose of 15 mg/ kg dichlorvos, time course data demonstrate that the time of peak effect for both RBC and brain ChE measurements is 1 3 hours post dosing and that by 24 hours post dosing, RBC cholinesterase activity has recovered to levels similar to the controls ( MRID 46153303). Therefore, the absence of biologically significant RBC ChE depression in the human study may be due to the absence of blood Page 4 of 17 sampling at the time of peak effect ( 1 3 hours), since in the human study, the first measurement did not occur until 24 hours after dosing.

B. Animals Single dose comparative cholinesterase studies in preweaning and adult rats which measured both RBC and brain ChE depression at 1 hour following oral exposure were analyzed by a Benchmark Dose ( BMD) procedure ( MRIDs 45805703, 45842301). The BMDS ( Benchmark Dose Software version 1.3.2) model was used to derive the BMD10, the estimated dose that results in 10% inhibition of cholinesterase, and the BMDL10, the lower 95% confidence interval on the BMD10, for the cholinesterase data evaluated. For this analysis, the continuous polynomial model was used with the default option of relative deviation for the benchmark response ( BMR) type. A BMR factor of 0.1 was the basis for BMD10 and BMDL10 derivation.

A BMDL10 of 0.8 mg/ kg ( BMD = 1.6 mg/ kg) based on female brain ChE depression was selected as the lowest value of all the studies available which were analyzed. Consistent with EPA's Draft Technical Benchmark Dose Guidance ( 2000), the BMDL, not the BMD, is used to extrapolate risk. BMD analysis of studies with pup and adult ChE depression results did not demonstrate any substantial age related numerical differences in BMDL values ( all values were approximately 1 mg/ kg) for either RBC or brain cholinesterase.

Repeated Dose Oral Studies A. Human In a single blind oral study ( MRID 44248801), 6 fasted male volunteers were administered 7 mg of DDVP in corn oil ( equivalent to approximately 0.1 mg/ kg/ d) via capsule daily for 21 days. Three control subjects received corn oil as a placebo. Baseline values for RBC cholinesterase activity for each study participant were determined. After dosing started, RBC cholinesterase activity was monitored on days 2, 4, 7, 9, 11, 14, 16, and 18, then on day 25 or 28 post dosing. No toxicity attributable to administration of DDVP was reported. Mean RBC cholinesterase activity was statistically significantly reduced in treated subjects on days 7, 11, 14, 16, and 18. These values were 8, 10, 14, 14, and 16 percent below the pre dose mean. Although the percent mean depression was less than 20%, the blood samples were not taken until just before the next day's dose, at the point of maximum recovery. Under the conditions of the study, a LOAEL for RBC cholinesterase inhibition was established at 0.1 mg/ kg/ d based on the consistent, statistically significant ChE depression over time, although ChE depression during the study was less than 20%. A NOAEL was not established.

The repeated dose human study has been criticized for a number of reasons including:

1) Too few subjects. There were six treated adult males and three adult males served as placebo controls. All of the treated males responded to some extent to repeated dosing of dichlorvos with a mean response of 16%. If there had been no response, then the argument that there were Page 5 of 17 insufficient subjects might have more merit, however, the Agency has determined that the administered dose is a LOAEL.

2) Use of males only. All subjects were adult males. Animal toxicity studies do not show evidence of gender susceptibility.

3) Administration of only a single dose level. A single dose level of 7 mg per person per day was administered for 21 days. This dose resulted in sufficient RBC cholinesterase inhibition that we consider the response to be a LOAEL. If there had been no response, interpretation of the results would have been problematic.

4) Blood sampling did not occur until 24 hours after dosing. This is considered a critical deficiency for the single dose study; however, after 21 days there is a clear response which the Agency considers a LOAEL. If blood had been sampled at 1 3 hours after dosing, RBC cholinesterase inhibition may have been somewhat greater.

B. Animal Comparative cholinesterase ( 7 day rat). In a comparative cholinesterase inhibition study ( MRID 46153304), dichlorvos was administered by gavage in seven daily doses of 0, 0.1, 7.5, or 15 mg/ kg/ day to groups of 5 rats/ sex beginning on either PND 12 ( pre weaning rats) or 42 ( young adults) and animals were sacrificed one hour after the last dose. RBC and brain ChE activities were measured in all animals in each study. In pre weaning rats, tremors were observed in 5/ 5 males and 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 the dosing interval. In addition, tremors were seen in one adult male after the last dose of 7.5 mg/ kg/ day. No clinical signs of toxicity were observed in the remaining groups. Dose related inhibition of RBC and brain ChE activities was apparent after repeated dosing in both adult and pre weaning rats. Biologically significant inhibition 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 the low dose 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 adults (> 50%) and at all doses for pups (> 20%). The LOAEL for inhibition of RBC cholinesterase was 0.1 mg/ kg/ day and a NOAEL was not identified based on findings in young adults. The LOAEL for inhibition of brain cholinesterase was 0.1 mg/ kg/ day and a NOAEL was not identified based on findings in pre weaning pups.

Subchronic neurotoxicity ( 90 day rat). In a subchronic oral neurotoxicity study ( MRID 42958101), dichlorvos 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 determination and 5 rats/ sex were allocated for neuropathology evaluation. Additionally, blood samples were collected for cholinesterase measurements prestudy 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 motor activity tests pretest and on study weeks 3, 7, and 12. Body weight and food consumption were measured weekly. Page 6 of 17 There was no treatment related mortality. Mean body weight in high dose females was consistently lower than the control ( 11 21%) throughout the study. No body weight effects were observed in any other animals, and there was no treatment related effect on food consumption. Tremors, salivation, exophthalmos, lacrimation, and 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 and mouth were also seen in high dose rats. Tremors were observed in three mid dose males and nine mid dose females. Generally, the clinical signs occurred during the third week of treatment in the mid dose animals and as early as the first week of dosing and throughout the study in the 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 neurohistopathological lesions and no apparent changes in brain weight or size were observed. Based on decreased cholinesterase activity and clinical cholinergic signs, the LOAEL for dichlorvos is 7.50 mg/ kg and the NOAEL is 0.1 mg/ kg.

Chronic ( One year dog). In a chronic feeding study ( MRID 41593101), groups of 4/ sex/ dose beagle dogs were administered dichlorvos 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 lowered 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 males ( 39.1 to 59.2%) and females ( 41.0 to 56.7%) in the mid dose group and in males ( 65.1 to 74.3%) and females ( 61.1 to 74.2%) in the high dose group. Although RBC cholinesterase activity was reduced in males ( 23.6%) and females ( 50.1%) at week 6 in the low dose group, this was believed to be residual effect on RBC cholinesterase of the higher dose of 0.1 mg/ kg/ day. RBC cholinesterase inhibition was not observed in this group after week 6. At time points after week 6, RBC cholinesterase activity was only significantly decreased in males ( 43.0 to 53.9) and females ( 38.0 to 51.9) in the mid dose group and in males ( 81.2 to 86.9%) and females ( 79.2 to 82.5%) in the high dose groups. Brain cholinesterase activity was significantly reduced in males ( 22%) in the mid dose group and in males ( 47%) and females ( 29%) in the high dose group. The NOAEL was 0.05 mg/ kg/ day and the LOAEL was 0.1 mg/ kg/ day based on plasma and RBC cholinesterase inhibition in males and females.

Other animal studies. There are several other animal studies by the oral route in which RBC and plasma cholinesterase were measured: 1) 90 day rat subchronic in rats ( MRID 41004701), LOAEL = 1.5 mg/ kg/ day based on plasma and RBC cholinesterase inhibition, NOAEL = 0.1 mg/ kg/ day; 2) Range finding study for the rabbit developmental study ( MRID 41802401), LOAEL = 1 mg/ kg/ day based on RBC cholinesterase inhibition, NOAEL = 0.1 mg/ kg/ day. Repeated dose ( 28 day) delayed neurotoxicity study in hens ( MRID 43433501), LOAEL = 0.3 mg/ kg/ day based on inhibition of brain cholinesterase, NOAEL = 0.1 mg/ kg/ day.

Endpoint Selection. Page 7 of 17 Acute RfD. In the past, the acute dosing study in humans was considered suitable for use in establishing an acute RfD, but recently received time course data in rats indicate that peak inhibition of RBC cholinesterase occurs 1 3 hours after oral dosing and that by 24 hours postdosing cholinesterase activity returns to near control levels. The risk assessment team concludes that the lack of cholinesterase measurements prior to 24 hours post treatment in the acute human study is a deficiency so critical that it has opted not to rely on the acute human study for either establishing an acute RfD or to decrease the interspecies uncertainty factor.

The rat acute BMDL10, 0.8 mg/ kg, was selected for assessment of acute exposure scenarios. An uncertainty factor of 100 ( 10x for interspecies differences and 10x for intraspecies variation) was applied. It was concluded that an additional special FQPA factor is not needed, since BMD analysis of studies with pup and adult ChE depression results for either RBC or brain cholinesterase inhibition did not demonstrate any substantial numerical differences in the acute BMDL values for either RBC or brain cholinesterase inhibition ( all values were approximately 1 mg/ kg). Based on this assessment, an acute RfD of 0.008 mg/ kg/ day for the general population was derived for DDVP.

Short term residential & occupational exposure. There are a number of repeated dose studies that are under consideration, either individually or collectively, for providing appropriate endpoints for risk assessment for short term durations.  The 21 day repeated dose study in humans with a LOAEL for RBC cholinesterase inhibition of 0.1 mg/ kg/ day is of an adequate duration for selection of endpoints.  In the 7 day repeated dose comparative cholinesterase study in rats, the LOAEL for adult rats for RBC cholinesterase inhibition was 0.1 mg/ kg/ day, whereas in pre weaning rats, 0.1 mg/ kg was a NOAEL for RBC cholinesterase inhibition.  In the 7 day repeated dose comparative cholinesterase study in rats, the NOAEL for inhibition of brain cholinesterase inhibition in adult rats was 0.1 mg/ kg/ day, whereas 0.1 mg/ kg/ day was a LOAEL in preweaning rats.

The DDVP risk assessment team concludes that the 21 day human study is sufficiently robust and is more reflective of the short term exposure duration of 30 days or less, and has therefore selected that study for assessment of short term risks via all routes of exposure.

Intermediate term residential & occupational exposure. There are a number of repeated dose studies that are under consideration, either individually or collectively, for providing appropriate endpoints for risk assessment for intermediate term durations.  The 21 day repeated dose study in humans with a LOAEL for RBC cholinesterase inhibition of 0.1 mg/ kg/ day is of an adequate duration for selection of endpoints.  The NOAEL in a 90 day rat subchronic neurotoxicity study was 0.1 mg/ kg/ day and the LOAEL was 7.5 mg/ kg/ day based on clinical signs of neurotoxicity and inhibition of plasma, RBC and brain cholinesterase.  In a chronic feeding study in dogs, the LOAEL for plasma and RBC cholinesterase inhibition was 0.1 mg/ kg/ day and the NOAEL was 0.05 mg/ kg/ day measured at 3 and 6 weeks. The NOAEL for brain cholinesterase inhibition measured at the end of the study was 0.05 mg/ kg/ day. Page 8 of 17 The findings in the repeated dose studies are consistent across species and over study durations ranging from seven days to one year, with the LOAEL or NOAEL fluctuating around 0.1 mg/ kg/ day for RBC or brain cholinesterase inhibition. The HED dichlorvos risk assessment team is of the opinion that the endpoint of RBC cholinesterase inhibition in the human repeated dose study is well supported by several animal studies and should serve as the basis for comparison in assessing short and intermediate term risks. A MOE of 100 is recommended to account for intraspecies variability ( 10x), the lack of NOAEL in this study ( 3x) and a Special FQPA factor of 3x. The Special FQPA factor is based on residual concern for the sensitivity shown by young rats to brain cholinesterase inhibition in the repeated dose comparative cholinesterase study ( MRID 46153304). A Special Factor of 3x is considered sufficient since the percent inhibition ( 25%) in brain cholinesterase in preweaning rats at 0.1 mg/ kg/ day is not substantial. The factor should be applied in any situation where the endpoint is based on RBC cholinesterase inhibition. A factor of 3x rather than 10x was used to account for a lack of a NOAEL since the RBC cholinesterase inhibition in humans during the exposure period of 21 days was minimal.

The dichlorvos risk assessment team acknowledges that there may be some uncertainty associated using the 21 day study for exposures up to 6 months in duration, particularly given that steady state has not yet been reached in the human study. However, the Team notes that for purposes of quantitative risk assessment, use of the steady state BMDL10 of 0.4 mg/ kg/ day from the rat 90 day subchronic study ( see below) with 10X factors for intra and inter species extrapolation yields a regulatory endpoint of 0.004 mg/ kg/ day. Use of the human LOAEL of 0.1 mg/ kg/ day with a 3X for LOAEL to NOAEL with a 10X factor for intra species extrapolation yields a regulatory endpoint of 0.003 mg/ kg/ day. These two approaches provide very similar regulatory endpoints. Thus, the human LOAEL provides a reasonable endpoint for extrapolating human health intermediate term risk.

Chronic RfD and long term residential & occupational. The same rationale described under short and intermediate term scenarios could be used for long term scenarios since study duration didn't seem to make any difference in the NOAELs and LOAELs; however, the risk assessment team concluded that it would be difficult to justify using a 21 day human study for chronic or long term scenarios. The risk assessment team recommends continuing to use the one year dog study for establishing a chronic oral RfD and to assess long term occupational or residential risk.

For the chronic dog study with a NOAEL of 0.05 mg/ kg/ day, an uncertainty factor of 300x was selected ( 10x for interspecies variation, 10x for intraspecies extrapolation, and 3x for a Special FQPA factor as described above. The risk assessment team considered reducing the interspecies factor to 3x based on the similarity of the human data to the dog data, but chose to continue with the standard 10x value based again on the difficulty in justifying use of a 21 day study ( with a LOAEL) to decrease the interspecies factor for a chronic study. Based on this information, a chronic oral RfD of 0.00017 mg/ kg/ day was established for DDVP based on the dog study. Page 9 of 17 Note on Human Studies Cited in MacGregor et al ( 2005)

In its submissions to, and discussions with the Agency about the risk assessment of dichlorvos, the registrant has consistently made the argument that the body of experimental animal and human data indicate that humans are no more sensitive to the cholinesterase inhibiting effects of dichlorvos than are laboratory animals, and therefore, the interspecies factor reflecting uncertainty about sensitivity across species should be 1x. In a publication appearing last year ( MacGregor et al, 2005), the registrant and its consultants reiterated their argument for removing the interspecies factor and cited key human and experimental animal studies conducted over four decades in support of their thesis.

EPA has looked at these studies and remain of the opinion that a weight of evidence argument such as MacGregor et al. present is only as robust as the individual studies that are used to build the argument. The publication lists 29 studies " available for assessment of DDVP toxicity potential", but only 11 of these are used for the quantitative interspecies comparison ( capsulized in Appendix A). There are four oral studies listed for quantitative comparison, two of which are discussed in this weight of evidence document ( Gledhill, 1997a, 1997c). One of the remaining oral studies, ( Slomka and Hine, 1981) utilizes a slow release formulation of dichlorvos entrained in plastic beads. The availability of dichlorvos in this formulation is unknown. The remaining study ( Gledhill, 1997b) is deficient as well ( Appendix A).

There are 7 human inhalation studies, 3 of which use children as subjects and are therefore are excluded in accord with the Human Studies Rule. Two of the remaining 4 studies ( Smith et al., 1972 and Witter et al., 1961) limit exposure to 2 hours or less which is of little use in assessing current use patterns, or for comparing with animal data. One study ( Stein et al., 1966) monitors exposure to workers over a few weeks, but it isn't possible from the study to determine what the actual exposures to the subjects were. One study ( Ueda and Nishimura, 1967) in which four subjects were exposed to relatively high levels for 2 days may have limited use for comparing with animal data.

The Agency has concluded that these studies are insufficient to support a weight of evidence argument that the interspecies factor should be reduced to 1X. Page 10 of 17 OP Cumulative Risk Assessment The Food Quality Protection Act ( FQPA) was passed by Congress in 1996. The FQPA made key changes to the approaches used by EPA to assess pesticide chemicals. One of these changes was the requirement to consider cumulative risk to those pesticides which act by a common mechanism of toxicity. Pesticides are determined to have a " common mechanism of toxicity" if they act the same way in the body that is, the same toxic effect occurs in the same organ or tissue by essentially the same sequence of major biochemical events. OPP established the organophosphate pesticides ( OPs) as a common mechanism group and in accordance with FQPA has developed a cumulative risk assessment for this group of pesticides ( USEPA, 2002a). DDVP is a member of the OP common mechanism group.

OPP has developed a guidance document for developing cumulative risks assessments under FQPA ( USEPA, 2002b). This guidance indicates that when developing multi chemical hazard assessments, comparison of toxic potency should be made using a uniform basis of comparison, by using to the extent possible a common response derived from a comparable measurement methodology, species, and sex for all the exposure routes of interest. In the OP cumulative risk assessment, brain ChE data from rat toxicity studies in duration of 28 days and longer have been used by EPA to estimate relative potency and to develop the points of departure for extrapolating cumulative risk. ChE inhibition of OPs typically reaches steady state in rats at or near 28 days of exposure. Thus, potency estimates for exposures in duration from approximately one month or longer are consistent and show less variation than potency estimates for shorter exposure durations. Brain data have been selected over RBC data as brain ChE inhibition represents a direct measure of the target tissue ( as opposed to blood data which is considered a surrogate measure) and brain ChE tend to have less variation and thus confer less uncertainty on cumulative risk estimates.

In the DDVP human multi dosing study, the subjects exhibited 8, 10, 14, 14, and 16 percent below the pre dose mean on days 7, 11, 14, 16, and 18 respectively. These data indicate that there is an increase in inhibition from days 7 to 18 of exposure. As such, steady state in humans may not have yet been reached during the DDVP study. The Agency notes given the relatively small increase ( 2%) in inhibition observed from days 14 to 18, it is unlikely that RBC ChE inhibition would increase substantially with prolonged exposure.

Incorporation of the results from the DDVP human multi dosing study may create a mismatch with the relative potency factors and points of departure being used in the cumulative risk assessment which are based on ChE inhibition at steady state. The Agency has determined that for the cumulative risk assessment, the inter species factor for oral exposure to DDVP will be 10X. This determination is based, in part, on uncertainties associated with lack of steady state ChE inhibition in the human study and potential mis matching with the data being used for relative potency and points of departure. The 10X inter species extrapolation factor is further supported by a comparison of the results from the human study with RBC BMD10s estimated by EPA previously ( USEPA, 2001) from the DDVP rat subchronic study where steady state was reached ( MRID no. 41004701; see table below). Dividing rat BMD10 of approximately 0.6 mg/ kg/ day by the human endpoint ( 0.1 mg/ kg/ day) yields a rat to human extrapolation factor of approximately 6X. It is notable that rat benchmark response is based on 10% RBC ChE Page 11 of 17 inhibition whereas the human endpoint is 16%. It is reasonable to expect that the dose to result in 10% RBC ChE inhibition in humans would be lower than that resulting in 16% RBC ChE inhibition. As such, the 6X ratio is likely to be higher ( ie, closer to 10X).

Sex and Age RBC Human ( male) 16% at 0.1 mg/ kg/ day on Day 18 Rat BMD10 BMDL10 Male 0.57 0.60 0.41   0.49 Female 0.65 0.45   0.54 Page 12 of 17 Bibliography Gledhill, A. ( 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: Lab Project Number: CTL/ P/ 5392: XH6063. Unpublished study prepared by Zeneca Central Toxicology Lab. 52 p. ( MRID 44248801)

Gledhill, A. ( 1997) Dichlorvos: A Study to Investigate the Effect of a Single Oral Dose on Erythrocyte Cholinesterase Inhibition in Healthy Male Volunteers: Lab Project Number: CTL/ P/ 5393: XH6064. Unpublished study prepared by Zeneca Central Toxicology Lab. 44 p. ( MRID 44248802)

USEPA, 2000. " Benchmark Dose Technical Guidance Document" Draft report. Risk Assessment Forum, Office of Research and Development, U. S. Environmental Protection Agency. Washington, DC. EPA/ 630/ R 00/ 001 USEPA ( 2001). Preliminary Organophosphorus Pesticide Cumulative Risk Assessment. Office of Pesticide Programs, U. S. Environmental Protection Agency. Washington, DC. http:// www. epa. gov/ pesticides/ cumulative/ pra_ op/.

USEPA ( 2002a). " Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity." January 14, 2002. ( 67 FR 2210; January 16, 2002) http:// www. epa. gov/ oppfead1/ trac/ science/# common USEPA ( 2002b). Revised Organophosphorus Pesticide Cumulative Risk Assessment. Office of Pesticide Programs, U. S. Environmental Protection Agency. Washington, DC. June 10, 2002. http:// www. epa. gov/ pesticides/ cumulative/ rra_ op Page 13 of 17 Table I. Guideline Toxicology Studies for Dichlorvos in Experimental Animals and Humans Study Type/ Guideline No. MRID No. Results Acute Oral Cholinesterase Inhibition Study ( 1st) in Adult Rats/ 870.1100 ( modified) 45805701 Acceptable ChEI NOAEL ( RBC and Brain) = not established ChEI LOAEL ( RBC and Brain) = 2.1 mg/ kg Acute Oral Cholinesterase Inhibition Study ( 2nd) in Adult Rats/ 870.1100 ( modified) 45805702 Acceptable ChEI NOAEL ( RBC and Brain) = 1 mg/ kg ChEI LOAEL ( RBC and Brain) = not established Acute Oral Cholinesterase Inhibition Study ( 3rd) in Adult Rats/ 870.1100 ( modified) 45805703 Acceptable ChEI NOAEL ( RBC and Brain) = 1 mg/ kg ChEI LOAEL ( RBC and Brain) = 5 mg/ kg RBC ChE ( F/ M) BMD10 = 1.4/ 1.7 mg/ kg; RBC ChE ( F/ M) BMDL10 = 1.2/ 1.3 mg/ kg; Brain ChE ( F/ M) BMD10 = 1.3/ 1.6 mg/ kg Brain ChE ( F/ M) BMDL10 = 0.8/ 1.0 mg/ kg Acute Oral Cholinesterase Inhibition Study in Preweaning Rat Pups/ 870.1100 ( modified) 45842301 Acceptable ChEI NOAEL ( RBC) = not established ChEI LOAEL ( RBC) = 1 mg/ kg ChEI NOAEL ( Brain) = 1 mg/ kg ChEI LOAEL ( Brain) = 5 mg/ kg PND8 RBC ChE ( F/ M) BMD10 = 1.5/ 1.8 mg/ kg; PND8 RBC ChE ( F/ M) BMDL10 = 1.0/ 1.3 mg/ kg; PND8 Brain ChE ( F/ M) BMD10 = 2.2/ 1.8 mg/ kg PND8 Brain ChE ( F/ M) BMDL10 = 1.6./ 1.5 mg/ kg PND15 RBC ChE ( F/ M) BMD10 = 1.3/ 1.5 mg/ kg; PND15 RBC ChE ( F/ M) BMDL10 = 1.1/ 1.2 mg/ kg; PND15 Brain ChE ( F/ M) BMD10 = 1.4/ 1.6 mg/ kg PND15 Brain ChE ( F/ M) BMDL10 = 1.0./ 1.3 mg/ kg Single Dose Cholinesterase Inhibition Study Humans ( Non Guideline) 44248802 Un Acceptable NOAEL = 1.0 mg/ kg/ day LOAEL = not established 70 mg/ person, single oral ( capsule) dose to 6 male volunteers with no placebos  missed time of peak effect Time Course of Cholinesterase Inhibition in Preweaning and Adult Rats/ 870.8223 ( Non Guideline) 46153303 Acceptable Brain and RBC enzyme activities were maximally inhibited one hour after single dosing in both adult and preweaning female rats. Thereafter, ChE inhibition in both compartments decreased to approximately control levels by 8 hours post dosing. Page 14 of 17 7 Day, Repeat Dose Cholinesterase Inhibition Study in Preweaning and Adult Rats/( Non Guideline) 46153304 Acceptable PND 18 ( M/ F) ChEI NOAEL ( Brain) = not established PND 18 ( M/ F) ChEI LOAEL ( Brain) = 0.1 mg/ kg/ d PND 48 ( M/ F) ChEI NOAEL ( Brain) = 0.1 mg/ kg/ d PND 48 ( M/ F) ChEI LOAEL ( Brain) = 7.5 mg/ kg/ d PND 18 ( M/ F) ChEI NOAEL ( RBC) = 0.1 mg/ kg/ d PND 18 ( M/ F) ChEI LOAEL ( RBC) = 7.5 mg/ kg/ d PND 48 ( M/ F) ChEI NOAEL ( RBC) = not established PND 48 ( M/ F) ChEI LOAEL ( RBC) = 0.1 mg/ kg/ d 21 Day Oral ( capsule) Cholinesterase Inhibition Study Humans ( Non Guideline) 44248801 Acceptable NOAEL = not established LOAEL = 0.1 mg/ kg/ day ( RBC ChE) 7 mg/ day for 21 Days in 6 male volunteers plus 3 male volunteers as placebos Single Dose and Repeated Dose Cholinesterase Inhibition Studies Humans ( Non Guideline) 44317901 Acceptable Phase I ( Single Dose of 35 mg) NOAEL = 0.5 mg/ kg/ day ( RBC ChE)

Phase II ( Repeated Dose of 21 mg/ day for 12 or 15 Days) NOAEL = not established LOAEL = 0.3 mg/ kg/ day ( RBC ChE)

28 Day Delayed Neurotoxicity Hen/ 870.6100 43433501 Acceptable Cholinesterase inhibition ( brain ChEI) NOAEL = 0.1 mg/ kg/ day LOAEL = 0.3 mg/ kg/ day No neuropathology.

90 Day Subchronic Oral Toxicity  Rat/ 870.3100 41004701 Acceptable NOAEL = 0.1 mg/ kg/ day LOAEL = 1.5 mg/ kg/ day ( plasma and RBC ChE)

90 Day Neurotoxicity  Rat/ 870.6200 42958101 Acceptable NOAEL = 0.1 mg/ day LOAEL = 7.5 mg/ kg/ day ( plasma, red blood cell ( RBC) and brain ChEI).

Chronic Feeding Dog/ 870.4100 41593101 Acceptable NOAEL = 0.05 mg/ kg/ day LOAEL = 0.1 mg/ kg/ day ( plasma and RBC ChEI in both sexes).

Chronic Inhalation Rats/ Guideline 00057695, 00632569 Acceptable NOAEL = 0.00005 mg/ L LOAEL = 0.0005 mg/ L based on plasma, RBC and brain cholinesterase inhibition. Page 15 of 17 aChronic Inhalation Human/ 870.4100 45812001, 00060486 Acceptable NOAEL = 0.125 Fg/ L ( 0.000125 mg/ L) LOAEL = 0.180 Fg/ L ( 0.000180 mg/ L) ( Headaches and RBC ChEI)

Developmental Toxicity Rat/ 870.3700 41951501 Acceptable Maternal toxicity NOAEL = 3 mg/ kg/ day LOAEL = 21 mg/ kg/ day ( clinical signs, decreased body weight gain and reductions in food consumption and efficiency) Developmental toxicity NOAEL = > 21 mg/ kg/ day ( HDT)

Developmental Toxicity Rabbit/ 870.3700 41802401 Acceptable Maternal toxicity NOAEL = 0.1 mg/ kg/ day LOAEL = 2.5 mg/ kg/ day ( mortality, decreased body weight gain at LOAEL)

Developmental toxicity NOAEL= > 7 mg/ kg/ day ( HDT) ChEI was not measured. in main study Range Finding: Doses were 0, 0.1, 1.0, 2.5, 5.0, 10 mg/ kg/ day Maternal toxicity ChE NOAEL = 0.1 mg/ kg/ day ChE LOAEL = 1.0 mg/ kg/ day Reproductive Toxicity  Rat/ 870.3800 42483901 Acceptable Parental/ Systemic NOAEL = 2.3 mg/ kg/ day LOAEL = 8.3 mg/ kg/ day ( decreased % of females with estrous cycle and increased % of females with abnormal cycling) Offspring NOAEL= 2.3 mg/ kg/ day LOAEL = 8.3 mg/ kg/ day ( reduced # dams bearing litter, fertility index, pregnancy index and pup weight).

a Although this study has been used previously to assess inhalation risk, children are included in the study as subjects, and therefore the study can not be relied on for risk assessment purposes in compliance with the [ HS Rule]. Page 16 of 17 Preliminary Developmental Neurotoxicity  Rat/( Non Guideline) 46153301 Acceptable Systemic NOAEL = 7.5 mg/ kg/ day Maternal Systemic LOAEL = not identified Maternal RBC ChEI NOAEL = 0.1 mg/ kg/ day Maternal RBC ChEI LOAEL = 1.0 mg/ kg/ day Maternal Brain ChEI NOAEL = 1.0 mg/ kg/ day Maternal Brain ChEI LOAEL = 7.5 mg/ kg/ day Maternal Systemic NOAEL = 7.5 mg/ kg/ day Offspring Systemic LOAEL = not identified Offspring RBC ChEI NOAEL = 1.0 mg/ kg/ day Fetuses ( GD 22) RBC ChEI LOAEL = 7.5 mg/ kg/ day Fetuses ( GD 22)

Brain ChEI NOAEL = 1.0 mg/ kg/ day Fetuses ( GD 22) Brain ChEI LOAEL = 7.5 mg/ kg/ day Fetuses ( GD22)

Offspring ( Pups) did not demonstrate ChEI during PND 2 22 Developmental Neurotoxicity  Rat/ 870.6300 46153302 Notacceptable Maternal LOAEL/ NOAEL could not be identified due to low viability indices Offspring LOAEL/ NOAEL could not be identified due to low viability indices Offspring Effects at 7.5 mg/ kg/ day ( HDT) included increased startle response in males on PND 23, impaired memory in males on PND 27 and 62, and alterations in brain morphometry on PND 62.

Study is unacceptable/ not upgradable Developmental Neurotoxicity  Rat/ 870.6300 46239801 Notacceptable LOAEL/ NOAEL could not be identified due to low viability index in controls.

No maternal or offspring effects in FOB, motor activity, auditory startle reflex habituation, learning and memory tests, brain weight, neuropathology and morphometry at 7.5 mg/ kg/ day ( HDT).

Study is unacceptable/ not upgradable Page 17 of 17 Appendix A.

MacGregor et al, 2005 Human Studies Usable? Citation Oral studies used in the interspecies comparison No _ Missed peak effect Gledhill, A. ( 1997a) Dichlorvos: A Study to Investigate the Effect of a Single Oral Dose on Erythrocyte Cholinesterase Inhibition in Healthy Male Volunteers: Lab Project Number: CTL/ P/ 5393: XH6064. Unpublished study prepared by Zeneca Central Toxicology Lab. 44 p. No _ Missed peak effect ( acute) & Gledhill 1997b dose is lower ( multidose) Gledhill, A. ( 1997b) Dichlorvos: A Study to Investigate Erythrocyte Cholinesterase Inhibition Following Oral Administration to Healthy Male Volunteers: Lab Project Number: XH5170: CTL/ P/ 5251. Unpublished study prepared by Central Toxicology Lab. 66 p.

Yes _ Multidose study used in the RA Gledhill, A. ( 1997c) Dichlorvos: A Single Blind, Placebo Controlled, Randomised Study to Investigate the Effects of Multiple Oral Dosing on Erythrocyte Cholinesterase Inhibition in Healthy Male Volunteers: Lab Project Number: CTL/ P/ 5392: XH6063. Unpublished study prepared by Zeneca Central Toxicology Lab. 52 p. No _ Plastic bead formulation _ limited bioavailability Slomka, M. B. and C. H. Hine. 1981. Clinical pharmacology of dichlorvos. Acta. Pharmacol. Toxicol. 49( Suppl. 5): 105_ 108.

Inhalation studies used in the interspecies comparison No _ children exposed Funckes, A. J., Miller, S., Hayes, W., 1963. Initial field studies in upper volta with dichlorvos residual fumigant as a malaria eradication technique. Bull. World Health Org. 29, 243_ 246. No _ children exposed _ study had been used in RA Johnston, J. E., Barraj, L., Petersen, B., Youngren, S. H., 2002. A reanalysis of observations on occupants of Arizona homes containing 20% vapona insecticide resin strips, Arizona II home study, Exponent Inc., Project Identification Number DDVP_ 02_ 01, December 4, 2002.

No _ children exposed Shell Chemical Com pany, 1970. The third Arizona home study: quantitation of DDVP residues in foods consumed by human volunteers exposed to No_ Pest Strip insecticide. May 1970, unpublished report from Shell Chemical Company.

No _ 1 hr exposure _ not relevant to use Smith, P. W., Mertens, H., Lewis, M. F., Funkhouser, G. E., Higgins, E. A., Crane, C. R., Sanders, D. C., Endecott, B. R., Flux, M., 1972. Toxicology of dichlorvos at operational aircraft cabin altitudes. Aerosp. Med. 43, 473_ 478. No _ Exposure levels to individuals uncertain Stein, W. J., Miller, S., Fetzer, L. E., 1966. Studies with dichlorvos residual fumigant as a malaria eradication technique in Haiti. III. Toxicological studies. Am. J. Trop. Med. Hyg. 15, 672_ 675. Limited _ 4 subjects exposed 2 days to high conc. Ueda, K.; Nishimura, M. ( 1967) Effect of Vapona/ Strips to Human Beings. ( Unpublished study prepared by Tokyo Dental College, Japan)

No _ 1 2 hr exposure _ not relevant to current use Witter, R. F.; Gaines, T. B.; Short, J. G.; et al. ( 1961) Studies on the safety of DDVP for the disinsection of commercial aircraft. Bulletin of the World Health Organization 24(?): 635_ 642.


[Federal Register Volume 77, Number 16 (Wednesday, January 25, 2012)]
[Notices]
[Pages 3779-3780]
[FR Doc No: 2012-1431]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-1999-D-4079 (Formerly Docket No. 1999D-0254)]

Guidance for Industry on Product Name Placement, Size, and
Prominence in Advertising and Promotional Labeling; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a guidance document entitled ``Product Name Placement,
Size, and Prominence in Advertising and Promotional Labeling.'' The
guidance is intended to clarify for applicants the requirements for
product name placement, size, prominence, and frequency in promotional
labeling and advertising for prescription human and animal drugs and
biological products. This guidance finalizes the draft guidance
published in January 1999.

DATES: Submit either electronic or written comments on Agency guidances
at any time.

ADDRESSES: Submit written requests for single copies of the guidance to
the Division of Drug Information, Center for Drug Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
51, Rm. 2201, Silver Spring, MD 20993-0002; or Office of Communication,
Outreach and Development (HFM-40), Center for Biologics Evaluation and
Research, Food and Drug Administration, 1401 Rockville Pike, Suite
200N, Rockville, MD 20852-1448. Send one self-addressed adhesive label
to assist that office in processing your requests. See the
SUPPLEMENTARY INFORMATION section for electronic access to the guidance
document.
    Submit electronic comments on the guidance to  http://www.regulations.gov. Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Regarding Human Prescription Drugs

    Ernest S. Voyard, Jr., Center for Drug Evaluation and Research,
Food and Drug Administration, 10903 Hampshire Ave., Bldg. 51, Rm. 3276,
Silver Spring, MD 20993,<PHONE_NUMBER>.

Regarding Prescription Human Biological Products

    Stephen Ripley, Center for Biologics Evaluation and Research (HFM-
17), Food and Drug Administration, 1401 Rockville Pike, Suite 200N,
Rockville, MD 20852-1448,<PHONE_NUMBER>.

Regarding Animal Prescription Drugs

    Julie Garnier, Center for Veterinary Medicine, Food and Drug
Administration, 7519 Standish Pl., Rockville, MD 20855,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance document entitled
``Product Name Placement, Size, and Prominence in Advertising and
Promotional Labeling.'' This guidance discusses the requirements for
product name placement, size, prominence, and frequency in promotional
labeling and advertising for prescription human and animal drugs and
biological products. The disclosure of the product name in promotional
labeling and advertising for all prescription human and animal drug and
biological products is important for the proper identification of such
products to ensure their safe and effective use.
    The placement, size, prominence, and frequency of the proprietary
and established names for human and animal prescription drug products
are specified in labeling and advertising regulations (21 CFR 201.10(g)
and (h); 202.1(b), (c), and (d)). These regulations are also applicable
to biological product labeling and advertising materials.
    The recommendations in this guidance pertain to product names in
traditional print media promotion (e.g., journal ads, detail aids,
brochures), audiovisual promotional labeling (e.g., videos shown in a
health care provider's office), broadcast media promotion (e.g.,
television advertisements, radio advertisements), and electronic and
computer-based promotional labeling and advertisements, such as
Internet promotion, social media, emails, CD-ROMs, and DVDs.
    In the Federal Register of March 12, 1999 (64 FR 12341), FDA
announced the availability of the draft guidance of the same title,
dated January 1999. FDA received six comments on the draft guidance,
five were from the pharmaceutical industry and one was from a consumer.
The majority of the comments related to requests to provide additional
clarifications and examples related to the individual recommendations
in the draft guidance. These comments were considered carefully during
the finalization of the guidance document. The guidance has been
revised in the following ways: (1) It clarifies certain concepts
previously discussed in the draft guidance and adds definitions for
certain terms; (2) it provides examples to illustrate the appropriate
juxtaposition and prominence of proprietary and established names for
products with one active ingredient and examples to illustrate the
juxtaposition of products with two or more active ingredients; (3) it
reorganizes and renames the draft guidance's sections pertaining to the
frequency of the disclosure of proprietary and established names in
various media into one section with three subsections--traditional
print promotional labeling and advertisements, audiovisual promotional
labeling and broadcast advertisements, and electronic and computer-
based promotional labeling and advertisements; and (4) it discusses the
use of proprietary and established names in columns in traditional
print promotional labeling and advertisements.
    The guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents FDA's
current thinking on this topic. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirements of the applicable statutes and regulations.

II. Comments

    Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. Identify
comments with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday.

III. Electronic Access

    Persons with access to the Internet may obtain the guidance at
either  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm, or http://www.regulations.gov.

    Dated: January 19, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012-1431 Filed 1-24-12; 8:45 am]
BILLING CODE 4160-01-P


Modeling-related citations & documents for AZ FIP NFRM docket

sjb 2012-11-14

Modeling documents  (all are EPA work products)

“Modeling files explanation and list”

	readme_modeling_files_NFR1.txt

“Revised PM Speciation for Cholla Unit 2”

	2006FinalDryBottomPC_FGD_FFpmSpeciationProfile_Cholla-Unit2-filtPM.xls

“Cholla merged stack impacts”

	Cholla_mrg23_visx_table.xls

“Cholla remodeling inputs and outputs”

	Cholla_NFR_remodeling.xls

“Coronado SCR impacts”

	Coronado_base_p_visx.xls

Modeling-related documents cited

(some of these are already in the docket from the proposal)

Interagency Workgroup On Air Quality Modeling (IWAQM) Phase 2 Summary
Report And Recommendations For Modeling Long Range Transport Impacts
(EPA-454/R-98-019), EPA OAQPS, December 1998,  HYPERLINK
"http://www.epa.gov/scram001/7thconf/calpuff/phase2.pdf"
http://www.epa.gov/scram001/7thconf/calpuff/phase2.pdf

	IWAQM_phase2.pdf

[guidance document, already in docket for proposal]

Proposed Rule: Source Specific Federal Implementation Plan for
Implementing Best Available Retrofit Technology for Four Corners Power
Plant: Navajo Nation Technical Support Document

	FCPP Technical Support Document 10-6-10.pdf

[Oct. 6, 2010, EPA rulemaking]

Measurements of Ambient Background Ammonia on the Colorado Plateau and
Visibility Modeling Implications, Salt River Project, Dr. Ivar Tombach,
Consultant, and Robert Paine, AECOM Environment, September 2010

	NH3 Monitoring Report  2010-09-22.pdf

[Sep., 2010, Public comment] [this is “Exhibit B” of APS’s
comments]

Federal Land Managers’ Air Quality Related Values Work Group (FLAG)
Phase I Report—Revised (2010), U.S. Forest Service, National Park
Service, U.S. Fish And Wildlife Service, October 2010.
http://www.nature.nps.gov/air/Pubs/pdf/flag/FLAG_2010.pdf

	FLAG_2010.pdf

[Oct. 2010, guidance document]

“CALPUFF Regulatory Update”, Roger W. Brode, Presentation at
Regional/State/Local Modelers Workshop, June 10–12, 2008;
http://www.cleanairinfo.com/regionalstatelocalmodelingworkshop/archive/2
008/agenda.htm

	BRODE_CA.pdf

[Additional document; June, 2008]

Estimating Total Sulfuric Acid Emissions from Stationary Power Plants,
Version 2010a, 1020636, Technical Update, Electric Power Research
Institute, April 2010)

	 2010 epri report h2so4.pdf

[Additional document; already in docket for proposal]


[Federal Register: March 3, 2010 (Volume 75, Number 41)]
[Notices]
[Page 9634-9635]
[DOCID:fr03mr10-99]

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DEPARTMENT OF TRANSPORTATION

Pipeline and Hazardous Materials Safety Administration

Office of Hazardous Materials Safety; Notice of Applications for
Modification of Special Permit

AGENCY: Pipeline and Hazardous Materials Safety Administration (PHMSA),
DOT.

ACTION: List of applications for modification of special permits.

-----------------------------------------------------------------------

SUMMARY: In accordance with the procedures governing the application
for, and the processing of, special permits from the Department of
Transportation's Hazardous Material Regulations (49 CFR Part 107,
Subpart B), notice is hereby given that the Office of Hazardous
Materials Safety has received the applications described herein. This
notice is abbreviated to

expedite docketing and public notice. Because the sections affected,
modes of transportation, and the nature of application have been shown
in earlier Federal Register publications, they are not repeated here.
Requests for modification of special permits (e.g. to provide for
additional hazardous materials, packaging design changes, additional
mode of transportation, etc.) are described in footnotes to the
application number. Application numbers with the suffix ``M'' denote a
modification request. These applications have been separated from the
new application for special permits to facilitate processing.

DATES: Comments must be received on or before March 18, 2010.

ADDRESS COMMENTS TO: Record Center, Pipeline and Hazardous Materials
Safety Administration, U.S. Department of Transportation, Washington,
DC 20590.
    Comments should refer to the application number and be submitted in
triplicate. If confirmation of receipt of comments is desired, include
a self-addressed stamped postcard showing the special permit number.

FOR FURTHER INFORMATION CONTACT: Copies of the applications are
available for inspection in the Records Center, East Building, PHH-30,
1200 New Jersey Avenue Southeast, Washington DC or at http://
regulations.gov.
    This notice of receipt of applications for modification of special
permit is published in accordance with Part 107 of the Federal
hazardous materials transportation law (49 U.S.C. 5 117(b); 49 CFR
1.53(b)).

    Issued in Washington, DC, on February 23, 2010.
Delmer F. Billings,
Director, Office of Hazardous Materials Special Permits and Approvals.

----------------------------------------------------------------------------------------------------------------
                                                                      Regulation(s)
 Application number        Docket number           Applicant             affected       Nature of special permit
----------------------------------------------------------------------------------------------------------------
                                          MODIFICATION SPECIAL PERMITS
----------------------------------------------------------------------------------------------------------------
8826-M..............  ......................  Phoenix Air Group,   49 CFR 172.101;      To modify the special
                                               Inc. Cartersville,   172.204(c)(3);       permit to authorize
                                               GA.                  173.27;              additional Division 1.5
                                                                    175.30(a)(1);        and 1.6 hazardous
                                                                    175.320(b).          materials and make
                                                                                corrections to reflect
                                                                                the current statutes
                                                                                and regulations
                                                                                changes.
11447-M.............  ......................  SAES Pure Gas, Inc.  49 CFR 173.187.....  To modify the special
                                               San Luis Obispo,                          permit to increase the
                                               CA.                                       number of pressure
                                                                                vessels from six to
                                                                                eight.
13057-M.............  ......................  MINTEQ               49 CFR 172 Subparts  To modify the special
                                               International Inc.   D, E and F;          permit by the deleting
                                               Canaan, CT.          173.24(c) Subparts   of three hazardous
                                                                    E and F of Part      materials from
                                                                    173.                 paragraph 6; change the
                                                                                length of continuous
                                                                                rollor coil from 10,000
                                                                                meters to 12,500
                                                                                meters; and authorize
                                                                                steel pallets in
                                                                                addition to wooden
                                                                                pallets in paragraph
                                                                                7.a.(5).
14282-M.............  ......................  T.F. Boyle           49 CFR 173.835(g)..  To modify the special
                                               Transportation,                           permit to authorize an
                                               Inc. (Boyle                               additional four Class
                                               Transportation)                           hazardous materials.
                                               Billerica, MA.
14650-M.............  ......................  Air Transport        49 CFR 172.101;      To modify the special
                                               International,       171.11;              permit to authorize
                                               L.L.C. Little        172.204(c)(3);       additional Division
                                               Rock, AR.            173.27;              1.4D explosives and to
                                                                    175.30(a)(1);        authorize additional
                                                                    175.320(b).          dedicated air charter
                                                                                flights.
----------------------------------------------------------------------------------------------------------------

[FR Doc. 2010-4035 Filed 3-2-10; 8:45 am]
BILLING CODE 4910-60-M


[Federal Register Volume 79, Number 68 (Wednesday, April 9, 2014)]
[Notices]
[Pages 19703-19704]
[FR Doc No: 2014-07888]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-71858; File No. SR-CBOE-2014-028]

Self-Regulatory Organizations; Chicago Board Options Exchange,
Incorporated; Notice of Filing and Immediate Effectiveness of a
Proposed Rule Change To Amend the Fees Schedule of Its CBOE Stock
Exchange

April 3, 2014.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(the ``Act''),\1\ and Rule 19b-4 thereunder,\2\ notice is hereby given
that, on March 26, 2014, Chicago Board Options Exchange, Incorporated
(the ``Exchange'' or ``CBOE'') filed with the Securities and Exchange
Commission (the ``Commission'') the proposed rule change as described
in Items I, II, and III below, which Items have been prepared by the
Exchange. The Commission is publishing this notice to solicit comments
on the proposed rule change from interested persons.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
---------------------------------------------------------------------------

I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange proposes to amend the Fees Schedule of its CBOE Stock
Exchange (``CBSX''). The text of the proposed rule change is available
on the Exchange's Web site (http://www.cboe.com/AboutCBOE/CBOELegalRegulatoryHome.aspx), at the Exchange's Office of the
Secretary, and at the Commission's Public Reference Room.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the Exchange included statements
concerning the purpose of and basis for the proposed rule change and
discussed any comments it received on the proposed rule change. The
text of these statements may be examined at the places specified in
Item IV below. The Exchange has prepared summaries, set forth in
sections A, B, and C below, of the most significant aspects of such
statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

1. Purpose
    CBSX proposes to amend its Fees Schedule. Currently, the Exchange
assesses no fees for cross trades that are not part of stock option
trades (and are not otherwise specified on the Fees Schedule). However,
CBSX has determined that it is economically prudent to assess fees for
such transactions at this time. As such, CBSX proposes to amend its
Fees Schedule to assess a fee of $0.0010 per share for cross trades
that are not part of stock option trades for transactions in securities
priced $1 or greater, and a fee of 0.10% of the dollar value of the
transaction for cross trades that are not part of stock option trades
for transactions in securities priced less than $1. These fees apply to
all portions of cross trades that are not part of stock option trades
and are not covered by another specific fee listed on the CBSX Fees
Schedule.
    The proposed changes are to take effect on April 1, 2014.
 2. Statutory Basis
    The Exchange believes the proposed rule change is consistent with
the Act and the rules and regulations thereunder applicable to the
Exchange and, in particular, the requirements of Section 6(b) of the
Act.\3\ Specifically, the Exchange believes the proposed rule change is
consistent with Section 6(b)(4) of the Act,\4\ which requires that
Exchange rules provide for the equitable allocation of reasonable dues,
fees, and other charges among its Trading Permit Holders and other
persons using its facilities. CBSX desires to assess fees for such
transactions to assist in funding CBSX's operational, regulatory and
administrative costs. The amounts of the proposed fees are within the
range of fees assessed by CBSX for other transactions. CBSX further
believes that the proposed changes are equitable and not unfairly
discriminatory because all market participants will be assessed the
same fees. CBSX believes that it is equitable and not unfairly
discriminatory to assess different fees for transactions in securities
priced $1 or greater and transactions in securities prices less than $1
due to different liquidity profiles and trading incentives for
securities priced at the two levels. Moreover, CBSX currently offers
similarly-differentiated pricing for other types of executions.
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    \3\ 15 U.S.C. 78f(b).
    \4\ 15 U.S.C. 78f(b)(4).
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B. Self-Regulatory Organization's Statement on Burden on Competition

    CBSX does not believe that the proposed rule change will impose any
burden on intramarket competition that is not necessary or appropriate
in furtherance of the purposes of the Act because the proposed fees
will be assessed to all market participants. CBSX does not believe that
the proposed rule change will impose any burden on intermarket
competition that is not necessary or appropriate in furtherance of the
purposes of the Act because the proposed fees only affect trading on
CBSX. CBSX desires to assess fees for such transactions to assist in
funding CBSX's operational, regulatory and administrative costs.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants, or Others

    The Exchange neither solicited nor received comments on the
proposed rule change.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    The foregoing rule change has become effective pursuant to Section
19(b)(3)(A) of the Act \5\ and paragraph (f) of Rule 19b-4 \6\
thereunder. At any time within 60 days of the filing of the proposed
rule change, the Commission summarily may temporarily suspend such rule
change if it appears to the Commission that such action is necessary or
appropriate in the public interest, for the protection of investors, or
otherwise in furtherance of the purposes of the Act. If the Commission
takes such action, the Commission will institute proceedings to
determine whether the proposed rule change should be approved or
disapproved.
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    \5\ 15 U.S.C. 78s(b)(3)(A).
    \6\ 17 CFR 240.19b-4(f).
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IV. Solicitation of Comments

    Interested persons are invited to submit written data, views and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. Comments may be submitted by any of
the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://www.sec.gov/rules/sro.shtml); or
     Send an email to<EMAIL_ADDRESS>Please include
File Number SR-CBOE-2014-028 on the subject line.

Paper Comments

     Send paper comments in triplicate to Secretary, Securities
and Exchange Commission, 100 F Street NE., Washington, DC 20549-1090.

All submissions should refer to File Number SR-CBOE-2014-028. This file
number should be included on the subject line if email is used. To help
the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml). Copies of the submission, all subsequent amendments, all
written statements with respect to the proposed rule change that are
filed with the Commission, and all written communications relating to
the proposed rule change between the Commission and any person, other
than those that may be withheld from the public in accordance with the
provisions of 5 U.S.C. 552, will be available for Web site viewing and
printing in the Commission's Public Reference Room, 100 F Street NE.,
Washington, DC 20549, on official business days between the hours of
10:00 a.m. and 3:00 p.m. Copies of the filing also will be available
for inspection and copying at the principal office of the Exchange. All
comments received will be posted without change; the Commission does
not edit personal identifying information from submissions. You should
submit only information that you wish to make available publicly. All
submissions should refer to File Number SR-CBOE-2014-028 and should be
submitted on or before April 30, 2014.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\7\
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    \7\ 17 CFR 200.30-3(a)(12).
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Kevin M. O'Neill,
Deputy Secretary.
[FR Doc. 2014-07888 Filed 4-8-14; 8:45 am]
BILLING CODE 8011-01-P