a) the Agency's conclusions for use of the human study for developing a point of departure for estimating risk in the single chemical, aggregate risk assessment and b) the Agency's determination that the human study cannot be used to reduce the interspecies factor in the cumulative risk assessment.

Board Response to the Charge Study Overview A single blind, randomized placebo controlled oral study was conducted with DDVP in which six healthy male volunteers were administered a daily dose of DDVP at approximately 0.1mg/ kg/ day and three volunteers were administered a placebo ( Gledhill 1997). DDVP was dissolved in corn oil and administered daily in a gelatin capsule to fasted subjects ( subjects did not eat after midnight prior to each morning dose) for a total of 21 days. Blood samples were collected for analysis of red blood cell ( RBC) cholinesterase activity. For each subject, the baseline level of RBC cholinesterase activity was established from seven pre dose samples, and a single blood sample was collected approximately 24 hours after dosing ( just prior to dosing on the following day) on days 1, 2, 4, 7, 9, 11, 14, 16 and 18 of the study. No blood samples were collected on 55 of 87 the last three days of the study ( days 19 21). After cessation of dosing, subjects returned approximately 1 week later ( on or about day 25) for a follow up analysis of RBC cholinesterase activity. The criterion for withdrawal from the study was a inhibition of RBC cholinesterase activity of 20% or more on a given day's analysis followed by a further decrease in activity in the next successive sample. A linear mixed model was fitted to the cholinesterase activity and significant differences were found within subjects and also between groups ( treatment versus placebo subjects) for pre dose and post dose cholinesterase activity.

Critique of Study The scientific validity of the repeated dose study for DDVP was determined by the relative strengths and weakness of the design and conduct of the study.

The strengths of the study were considered to be as follows:   The repeat dosing paradigm affords the opportunity to more critically evaluate the sustained nature of RBC cholinesterase inhibition associated with OPs.   The analysis of RBC cholinesterase activity is fairly robust, given the assessment of predose baseline values on 7 separate occasions. The baseline values were fairly consistent both within and between subjects ( 16,000   21,000 IU).   A low, but statistically significant effect was observed in RBC cholinesterase inhibition.

There are, however, numerous weaknesses of the study that are relevant to the utility of these data in establishing a point of departure for use in single chemical, aggregate and cumulative risk assessments for DDVP. These weaknesses included:

  A single dosage was used, preventing establishment of dose response relationships.

  The sample size was small and included only male volunteers. In this regard, it is not clear whether the study was properly powered, given that no sample size calculations seem to have been used in order to arrive at the number of volunteers used in the study.

  RBC cholinesterase inhibition was determined only at 24 hours post dosing. Although organophosphates are known to show prolonged inhibition of cholinesterase activity, it was not clear whether the peak of RBC cholinesterase was established.

  The sponsor did not include the analysis of plasma cholinesterase measurements in the study. The reason for this omission is not clear, and it was noted that virtually every toxicological and exposure assessment study that has focused on cholinesterase inhibition due to organphosphorus insecticides includes measurement of both plasma ( serum) cholinesterase and RBC cholinesterase. The combination of these measurements has been used routinely for risk assessments 56 of 87 by numerous regulatory agencies, including the EPA, as well as by clinicians who diagnose pesticide poisonings. Current worker surveillance programs in some states ( California and Washington) require measurement of both plasma and erythrocyte cholinesterase, and both measurements are used in combination to initiate workplace investigations and remove workers from pesticide related job activities until enzyme activities return to baseline.

  Sampling was incomplete because the last day of analysis of enzyme inhibition was day 18 but dosing continued until day 21. It is not clear whether any additional decrease in enzyme activity would have been observed on days 19 21. In the sampling schedule outlined above, the maximum time gap between samples during the dosing period ( days 1 21) was three days ( between days 11 and 14). Logically then, an additional sample would have been taken on day 21 or 22, the time in the study when maximum effects might be observed. In this regard, two subjects presented with inhibition values of 22 and 23%, exceeding the 20% cutoff for subsequent analysis and consideration for withdrawal on day 18 of the study. The lack of additional measurements in these subjects during the remainder of the dosing period is scientifically inadequate and ethically troublesome.

  It is neither clear nor convincing that steady state inhibition of RBC cholinesterase activity was achieved in the study. The data suggest that the level of enzyme inhibition was still increasing, particularly in the time period from 11 18 days, with a difference of 16% in activity on Day 18 compared to pre dose values. Dosing was stopped on Day 21, with no further analysis until approximately 4 days after cessation of dosing. Although the difference in activity between day 18 post dose and the average of the pre dose measurements was deemed to be " not biologically significant" by the study sponsor, the possibility that RBC cholinesterase inhibition may have reached or exceeded 20% by the end of the study cannot be excluded.

  There was a lack of appropriate follow up in all subjects in this study. As noted earlier, two subjects presented with inhibition values of 22 and 23%, exceeding the 20% cut off for subsequent analysis and consideration for withdrawal on Day 18. However, there were no additional analyses of RBC cholinesterase activity in these individuals on days 19 21 of dosing. Additionally, a blood sample was collected within 4 to 10 days following completion of the 21 day dosing period for all subjects. The mean inhibition of the enzyme observed at seven days following cessation of dosing was 83%, suggesting little if any recovery of enzyme at this time, but these data were not analyzed for statistical significance. Furthermore, one subject ended his participation in the study ( day 25) with RBC cholinesterase inhibition greater than 20%. In all cases, there was no additional follow up of the subjects after the single post dose analysis of cholinesterase activity.

HSRB Consensus and Rationale 57 of 87 The Board concluded that:

a) The DDVP repeat dose human toxicity study was sufficiently robust for developing a point of departure for estimating dermal, incidental oral, and inhalation risk from exposure to DDVP in the single chemical risk assessment.

In specific response to the Agency's charge question, the HSRB concluded that there are numerous technical limitations to the data obtained in the study. In addition to the weaknesses of the study design and execution outlined above, the HSRB concluded that the evaluation of only a single dose level of DDVP along with the omission of plasma cholinesterase measurements greatly limit value of this study in terms of producing new knowledge that can be used in the regulatory process and in medical diagnosis. Furthermore, study investigators have an obligation to design a study that provides appropriate oversight of subjects until indications of the effects of the administered dose are no longer present, and the Board considered that the design of this study which continued intentional dosing without collection of blood samples for cholinesterase analysis was not defensible scientifically. Following considerable discussion, the HSRB concluded that the dosage evaluated in the repeat dosing human study can be used as a LOAEL for the single chemical aggregate risk assessment for DDVP. Although a study using a single dose level is not ideal for establishing a LOAEL, there was general consensus that RBC cholinesterase is a well characterized endpoint for compounds that inhibit acetylcholinesterase activity and therefore, because the decreased activity in RBC cholinesterase activity observed in this study was at or near the limit of what could be distinguished from baseline values, it was unlikely that a lower dose would produce a measurable effect in RBC cholinesterase activity. However, the HSRB strongly recommended that, in most cases, studies in human subjects designed to define the NOAEL or LOAEL for a compound should include more than a single dose level.

b) Results of the DDVP repeat dose human toxicity study should not be used to support reducing the default 10X inter species factor in the cumulative risk assessment of the organophosphate pesticides.

Although the data obtained in this study can be used to establish a point of departure for the single chemical aggregate risk assessment, the consensus of the HSRB was that the scientific limitations of the study design do not justify its use in the cumulative risk assessment. In particular, the lack of sample collection through to the completion of dosing, the lack of a clear demonstration that steady state inhibition of RBC cholinesterase inhibition had been achieved, and the lack of any dose response data limit the overall utility of the human data. Accordingly, the HSRB recommended that the default interspecies uncertainty factor should be applied for the cumulative risk assessment for DDVP.

Charge to the Board 58 of 87 b. The Agency has concluded that other human studies made available to the Board do not provide sufficient scientifically sound information to warrant any reduction in the 10X inter species uncertainty factor used to derive reference dose values for DDVP based on animal toxicity endpoints.

Please comment on the scientific evidence that supports these conclusions.

Board Response to the Charge HSRB Consensus and Rationale The HSRB concluded that the other DDVP human toxicity studies available for the Board's consideration should not be used for determining a reduction in the 10X uncertainty factor to derive reference dose values for DDVP based on animal toxicity endpoints.

The Board's deliberations for this question focused on the acceptability or not of these human studies for the Agency's intended purposes, rather than on the evaluation of the magnitude of the interspecies uncertainty factor. Since the results of animal studies or benchmark dose modeling were not provided to the Board, the review was restricted to the evaluation of the acceptability of the human studies for the intended purposes. The Board concluded these other human studies did not warrant use in determining the interspecies uncertainty factor because of policy considerations ( e. g., exposures involving infants, children, pregnant women) or due to uncertainty associated with the study itself ( e. g., inappropriate duration, questionable route, exposure data of limited utility, lack of time course data on critical effect). Board concerns regarding these other human studies are provided in Table 1.

While the studies reviewed are not useable either because they are unacceptable due to policy considerations or due to uncertainty associated with the study itself, the Board also suggested that the Agency should take a critical hard look at those studies that are ethically acceptable ( e. g., the ones that did not include exposures of children and pregnant women), to the extent to which they can be informative about the magnitude of the interspecies uncertainty factor. In making such evaluations, the Agency should consider taking into account: ( 1) applicability of Haber's law, ( 2) nature of the toxic moiety, and ( 3) the relative importance of interspecies differences in pharmacokinetics and sensitivity. Further, consideration should be given to the manner in which the data from the different species are pooled and analyzed ( e. g., continuous response versus maximal response). 59 of 87 Table 1. Evaluation of Specific DDVP Human Studies Provided to the HSRB Reference Observations/ Concerns Glendhill Acute toxicity study Time course measurements of cholinesterase Cavagna ( 1970) Conducted in newborns Slomka ( 1981) Exposure through plastic bead ( polyvinyl resin) formulation; rate of absorption not known; data provided as ranges Cervoni ( 1969) Efficacy trial; measurement of cholinesterase inhibition not the main focus; no assurance of consistent methods of measurement of inhibition Leary ( 1974) Exposure via insecticide strips; possibility children were involved, but composition of families not given; inhalation route   caveat of dose calculations; no information on consent of subjects Smith ( 1972) Performed in altitude chamber; short term inhalation study; no information on consent of subjects Cavagna ( 1969) Exposure via insecticide strips included pregnant women, infants and children in a hospital Pena Chavarria ( 1969) Exposure of patients ( most of them anemic, treated for parasite infection); not designed to identify NOAEL or LOAEL Stein ( 1966) Insufficient information on the time course of cholinesterase inhibition; doses not quantitated Funckes ( 1963) Study population included children, some below six years; time course evaluation on inhibition insufficient Witter ( 1961) Simulated aircraft cabin; one hour exposures; time course information lacking Gratz ( 1963 Inadequate information to evaluate dose and NOAEL; inadequate information about how many people exposed at each concentration; single application based exposures 5.2. Ethical considerations Charge to the Board a. The Agency requests that the Board provide comment on the following: 60 of 87 Whether references to the test material as a drug and other statements that could indicate the study constituted medical research, that appear in the materials used to obtain informed consent should be considered significantly deficient relative to the ethical standards prevailing when the study was conducted;

Whether the administration of the test material for three additional days without monitoring subjects' cholinesterase levels following the detection of cholinesterase inhibition greater than 20 % in some subjects should be considered significantly deficient relative to the ethical standards prevailing when the study was conducted; and Whether the lack of medical surveillance of subjects, following the termination of dosing, to establish the subjects' cholinesterase levels returned to normal should be considered significantly deficient relative to the ethical standards prevailing when the study was conducted; and b. The Agency asks that the Board provide comment on the following, taking into account all that is known about the ethical conduct of the Gledhill repeated dose study:

OPP's conclusion that there is not clear and convincing evidence that the conduct of the research was fundamentally unethical; and Whether there is clear and convincing evidence that the conduct of the Gledhill repeat dose study was significantly deficient relative to the ethical standards prevailing when the study was conducted.

Board Response to the Charge Brief Overview of the Study As noted above, the study was conducted in 1996 by the Zeneca Central Toxicology Laboratory, Cheshire, United Kingdom. The study sponsor was the Amvac Chemical Corporation. The protocol documents specifically state that the research was conducted in compliance with the guideline of the Declaration of Helsinki, 1964, as amended through 1989.

Critique of Study The Board concurred with the Agency's factual observations of the strengths and weaknesses of the study, as detailed in Carley ( 2006e). However, further comments are warranted with regard to: 1) whether the provisions in the protocol for monitoring the subjects adequately protected them, and 2) whether the documentation and process of study subject enrollment was sufficient to meet prevailing standards of voluntary informed consent.

1. Monitoring of Subjects While Receiving Study Compound 61 of 87 The protocol permitted subjects to continue to be administered the study compound for three days following the detection of RBC cholinesterase inhibition of greater than 20%. Given that study subjects were not monitored during most of the study ( and were not full time residents at the study laboratory), it was possible that they might develop clinically significant symptoms during this period and no one would be available to detect that and to treat them. The Board concluded that this aspect of the study design was inadequate. However, given that there had been a prior similar study at triple the dose used in this study, and that study had demonstrated minimal symptoms, the Board could not conclude that there was clear and convincing evidence that this element of the study design could have resulted in serious harm based on the knowledge available to the investigators at the time.

2. Monitoring of Subjects at End of Study The protocol also provided that, at the end of the study, inhibition levels would not be retested for periods as long as seven days even though some subjects had RBC cholinesterase inhibition of greater than 20%. During this period of time, due to the longacting nature of the study compound, subjects' cholinesterase inhibition levels could have been increasing, and thus symptoms might have developed and, theoretically have become serious at a time when they were being infrequently monitored. The Board determined that this aspect of the study design was inadequate. However, as noted above, given that there had been a prior similar study at triple the dose used in this study, and that study had demonstrated minimal symptoms, the Board could not conclude that there was clear and convincing evidence that this element of the study design could have resulted in serious harm based on the knowledge available to the investigators at the time.

The inadequate monitoring during and at the end of the study undermines the scientific value of the study. The fact that the research subjects were unsupervised during the study, and the ascertainment of adverse event data was through self report, renders the data establishing a NOAEL suspect. The risk of a " false negative" conclusion is quite high. In addition, the failure to achieve a steady state in the inhibition of acetyl cholinesterase activity may render these data inadequate as well, and of limited utility. This fact, also noted in the Board's scientific review, can negatively influence the prospective benefit to risk ratio.

3. Informed Consent It is clear that the written documentation for informed consent failed to fully meet the standards outlined of the 1989 version of the Declaration of Helsinki.

In particular, the information sheet that was given to research subjects as an appendix to the signed informed consent document under the subheading Possible Adverse Events noted that if " any symptoms possibly due to enzyme blocking did occur, they could rapidly be reversed by a specific antidote." Although that statement is a correct statement of the scientific issue, it failed to take account the fact that this study did not involve subjects remaining under 24 hour supervision. For most of the time, the 62 of 87 subjects would not be under any supervision. Given that enzyme inhibition could build up over time due to the long acting nature of the compound being studied, symptoms could likely occur at a time when there was no one available to administer the antidote. Telling the subjects that an antidote could rapidly reverse symptoms without explaining that there were circumstances in which that antidote would not be readily available was not an adequate way to inform subjects of the true nature of this risk.

In hindsight, it is clear that the documentation provided fails to rigorously meet the standards of voluntary informed consent applicable to studies conducted in the United Kingdom in 1996. However, there was not clear and convincing evidence that these deficiencies knowingly and seriously impaired the informed consent process.

HSRB Consensus and Rationale The Board concluded that:

a) The DDVP repeat dose oral human toxicity study failed to fully meet the specific ethical standards prevalent at the time the research was conducted.

b) There was no clear and convincing evidence that the research was fundamentally unethical intended to seriously harm participants or that informed consent was not obtained.

c) There was no clear and convincing evidence of significant deficiencies in the ethical procedures that could have resulted in serious harm ( based on the knowledge available at the time the study was conducted) nor that information provided to participants seriously impaired their informed consent.

The Board determined that there was not clear and convincing evidence that references to the test material as a drug and other statements that could indicate the study constituted medical research, that appear in the materials used to obtain informed consent should be considered significantly deficient relative to the ethical standards prevailing when the study was conducted. These statements are highly undesirable, and should not be used as part of modern day practice in writing such consent materials. Nonetheless, it was unfortunately not uncommon for such wording to have been used in consent materials in the past. In addition, other wording in the consent materials clearly advised subjects that this was a study involving consuming an insecticide. The Board, however, specifically rejects the arguments of the study sponsor that it was appropriate to use the " drug" terminology because the consent materials were generic materials used for a variety of studies. It also rejects the study sponsor's argument that because the test material is sometimes used as a drug, it was appropriate to use that terminology in this study even though this study in no way related to its use as a drug.

For the reasons discussed above, the Board determined that there was not clear and convincing evidence that the administration of the test material for three additional days without monitoring subjects' cholinesterase levels following the detection of 63 of 87 cholinesterase inhibition greater than 20 % in some subjects could have led to serious harm. There the study should not be considered significantly deficient relative to the ethical standards prevailing when the study was conducted.

( 3) For the reasons discussed above, the Board determined that there was not clear and convincing evidence that following the termination of dosing, the lack of medical surveillance to establish the subjects' cholinesterase levels returned to normal could have led to serious harm. Therefore the study should not be considered significantly deficient relative to the ethical standards prevailing when the study was conducted.

The Board concluded that the Agency can rely on the results of this study, as appropriate under current pesticide laws, given the absence of clear and convincing evidence that the research was fundamentally unethical or significantly deficient relative to the ethical standards prevailing when the study was conducted.

6. Ethephon Charge to the Board Ethephon is an organophosphorus compound that, upon absorption into plants, forms ethylene gas which is an important component of the plant hormone complex. The Agency is conducting an aggregate ( single chemical, multi route) risk assessment of ethephon.

Scientific consideration The Agency's WOE document and DERs for ethephon describe the study design and results of the ethephon repeat dose, oral, human toxicity studies. The WOE document also discusses the Agency's conclusions regarding the usefulness of the human studies in the aggregate, single chemical risk assessment. The Agency has concluded that the 28 day human study is sufficiently robust to establish a point of departure for extrapolating acute and chronic dietary risk.

Please comment on the scientific evidence that supports this conclusion.

Board Response to the Charge Brief Overview of the Study According to the Agency's weight of evidence document ( WOE) ( Kent 2006) , " ethephon is an organophosphorus compound that, upon absorption into plants, forms ethylene gas which is an important component of the plant hormone complex. The production of ethylene by plants occurs naturally as crops mature but it can be slow during periods of unfavorable weather. Ethylene generated from ethephon is absorbed by the plant tissues and moderates the growth process. It is not similar in structure to other 64 of 87 organophosphate pesticides. Ethephon registrants have submitted many toxicity studies to support the continued pesticidal use of the chemical, and among these studies are two involving direct dosing of human subjects that OPP is considering using to establish endpoints to assess risk from exposure to ethephon. The WOE document compares the strengths and weaknesses of the human and animal toxicity studies and discusses how the human studies fit in 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."

According to the WOE document, " as a strong acid, ethephon is corrosive to the skin and eyes ( Category I). In acute and subchronic neurotoxicity studies in rats, there were signs of neurotoxicity at doses of 500 mg/ kg and above ( acute) and 300 mg/ kg ( subchronic). In dogs there were no clinical signs of neurotoxicity evident at 75 mg/ kg/ day although plasma and RBC cholinesterase were inhibited in animals at doses as low as 7.5 mg/ kg/ day."

There are two human studies under consideration, both involve direct dosing of human subjects and are repeated dose oral studies, one for 28 days duration ( Reese 1972) and the other for 16 days ( Weir 1977).

28 Day Oral Toxicity Study In a non guideline oral toxicity human study ( Reese 1972), ethephon was administered by capsule in a powdered formulation ( 10% a. i. weight/ weight) of hydrated silica and starch to human adults ( 5/ sex) at an average dose of 1.8 mg a. i./ kg/ day or placebo 0 mg/ kg/ day ( 3/ sex) for 28 consecutive days. Administration of the test material or the placebo was given orally by capsule divided into three daily doses. Each subject received 2 capsules postprandially for the first two dosing periods; the third dose was given at the end of the work day in order to simulate as closely as possible ingestion of the material as a crop residue. The capsules were dispensed daily ( 5 days/ week) by an assistant who observed the subjects while they took each capsule and recorded solicited comments related to the ingestion of the material during the first 8 hours. The subjects and the assistant did not know which capsules were placebo or the test material. Each Friday, the subjects received a supply of capsules to be taken during the two day weekend. All subjects were monitored regularly for adverse effects. Hematology measurements, clinical chemistry and urinalysis were conducted initially and on Days 7, 14, 21, 28 and 2 weeks following the last administration. ChE ( plasma and RBC) determinations were conducted using the   pH/ hr method ( modified Michel method) initially, and on Days 1, 2, 7, 14, 28 and 2 weeks after the last administration.

Critique of 28 Day Oral Toxicity Study MRID 00036510 The ethephon subjects, though exhibiting normal physical appearance and behavior, developed symptoms of diarrhea and increased urination and bowel movement. Three females and one male experienced a sudden onset of diarrhea or an urgency of bowel movement of 1 4 days duration during the first week of the compound 65 of 87 administration; the one male also experienced loose stools for 2 weeks. Another male complained of stomach cramps or gas for the duration of the study. One subject in the ethephon group was aymptomatic. Five subjects experienced increased urgency and frequency of urination, 4 of whom experienced this symptom throughout the study. Two subjects experienced decreased appetite while a third ( with diarrhea) experienced increased appetite during the first 2 days of the study. It was stated that the symptoms were " consistent with exposure to a cholinesterase inhibitor." The WOE document stated " the clinical signs observed in the study, diarrhea and increased frequency of urination, are consistent with a cholinergic mode of toxicity, but other signs associated with a cholinesterase inhibitor such as pinpoint pupils ( miosis), sweating, runny nose, tearing, salivation, respiratory distress and muscle fasciculation ( twitching), were not seen [ sic]; [ and] the test subjects reported symptoms as they considered appropriate, and it is difficult to interpret what the self reported symptoms mean in terms of a biological response." In fact, it is unknown if symptoms or signs associated with a cholinesterase inhibitor were seen; they may not have been monitored or specific requests for their reported made by the investigators. However, these symptoms, probably related to irritant effects, are important results.

The Agency's Data Evaluation Record ( Khasawinah) and the WOE documents both stated " None of the placebo subjects had similar complaints." This is probably not correct since according to the investigators at least two of these controls were symptomatic as well some test and control subjects also exhibited some atypical lymphocytes of unknown origin.

The WOE document states " Unexpectedly, plasma and RBC ChE activities were similar or slightly higher than initial values in the test subjects. ([ The] details of the ChE determinations were not provided.)" However, the ChE levels were not related to the diarrhea occurring in the subjects upon examination of the time of symptom occurrence and ChE data provided. The WOE document states " No compound effects regarding hematology, clinical chemistries and urinalysis were reported", except the atypical lymphocytes of some.

It was concluded by the investigators of this study that the daily dose of 1.8 mg/ kg/ day is the LOAEL for the oral ingestion of ethephon in human subjects. However, that is quite uncertain since lower doses were not given.

16 Day Oral Toxicity Study In the other non guideline oral toxicity human study ( Weir 1977), ethephon was administered by capsule in a powdered formulation ( 2.5% a. i. weight/ weight) of hydrated silica and starch to human adults ( 10/ sex) at an average dose of 0.5 mg a. i./ kg/ day or placebo 0 mg/ kg/ day ( 6 males and 4 females) for 16 consecutive days followed by a 29 day recovery period ( phase three). The dosing phase ( phase two) was preceded with a 6 day period ( phase one) where all subjects received daily placebos. Administration of the test material or the placebo was given orally by capsule divided into three daily doses. Each subject received two capsules postprandially for the first two dosing periods; the 66 of 87 third dose was given at the end of the work day in order to simulate as closely as possible ingestion of the material as a crop residue. The capsules were dispensed daily ( 5 days/ week) by an assistant who observed the subjects while they took each capsule and recorded solicited comments related to the ingestion of the material for 8 hours. The subjects and the assistant did not know which capsules were placebo or the test material in of the study phases. Each Friday, the subjects received a supply of capsules to be taken during the two day weekend. All subjects were monitored regularly for adverse effects. Hematology measurements and clinical chemistry were conducted on blood samples collected during phases I, II and III while urinalysis was conducted on samples collected during phase II. ChE ( plasma and RBC) determinations were conducted using the   pH/ hr method ( modified Michel method) on blood collected during phases I, II, and III.

Critique of 16 day Oral Toxicity Study No clinical symptoms were reported, but it is not known if this was an omission as the report does not state that there were no symptoms or signs. Hematological, clinical chemistry values and urinalysis parameters were comparable to the placebo controls. The updated executive summary of the Agency Data Evaluation Record ( Khasawinah) for the 16 day human study stated: " Plasma and RBC ChE activities were significantly inhibited in both placebo and test groups. Therefore, this finding makes any conclusions regarding the effects attributable to ethephon administration impossible. This is in contradiction to the study authors overall conclusion that a daily ethephon oral dosage of 0.5 mg/ kg/ day produces significant plasma ChE inhibition, which is reversible in 15 days." The study report states " Plasma cholinesterase was significantly inhibited for the placebo group at 4, 8, 12, and 16 days during the dosage period. In the test group, plasma cholinesterase was also depressed ( greater than the placebo group) at 4, 8, 12, and 16 days during the dosage period. Recovery does occur as indicated by the 15 and 29 post dosage values. RBC cholinesterase inhibition was similar for both placebo and test groups ( slightly depressed in both groups) on days 4, 12, and 16 of the dosage period and day 15 of the recovery period." Investigators also say that the test group plasma values were significantly different than the placebo group values.

It appears that either the method of testing cholinesterase was poor, or, less likely, something else was depressing plasma cholinesterase in this latter study while increasing it in the former study. Possibly, as the ethephon risk assessment team concluded, measures of blood cholinesterase, either plasma or RBC, were not appropriate for endpoint selection for ethephon.

According to the WOE document ( Kent 2006) " The OPP/ HED RfD Peer Review Committee determined on February 10, 1994 that the reference dose ( RfD) should be based on the 28 day study in human subjects ( MRID 00036510). Clinical signs of toxicity were observed at 1.8 mg/ kg/ day ( only dose tested) and included diarrhea, urgency of bowel movements, urinary urgency and stomach cramps." 67 of 87 A Report from EPA, Office of Pesticide Programs, Health Effects Division, Hazard Identification and Assessment Review Committee ( HIARC) dated 4/ 1/ 98 states in reference to the 28 day human study: " This human study is considered to be of better quality and the findings more reliable than the 16 day human study previously used to define the RfD." Since 1994, the HIARC has repeatedly ( 8/ 9/ 94, 4/ 1/ 98, 7/ 15/ 02 and 11/ 5/ 02) selected the 28 day human study to assess all relevant exposure scenarios, and at the last HIARC meeting, a weight  of  evidence comment regarding endpoint selection was included: " HIARC had considered experimental animal studies on ethephon and concluded this human study was most appropriate for selection of the endpoint of toxicity for risk assessment. The clinical signs of toxicity in this human study occurred at dose levels that were much lower than seen in experimental animals." " Despite the limitations of the study, and the equivocal nature of the reported findings, the HED ethephon risk assessment team believes that, in the absence of data ruling out the observed effects as inconsequential, the 28 day human study is the most appropriate study to use for assessing both the acute and chronic dietary risks of ethephon."

The WOE document stated: " A number of conclusions relevant to endpoint selection can be drawn from the database of ethephon oral toxicity studies in humans and animals: ( 1) ethephon is neurotoxic in animal studies only at high doses ( 300 mg/ kg and above), ( 2) ethephon inhibits blood cholinesterases, in particular plasma cholinesterase in animals and humans at relatively low doses, ( 3) brain acetylcholinesterase is insensitive to ethephon in adult animals. Accordingly, the team then debated whether to use effects in animals ( LOAEL approximately 80 mg/ kg/ day) or in humans ( LOAEL of 1.8 mg/ kg/ day) for endpoint selection, and opted as a matter of prudence to base endpoint selection on effects observed in humans." The Board concluded that this is much lower than that expected from the animal studies, however, the second study informs and provides the level of uncertainty to accept this LOAEL and use it as a POD.

The WOE document concluded by stating: " The point of departure for the dietary assessments use of a LOAEL was applied to the POD to obtain a reference dose of 0.06 mg/ kg/ day for assessment of both acute and chronic dietary risks was 1.8 mg/ kg/ day ( with an uncertainty factor of 10x for intraspecies variability and a 3x factor for use of a LOAEL  )"

HSRB Consensus and Rationale The ethephon 16 day human oral toxicity study ( second study) had no value on its own, but it did inform the ethephon 28 day human oral toxicity study ( first study); it allows one to consider the results of the first study in light of the information gained there from. The Board approved the first study for use in EPA risk assessments, emphasizing that the scientific quality is not adequate on its own, and that the dose level administered was almost certainly not the lowest dose at which adverse effects are likely to be observed. However, its use in lieu of the animal studies, will result in greater protection for exposed human populations. 68 of 87 6.2. Ethical considerations Charge to the Board In its ethics review of this research, EPA documented that the study reports contained very little information concerning the ethical conduct of the research and that the available information raised no ethical concerns. The Agency asks that the Board provide comment on the following, taking into account all that is known about the ethical conduct of each study:

OPP's conclusion that there is not clear and convincing evidence that the conduct of the research was fundamentally unethical; and whether there is clear and convincing evidence that the conduct of the study was significantly deficient relative to the ethical standards prevailing when the study was conducted.

Board Response to the Charge Brief Overview of the Study Two studies involving repeat high and low dose oral exposure of human subjects to ethephon ( ethrel) were evaluated. Both studies were performed by Litton Bionetics, Inc. of Bethesda, Maryland. The studies were sponsored by Amchem Products, Inc., of Ambler, Pennsylvania. Both studies were conducted prior to publication of U. S. regulations ( drafted 1974, adopted by DHHS and FDA in 1981) or the Common Rule ( adopted by EPA in 1991), so the regulatory standards established by 45 CFR 46 with respect to conduct of research involving human subjects cannot be applied in this retrospective evaluation. The low dose study, however, was performed after the 1972 Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA) went into effect, and is subject to the regulations contained therein. In particular, FIFRA Section 12( a)( 2)( P) states that "[ i] t shall be unlawful for any person   to use any pesticide in tests on human beings unless such human beings ( i) are fully informed of the nature and purposes of the test and of any physical and mental health consequences which are reasonably foreseeable therefrom, and ( ii) freely volunteer to participate in the test." Both studies were also are expected to be in compliance with the ethical standards for research involving human subjects established by the 1964 version of the Declaration of Helsinki.

Critique of Study The Board concurred with the factual observations of the strengths and weaknesses of the study, as detailed in the EPA's Initial Ethics Review of Ethephon Human Study, dated March 17, 2006. However, further comments are warranted regarding: 1) whether the repeat high dose oral exposure protocols used were designed to minimize risks to study participants; and 2) whether the documentation and process of 69 of 87 study subject enrollment was sufficient to meet prevailing standards of voluntary informed consent.

1) Minimization of Risks to Study Participants The two repeat high and low dose oral exposure studies were performed in 1971 and 1973, respectively. The high dose study involved repeated dosing, over a 28 day period, of 12 subjects ( six men and six women) with 1.8 mg/ kg body weight of ethephon per day by oral ingestion. Four subjects ( two men and two women) received placebo control. The study documents provide no clear justification for the selection of the 1.8 mg/ kg body weight dose, other than passing reference to " a preliminary dose range study   carried out in two human subjects. ( Litton 1972).

On weekdays, clinical symptoms were monitored continuously for eight hours following ingestion of the test compound; after hours and on weekends, subjects were requested to self report any adverse clinical symptoms. There was no mention in the documents reviewed by the Board that the investigators made provision for observation or rescue during these off hours. Laboratory analyses, including analysis of blood and urine samples, were performed weekly during the study and also two weeks after last exposure. A large number of study subjects receiving the active compound exhibited clinical symptoms clearly associated with ethephon exposure, including diarrhea and other gastrointestinal disorders ( 4 participants), increased frequency and urgency of urination ( 5 participants), and persistent abdominal pain ( 1 participant). Laboratory analyses also revealed transient elevations in blood glucose and increased inhibition of plasma cholinesterase in subjects receiving ethephon. No stopping criteria were listed in the final report, nor was there evidence that the investigators considered halting the trial even after large numbers of study participants began to report adverse clinical symptoms.

The low dose study involved repeated dosing, over a 16 day period, of 20 subjects ( 10 men and 10 women) with 0.5 mg/ kg body weight of ethephon per day by oral ingestion. Ten subjects ( six men and four women) received placebo control. The study documents again provide no clear justification for the selection of the 0.5 mg/ kg body weight dose, other than indirect reference to the high dose study described above.

As before, clinical symptoms were monitored continuously for eight hours and self reported after hours and on weekends. Laboratory analyses were performed on days 1, 9, and 16, and two weeks following last dose. No adverse clinical events were reported. Surprisingly, the report even fails to mention that no adverse clinical events were seen, leading several Board members to suspect that adverse event data was not rigorously collected.

2) Voluntary Informed Consent Neither study contained sufficient information for the Board to adequately determine whether or not the informed consent process used to enroll study participants met the standards outlined in FIFRA Section 12( a)( 2)( P) and the 1964 version of the 70 of 87 Declaration of Helsinki. Each of the final study reports provided to the Board contained only but the briefest of statement as to the nature of the voluntary informed consent process:

" Sixteen human volunteers judged to be in good health as ascertained by prephysical interview, physical examination and selected clinical laboratory evaluations were chosen for the study. All subjects were thoroughly briefed on the nature and present use of the test product, the animal toxicity data, and the potential pharmacological side effects."

" All subjects were thoroughly informed on the nature and present use of the test substance, the animal toxicity data, potential pharmacologic side effects, and the results of the prior study in human volunteers. Based on this briefing, consent documents were obtained from all subjects."

Although the 1973 low dose study does contain reference to written consent documents, these were unavailable for review.

Despite the paucity of documentation, several Board members expressed concern over what they consider to be potential violations of accepted standards of informed consent:

  Circumstantial evidence suggests that employees of Litton Bionetics, Inc., may have been enrolled as study participants. For example, there was mention of four study participants " working in the same building." The possible participation of employees in a laboratory directed research project raised issues of coercion and voluntariness.   In the high dose study, a large number of study subjects receiving active compound exhibited clinical symptoms clearly associated with ethephonexposure including diarrhea and other gastrointestinal disorders, increased frequency and urgency of urination, and persistent abdominal pain. Not a single study participant, however, withdrew from the study over the 28 day monitoring period, regardless of the severity of illness. This again raised questions about the voluntary nature of participation in research.

HSRB Consensus and Rationale The Board concluded that:

a) The both the 28 and 16 day oral human toxicity studies failed to fully meet the specific ethical standards prevalent at the time the research was conducted.

b) There was no clear and convincing evidence that the research is fundamentally unethical intended to seriously harm participants or that informed consent was not obtained. 71 of 87 c) There was no clear and convincing evidence of significant deficiencies in the ethical procedures could that have resulted in serious harm ( based on the knowledge available at the time the study was conducted), nor that information provided to participants seriously impaired their informed consent.

Although these two studies appear to lack justification for the dose selection, as well as clear stopping criteria to prevent serious harm to research participants, the Board does not believe that there was clear and convincing evidence that these studies could have resulted in serious harm based on the knowledge available to the investigators at the time.

There were indications of informed consent deficiencies. Nevertheless, given the paucity of information provided there was no evidence that the voluntary informed consent process used in these two studies failed to meet the few regulatory and ethical standards applicable to research conducted in 1971 1973.

The Board concluded that there was no obvious reason why the Agency cannot rely on the results of this study, as appropriate under current pesticide laws, given the absence of clear and convincing evidence that the research was fundamentally unethical or significantly deficient relative to the ethical standards prevailing when the study was conducted.

7. Hydrogen Cyanide Charge to the Board When sodium cyanide is used as a fumigant, hydrogen cyanide is generated by acidification. Because residues of HCN may remain on fumigated citrus, the Agency is conducting an acute dietary risk assessment of hydrogen cyanide.

7.1. Scientific considerations The Agency's WOE document describes a lack of data appropriate for developing an acute dietary risk assessment for hydrogen cyanide. The WOE and DER present the results from a clinical trial with amygdalin and the usefulness of this clinical trial in the acute dietary risk assessment for hydrogen cyanide. The Agency has concluded that the clinical trial is appropriate for establishing a point of departure in the acute dietary risk assessment for hydrogen cyanide.

Please comment on the scientific evidence that supports this conclusion.

Board Response to the Charge Brief Overview of the Study 72 of 87 The clinical trial of amygdalin for treatment of cancer ( Moertel et al., 1982), which included the preliminary pharmacology and toxicology study ( Moertel et al., 1981), involved the administration, under controlled circumstances, of known amounts of amygdalin to patients with terminal cancers for which no known treatments were available. Amygdalin was administered intravenously for 21 days ( 4.5 g/ m2), followed by oral maintenance therapy of 500 mg ( three times per day), plus a " metabolic therapy" consisting of diet, pancreatic enzymes, and vitamins. Most patients were administered the standard dose regimen, but a small number received a high dose regimen.

Clinical signs and symptoms consistent with cyanide toxicity ( nausea, vomiting, headache, dizziness, mental obtundation) were observed in some patients following a single 500 mg oral dose of amygdalin. The conclusions regarding toxicity were based largely on several patients who developed such symptoms when they took two 500 mg doses too close together or ate foods such as raw almonds that are rich in ß glucosidase, an enzyme that causes the release of cyanide from amygdalin. In such patients, the symptoms typically resolved when oral amygdalin was discontinued, the dose was reduced, or the patients stopped eating the critical foods. In the pharmacology and toxicology study, the responses of two patients challenged with almonds provided further support for the conclusion that the symptoms reflected cyanide toxicity. In some patients, the appearance of symptoms was associated with relatively high blood cyanide levels, which in some instances approached levels observed in human fatalities (> 3 µ g/ mL). A dose of 500 mg was interpreted as a minimal effect level but not as a NOAEL.

Critique of Study The trial had several strengths. The sample size was large, including 178 patients. Blood cyanide levels were assessed several times, at completion of intravenous ( i. v.) treatment, 48 hours after initiation of oral treatment, and at every subsequent evaluation. Measurements were made two hours after the first morning dose of oral amygdalin, when the maximum elevation in cyanide was anticipated. The trial employed a good operational definition of the clinical outcome of interest in the trial, which was tumor progression.

The trial also had several weaknesses. First, it was not blinded and did not include a placebo group. Second, insofar as the primary aim was to assess the effectiveness of amygdalin as a treatment for advanced cancer, the assessment of potential cyanide toxicities was not as systematic as the assessment of tumor progression. As in any clinical trial of drug efficacy, side effects were recorded, however, these side effects were examined in relation to whole blood cyanide levels. Oral dosing with amygdalin did not begin until 21 days of i. v. treatment had been completed. It is unlikely that this introduced a bias, however. In contrast to delivery by oral route, amygdalin delivered i. v. is largely excreted unchanged in urine without conversion to cyanide. Whole blood cyanide levels were undetectable following i. v. dosing, making it likely that the rise observed following oral dosing was not confounded by the prior i. v. dosing. Third, patients who participated in the study were terminally ill with cancer. Although the 73 of 87 inclusion criteria required that patients be in " good general condition" and ambulatory, they are, nevertheless, likely to represent a particularly sensitive subgroup, thus providing a conservative estimate of the hydrogen cyanide dose at which toxicities occur. Fourth, all clinical signs and symptoms of toxicity ( nausea, vomiting, headache, dizziness, mental obtundation, and dermatitis) were observed with nearly equivalent frequencies during i. v. and oral dosing. Many of these signs and symptoms might be increased in terminal cancer patients anyway, and thus unrelated to amygdalin or cyanide. Moreover, if these were indications of toxicity related solely to elevations in blood cyanide, they would not be expected to have occurred with equal frequency during i. v. and oral dosing. The data from the natural experiments within the trial, such as when the doses of individual patients who developed symptoms were changed or the patients were challenged, provides the most persuasive evidence of an increased risk of cyanide toxicity in patients administered amygdalin.

HSRB Consensus and Rationale The Board concluded that data from the amygdalin trial could be used for establishing a point of departure in the acute dietary risk assessment for hydrogen cyanide.

Despite its limitations, this study provides the best data we are likely to ever have on which to establish a POD for this purpose. Given the severity of the effect, the steepness of the dose response relationship, and the apparent inter individual differences in response to a given dose, it would be imprudent to undertake an intentional dosing study of healthy humans in order to establish a LOAEL and NOAEL for hydrogen cyanide.

7.2 Ethical considerations Charge to the Board In its ethics review of this research, EPA did not identify any deficiencies with respect to the ethical conduct of this research. The Agency asks that the Board provide comment on the following, taking into account all that is known about the ethical conduct of this study:

OPP's conclusion that there is not clear and convincing evidence that the conduct of the research was fundamentally unethical; and whether there is clear and convincing evidence that the conduct of the study was significantly deficient relative to the ethical standards prevailing when the study was conducted.

Board Response to the Charge Brief Overview of the Study 74 of 87 Two related studies are being evaluated. Both were sponsored by the National Cancer Institute. The first study was a pharmacologic and toxicological study involving six subjects which took place at the Mayo Clinic ( Rochester, MN), with the results being published in the Journal of the American Medical Association in 1981 ( the Board assumed the study was conducted 1979 1980). Although the published report does not describe the ethical standards to which the researchers adhered, the Board assumed that as a federally funded study, the research would have been subject to the then current version of the federal DHHS [ DHEW] regulations ( 45 CFR Part 46) that would later become the Common Rule. The second study was essentially a Phase II follow up to the first study, involving 178 subjects who were enrolled at four sites ( Mayo Comprehensive Cancer Center, Mayo Clinic, Rochester, MN; UCLA Johnson Comprehensive Cancer Center, Los Angeles, CA; Memorial Sloan Kettering Cancer Center, New York, NY; and University of Arizona Cancer Center, Tucson, AZ). The results of that second study were published in the New England Journal of Medicine in 1982. That article also does not specify the specific ethical rules under which the study was conducted, and this Board again assumes that it would have been subject to the then current version of the predecessor regulations ( DHHS [ DHEW], 45 CFR Part 46) to the current Common Rule.

Critique of Study The Board concurred with the factual observations about the study, as detailed in Carley ( 2006h).

In particular, the Board concurred with the key observation regarding the difference between this study and the other studies that the Board has heretofore been asked to review. This study involved testing a compound for its safety and efficacy in treating a medical problem. As such, the ethical evaluation of this study was significantly different from that of a study involving exposing subjects to a pesticide. A major consideration in evaluating the ethics of such a study involved determining whether the two arms of the study were in clinical equipoise, a concept that was only in its earliest stages at the time of this study. Nonetheless, it does appear that this study would meet even the modern day understanding of that concept. All of the subjects were persons with histologically proven cancer for which no standard treatment was known to be available. The subjects received either a standard dose or a high dose of amygdalin ( Laetrile). Prior to this study being conducted, there was substantial uncertainty regarding whether this compound might indeed be a safe and effective treatment for many forms of cancer. As stated in the New England Journal of Medicine article, it had " eclipsed any other unorthodox therapy ever used for any disease in our time." Thus, conducting this study served to answer an important medical question of that time period.

Moreover, the published report of the second study indicated compliance with all of the procedural protections that would be required today. It notes that all " patients were fully informed about the experimental and unorthodox nature of the treatment program as well as any possible alternative treatment available to them. A signed form giving informed consent, approved by the Human Subjects Committee at each of the four 75 of 87 participating centers, was obtained from each patient." ( The actual forms were not available for review by the Board.) The article further noted that " the methods of this trial were entirely comparable to those employed in studies of any new agent being developed and tested for cancer treatment through more traditional channels."

HSRB Consensus and Rationale The Board concluded that: a) The hydrogen cyanide human oral toxicity study appeared to meet the specific ethical standards prevalent at the time the research was conducted.

b) There was no evidence that the research was fundamentally unethical intended to seriously harm participants or that informed consent was not obtained.

c) There was no evidence of significant deficiencies in the ethical procedures that could have resulted in serious harm ( based on the knowledge available at the time the study was conducted) nor that information provided to participants seriously impaired their informed consent.

Although the Board based its determinations only on the two published articles, it did not find any ethical flaws in the conduct of these two studies. The article described appropriate informed consent procedures. The risks and potential benefits of the dosing were appropriate for a medical treatment study for this particular cancer population.

The Board concluded that there was no obvious reason why the Agency cannot rely on the results of this study, as appropriate under current pesticide laws, given the absence of clear and convincing evidence that the research was fundamentally unethical or significantly deficient relative to the ethical standards prevailing when the study was conducted.

8. Amitraz Charge to the Board Exposure to amitraz can result in neurotoxicity as evidenced by clinical signs such as ataxia, ptosis, emesis, labored respiration, muscular weakness, tremors, hypothermia and bradycardia. The Agency is conducting an aggregate ( single chemical, multi route) risk assessment of amitraz.

8.1. Scientific considerations The Agency's WOE document and DERs for amitraz describe the study design and results of the amitraz acute oral and dermal toxicity human studies and the human metabolism study. The WOE document also discusses the Agency's conclusions regarding the usefulness of the human studies in the single chemical risk assessment for 76 of 87 acute and chronic oral exposures in addition to dermal and inhalation exposures of various durations. For oral exposure, the Agency has concluded that the combined results from the single oral dose study and human metabolism study establishes a dose response relationship in human subjects and that the single oral dose study is appropriate for developing a point of departure for acute and chronic dietary risk, short term oral exposure, and inhalation exposures of various durations. The Agency has further concluded that the human dermal study is appropriate for developing a point of departure for dermal exposures of various durations.

Please comment on the scientific evidence that supports these conclusions.

Board Response to the Charge Overview The HSRB was asked to comment on the scientific evidence that supports the following conclusions:

1. For oral exposure, the Agency concluded that the combined results from the single oral dose study and human metabolism study establish a dose response relationship in human subjects, and that the single oral dose study is appropriate for developing a point of departure for acute and chronic dietary risk, short term oral exposure, and inhalation exposures of various durations.

2. The Agency further concluded that the human dermal study is appropriate for developing a point of departure for dermal exposures of various durations.

Amitraz [ N'( 2,4 dimethylphenyl) N[[( 2,4 dimethylphenyl) imino] methyl] Nmethylmethanimidamide is an insecticide/ acaricide with wide range of registered uses in the United States. The toxicity profile for amitraz has not been characterized completely, especially developmental and reproductive effects. Neurotoxicity is considered the most sensitive effect resulting from exposure to amitraz. Neurotoxicity has been demonstrated in multiple species ( baboon, cat, dog, mouse, rat and rabbit). Clinical signs include central nervous system depression, ataxia ( loss of coordination), ptosis ( droopy eyelids), emesis ( vomiting), labored respiration, muscular weakness, tremors, hypothermia and bradycardia ( slow heartbeat). Similar signs are seen in humans. The Agency's evaluation of amitraz included three human studies: a 1984 oral dose metabolism study Campbell 1984), a 1992 oral dose tolerance study ( Cass 1992) and a 1997 dermal dose tolerance study ( Langford 1997).

Critique of Oral Dose Metabolism Study ( 1984)

Radio labeled amitraz was orally administered to rats, mice, baboons and humans. The two human volunteers received a single 0.25 mg/ kg dose of amitraz by capsule. This dose caused dry mouth, drowsiness, disorientation, decreased temperature, bradycardia, and slightly pale appearance in both subjects, persisting up to 12 hours after dosing. One 77 of 87 subject fell asleep for 6 hours following dosing. Psychomotor testing was not included in the protocol. Approximately 44% of the dose was excreted within 12 hours, with 63% excreted within 24 hours. Study deficiencies included the small number of subjects ( N= 2), testing of males only, and no control group. Sex differences in the repeat dose animal studies have shown that females are more sensitive than males. The study investigators concluded that humans were more sensitive to amitraz than were other species included in the metabolism study.

The occurrence of multiple signs and symptoms in both subjects and the continued bradycardia up to 12 hours post dosing suggest that the 0.25 mg/ kg dose was not the lowest adverse effect level for amitraz in humans. Because there was only one dose level, it was not possible to glean any information regarding dose response from this study. Incomplete excretion of the amitraz metabolites at 24 hours post dosing suggests that some portion of the dose was present on the day following dosing, albeit not at levels sufficient to produce the frank signs and symptoms observed on the day of dosing.

Critique of Single Oral Dose Study ( 1992)

The design was a single oral dose double blind tolerance study. The primary objective of this study was to determine the tolerance of male volunteers to a single dose of amitraz at two different dose levels ( 0.0625 and 0.125 mg/ kg), with a placebo control. Six subjects completed the study. Each subject received each of the doses and the placebo. Dosing events were separated by at least 14 days for each subject. The dosing regimen was thoughtfully constructed, beginning with the lower dose, and moving to the higher dose when it was observed that the lower dose was well tolerated. The subjects were admitted to a clinical pharmacology unit the evening before each dosing and remained there for 36 hours. Complete physical examinations were conducted before and after the study. The subjects were followed for at least three weeks following the study. The most sensitive neurologic endpoints measured in this study were two psychomotor performance tests: choice reaction time and critical flicker fusion threshold. The psychomotor performance tests were administered pre dose, 2.5 hours, and 8 hours following dosing. The report provides tabular and graphic representation of the results of these tests, but no statistical analyses were conducted. Study deficiencies included the small number of subjects ( N= 6), and the testing of males only. The study investigators concluded that no effects were observed from the single oral dose in any of the subjects.

The major concern with this study was whether " no effect" was truly observed. The study report was deficient in its description of the psychomotor performance testing, and in the rationale for selecting these tests. There were no descriptions of the specific procedures followed for the psychomotor tests, no standard operating procedures, and no quality assurance documentation. Also, there was no evidence provided in the report to indicate that these tests were the most sensitive available. A review of the current scientific literature, and discussions with leading scientists in this area of expertise would permit the Agency to determine if these psychomotor test results are adequate to characterize a " no effect" level in regard to neurotoxicity for amitraz. 78 of 87 Critique of Dermal Toxicity Study ( 1997)

This study was a double blind sequential dosing study with a randomized crossover and a placebo group. The study aims were to 1) establish a no effect level for acute effects following repeated dermal doses of amitraz, 2) produce data that would permit calculation of margins of safety for agricultural workers. Eight male volunteers were given a total dose of either 0, 8, 16 or 24 mg/ kg amitraz, applied dermally as four equal doses of 0, 2, 4 or 6 mg/ kg in an aqueous 1: 1 ( w/ w) slurry every 2.5 hours over 10 hours. Starch, 1: 1 ( w/ w) in water, was used as a placebo. Each of these amitraz experiments involved a timed series of dosing events ( 0, 2.5, 5.0, and 7.5 hours), followed by a washing event at 10 hours. Each dose within an experiment was applied to a different 20 cm2 skin surface area, so the total skin surface treated in each experiment was 80 cm2. Thus, skin loadings for the three experiments were 7,000, 14,000, and 21,000 µ g/ cm2, corresponding to the three dose levels ( 8 mg/ kg, 16 mg/ kg, 24 mg/ kg), assuming a body weight of 70 kg. No differences were observed between treatment and placebo for any of the measured endpoints. No urinary metabolite monitoring was conducted to confirm that amitraz had been absorbed. The study report is deficient in its description of the psychomotor performance testing, and in the rationale for selecting these tests. There is no description of the specific procedures followed, no standard operating procedures, and no quality assurance documentation. Also, there is no evidence provided in the report to indicate that these tests were the most sensitive available. A review of the current scientific literature, and discussions with leading scientists in this area of expertise would permit the Agency to determine if these psychomotor test results are adequate to characterize a " no effect" level in regard to neurotoxicity for amitraz.

The primary deficiency of this study is that it does not provide a realistic worker exposure scenario; that is, the exposures of the subjects in these experiments did not correspond to exposures likely to be seen among workers. Large amounts of amitraz ( 140 420 mg) were applied to a relatively small skin surface area ( 80 cm2) in the experiments, whereas we typically see much larger skin surface areas exposed to smaller amounts among workers. For example, the hands, a skin surface commonly exposed to pesticides, have a total surface area of 990 cm2, or 12 times greater than the exposed skin surface area in this experiment ( USEPA 1997). If both the hands and forearms were exposed, the total exposed surface area would be 3,900 cm2, or 49 times the surface area exposed in this study. This discrepancy is important, as it has a major impact on the amount of compound that can be absorbed within a defined time period. Dermal dosing studies require careful consideration of three factors: mass applied to the skin, surface area treated, and the duration of exposure. These three factors are typically used to determine the flux of a chemical through the skin ( e. g., mg/ cm2/ hr). Percent absorbed is highly dependent on the skin loading, or mass applied per unit area ( e. g., mg/ cm2). The relationship between skin loading and percent absorbed was made clear in a review of studies in the rat by Zendzian ( 2000). In the case of azinphos methyl, for example, a loading of 3 nanomole/ cm2 for 10 hours resulted in 23% absorption, a loading 10 fold higher ( 29 nmolesM/ cm2) resulted in 15% absorption, and a further 10 fold increase in loading ( 293 nmoles/ cm2) resulted in only 2.9% absorption. These azinphos methyl loadings, expressed as mass per unit area, were 0.95, 9.2, and 93 µ g/ cm2, respectively. In 79 of 87 earlier dermal dosing studies involving humans, radio labelled pesticides were applied at loadings of 4 and 40 µ g/ cm2 ( Feldmann and Maibach 1974). It is evident that the skin loadings in the amitraz study were several orders of magnitude higher than those used in the above cited studies. The key point is that chemical loadings on small areas of skin result in relatively small amounts of chemical absorbed. In this dermal toxicity study, the loadings were so high that the three " dose" levels were essentially equivalent in terms of dermal absorption potential.

If it is assumed that the flux of amitraz in these experiments was approximately 2 µ g/ cm2/ hr, as has been estimated from a study of chlorpyrifos, a lipophilic insecticide with a similar molecular weight ( Nolan et al. 1984), then the total mass absorbed in the amitraz experiments over 10 hours would have been approximately 1,000 µ g ( 1 mg), or an absorbed dose of 0.014 mg/ kg. If this same flux were applied to an exposure to the hands and forearms of a worker, the total mass absorbed would be approximately 50,000 µ g ( 50 mg), or an absorbed dose of 0.71 mg/ kg, well above both the 0.125 mg/ kg single oral dose " no effect" level, and the 0.25 mg/ kg single oral dose that elicited multiple signs and symptoms of neurotoxicity. It is for this reason that the amitraz dermal toxicity study cannot be considered a " no effect" study for risk assessment purposes.

HSRB Consensus and Rationale a. The Board concluded that the results from the single oral dose study are informed by the human metabolism study such that the single oral dose study is appropriate for developing a point of departure for acute and chronic dietary risk and short term oral exposure.

The appearance of overt signs and symptom of toxicity in the 1984 oral metabolism study at a dose of 0.25 mg/ kg provides some confidence that the highest dose ( 0.125 mg/ kg) in the 1992 single oral dose study represent a no observable adverse effect level ( NOAEL) for an acute dietary exposure to amitraz No effects of neurologic toxicity were observed in any of the study subjects at 0.125 mg/ kg. This conclusion rests on the assumption that the psychomotor tests applied to the subjects are the most sensitive endpoints for neurotoxicity, and that they were conducted properly. There was considerable uncertainty regarding these psychomotor tests, as the procedures used were not described in the study, and on quality assurance information was provided. Thus, the findings from this study should be used with caution for risk assessment purposes.

b. The Board concluded that the combined results from the single oral dose study and the human metabolism study were not appropriate for developing a point of departure for chronic dietary risk, short term oral exposure, or inhalation risk.

A single oral dose of 0.25 mg/ kg elicited frank symptoms of toxicity in both subjects in the 1984 metabolism study. Multiple signs and symptoms were observed in the subjects for several hours post dosing, and at least one sign ( bradycardia) was still present at 12 hours post dose. Excretion of radio labeled metabolites was incomplete ( 62%) at 24 hours. The proposed NOAEL is only one half the dose used in the 1984 80 of 87 study. Thus, subjects exposed to repeated daily doses, as would occur in short term or chronic oral dose studies, would achieve a cumulative dose of 0.25 mg/ kg within 48 hours. It seems quite possible that repeated short term oral exposures or chronic oral exposures would elicit at least some effects in humans within a very few days. Thus, the available data do not demonstrate a no effect level for multi day oral exposures. In regard to inhalation exposures, absorption through the respiratory tract is generally more efficient than absorption through the gastro intestinal tract. It is quite possible that adverse effects would have been observed in an inhalation exposure study that delivered 0.125 mg/ kg as a single dose. Also, an oral dose study would not capture adverse effects unique to exposure by the inhalation route. Thus, the available data do not demonstrate that the oral NOAEL and the inhalation NOAEL are equivalent.

c. The majority of the Board concluded that the human dermal study was not appropriate for developing a point of departure for dermal exposures of various durations.

The HSRB members did not consider the dermal toxicity study to be a valid scientific study for risk assessment because: 1) the study involved extremely high loadings ( mass per unit surface area) of amitraz on the skin, making the three dose levels used in the study very nearly equivalent in regard to dermal absorption potential, and not equivalent to worker exposure scenarios; 2) the study did not demonstrate an effect ( i. e., the study was equivalent to a " NOAEL only" study); and 3) there was no corroborating evidence to demonstrate that an internal dose had been delivered to the subjects by the dermal route. One member of the HSRB, while agreeing with these scientific criticisms, considered that the study might still be of use to the Agency.

8.2. Ethical considerations Charge to the Board a. The Agency requests that the Board provide comment on the following:

With respect to the Campbell ( 1984) research, whether the lack of medical surveillance of subjects, following the termination of dosing, to establish that subjects' signs of adverse effects had returned to normal should be considered significantly deficient relative to the ethical standards prevailing when the study was conducted; and With respect to the Cass ( 1992) and the Langford ( 1998) studies, whether references to the test material as a drug and other statements that could indicate the study constituted medical research, that appear in the materials used to obtain informed should be considered significantly deficient relative to the ethical standards prevailing when the study was conducted; and b. The Agency asks that the Board provide comment on the following, taking into account all that is known about the ethical conduct of each study: 81 of 87 OPP's conclusion that there is not clear and convincing evidence that the conduct of the research was fundamentally unethical.

Whether there is clear and convincing evidence that the conduct of the study was significantly deficient relative to the ethical standards prevailing when the study was conducted.

Board Response to the Charge The compound amitraz is an alpha two adrenergic agonist that produces sympatholytic effects leading to sedation and other neurological signs and symptoms, as well as cardiovascular depression with a drop in blood pressure and heart rate. The studies under ethical review include two metabolic studies in 1984 using C14 radiolabeled isotope technology, a 1992 oral dosing study, and a 1998 dermal absorption study.

The two metabolic studies were performed in 1984 and involved two volunteer subjects. The oral dosing study was performed in 1992 and involved six research subjects ( with an additional ( 1) subject withdrawn for an unrelated rash). The oral dosing study was a double blind, randomized, placebo controlled, crossover study involving two different doses. The oral dosing study progressed in three phases, escalating from the lower dose to the higher dose. The protocol stated that the research was in compliance with the 1989 version of the Declaration of Helsinki, an early version of good clinical practice ( GCP) guidelines promulgated by the EMEA ( 111 3976 88 EN), the ABPI Guidelines for Medical Experiments in Non Patient Human Volunteers ( 1988, 1990), the 1986 RCP Guidelines on Research Using Healthy Volunteers, the FDA Compliance Program for Drugs and Biologics and the GCP guidelines from Japan that were current in 1992 ( Notification No. 874 from the Ministry of Health and Welfare). The approval of the research ethics committee was given on November 20, 1991, but no information was provided about the substance and process of that review.

The dermal absorption study was performed in 1998 and involved eight research subjects. The study was a double blind, randomized, placebo controlled, crossover study involving three different doses ( in a four phase dose escalation design). The protocol stated that the research was in compliance with the above standards, with the updated GCP guidelines promulgated in 1996. The approval of the research ethics committee was given on December 22, 1997, although no information is provided about the substance and process of that review.

Critique of Study The Board concurred with the factual observations of the strengths and weaknesses of the two 1984 metabolic studies, as detailed in Carley ( 2006g). Specifically, there is no justification for the dose selection, no record of independent committee review, and no record of informed consent ( other than the description of the participants as volunteers. The dose selected did result in adverse events as might be 82 of 87 expected from the administration of a product with this pharmacological profile. The period of recorded observations was eight hours, and stated observation time was 12 hours. Although the period of observation was insufficient to assure that the physiologic condition of the volunteers had returned to baseline, the known physiologic effects of the compound are such that the period of observation was sufficient to assure the lack of significant adverse effects.

The Board concurred with the factual observations of the strengths and weaknesses of the 1992 oral dosing study as documented in Carley ( 2006h). Of note was that the volunteer information included information about the risks of the administration of the study compound which were relatively complete in the scope of the risks described ( yet absent a few details within each organ system).

The Board concurred with the factual observations of the strengths and weaknesses of the 1998 dermal absorption study, as documented in Carley ( 2006i). Although concern has been expressed about the choice of dose, the study design involved a dose escalation such that adverse events at lower doses could have been anticipated.

HSRB Consensus and Rationale The Board concluded that:

a) The amitraz acute oral and dermal human toxicity studies failed to fully meet the specific ethical standards prevalent at the time the research was conducted.

b) There was no clear and convincing evidence that the research was fundamentally unethical intended to seriously harm participants or that informed consent was not obtained.

c) There was no clear and convincing evidence of significant deficiencies in the ethical procedures that could have resulted in serious harm ( based on the knowledge available at the time the study was conducted), nor that information provided to participants seriously impaired their informed consent.

Although the Board concurred in the noted deficiencies with the 1984 metabolic studies, the Board did not consider the lack of documentation of medical supervision following the termination of dosing in the 1984 metabolic studies to be significantly deficient relative to the ethical standards prevailing when the study was conducted.

The Board also acknowledged the observations that the 1992 oral dosing study and the 1998 dermal absorption study includes potentially misleading references in the informed consent documents. However, the Board does not believe that these deficiencies could have resulted in serious harm based on the knowledge available to the investigators at the time, nor seriously impaired the informed consent of the research subjects. As such, the Board did not consider these findings significantly deficient relative to the ethical standards prevailing when the study was conducted. 83 of 87 The Board concurred with the assessment of the Agency that there was not clear and convincing evidence that the conduct of the research was fundamentally unethical. The research as designed and conducted was not intended to seriously harm participants nor failed to obtain informed consent. Thus, the Board concluded that there was no ethical objection to the appropriate use of the data from these studies ( as discussed in the scientific assessment) given the absence of clear and convincing evidence that the research was fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time. 84 of 87 REFERENCES Campbell J. 1984. A Comparison of The Metabolism of ( 14c) AMITRAZ in Rats, Mice, Baboon and Human . FBC Limited. EPA Trid No 350109 025. 20 Pages Carley. 2006a. United States Environmental Protection Agency Initial Ethical Review of Aldicarb Human Study.

Carley J. 2006b. United States Environmental Protection Agency, Initial Ethics Review of Methomyl Human Study. REF: McFarlane, P., Sanderson, J., Freestone, S. ( 1998) A Randomised Double Blind Ascending Oral Dose Study with Methomyl to Establish a No Adverse Effect Level: Lab Project No. HLO 1998 00969. Unpublished study prepared by Inveresk Clinical Research. 468 Pages MRID 44721401. 8 Pages Carley J. 2006c. Initial Ethics Review of Oxamyl Human Study: REF: McFarlane, P., Freestone, S. ( 1999) A Randomised Double Blind Ascending Oral Dose Study with Oxamyl: Lab Probject No. HLO 1998 01505. Unpublished study prepared by Inveresk Clinical Research. 624 Pages. MRID 44912301. 8 Pages.

Carley J. 2006d. Initial Ethical Review of AZM Human Study; REF: McFarlane, P., Freestone, S. ( 1999) A Randomised Double Blind Placebo Controlled Study with Azinphos Methyl to Determine the No Effect Level on Plasma and RBC Cholinesterase Activity after Repeat Doses. Unpublished study prepared by Inveresk Clinical Research, Ltd., Tranent, UK; Lab Project ID 013580. 634 Pages MRID 45476101.

Carley J. 2006e. Initial Ethics Review of DDVP Human Study: REF: Gledhill, A. J. ( 1997) Dichorvos: A Single Blind, Placebo Controlled, Randomized Study to Investigate the Effects of Multiple Oral Dosing on erythrocyte Cholinesterase Inhibition in Healthy Male Volunteers. Unpublished Study prepared by Zenecca Central Toxicology Laboratory and Medeval Ltd. 52 Pages. MRID 44248801. 10 Pages.

Carley J. 2006f. Initial Ethics Review of Amygdalin Human Study. REF: Moetel, C,; Ames, M,; Kovach, J.; et al ( 1981) A Pharmacologic and Toxicological Study of Amygdalin. JAMA 45( 6): 591 594. MRID 46769601.

Carley J M. 2006g. Initial Ethical Review of Amitraz Human Study: REF: Campbell, J. ( 1984) A Comparison of the Metabolism of 14 C Amitraz in rat, mouse, baboon and human. Unpublished study performed by FBC Ltd., Chesterford Park Research Station, UK, under project number Metab/ 84/ 01. 20 Pages Carley J. 2006h. Initial Ethical Review of Amitraz Human Study: REF: Cass, L ( 1992) T 344, Amitraz: Report of A Double Blind Tolerance Study of Amitraz in Six Adult Healthy Volunteers: Lab Project. Number RD 197/ 20170. Unpublished study prepared by Simbec Research Ltd. MRID 43283101. 136 Pages 85 of 87 Carley J. 2006i. Initial Ethics Review of Amitraz Human Study: REF: Langford, H. ( 1998) Amitraz ( Code AE B049974): Human Volunteer Double Blind Dermal Tolerance Study: Lab Project Number: C00350: TOX 97228: RD 197/ 21690. Unpublished study prepared by Simbec Research Ltd. MRID 4463901. 243 Pages.

Doherty J. 1999. United States Environmental Protection Agency. Special Non Guideline Cholinesterase Study with Human Volunteers. Citation: P. McFarlane and S. Freestone, A Randomized Double Blind Placebo Controlled Study with Azinphos Methyl to Determine the No Effect Level on Plasma and RBC Cholinesterase Activity After Repeated Doses. Inveresk Research, Study No. ICR 013580, April 15, 1999. MRID No 45476101. Bayer Corporation. 13 Pages.

DuPont. 2006. Written Comments from DuPont Crop Protection for Consideration by the Human Studies Review Board ( HSRB) and the US Environmental Protection Agency. 71 FR 12194, March 9, 2006; Docket ID Number EPA HQ ORD 2006 0187, pp. 5 6.

Feldmann RJ, Maibach HI. 1974. Percutaneous penetration of some pesticides and herbicides in man. Toxicol Appl Pharmacol. 28: 126 32. 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. AMVAC Chemical Corporation. Report No: CTL/ P/ 5392, Study No. XH6063, MRID No. 442488 01. 53 Pages.

Khasawinah. United States Environmental Protection Agency. Supplement to HED Document No. 001394, 007214  DER for MRID No. MRID: 00036510. Ethephon  Oral Study  Humans. This supplement provides an Executive Summary to upgrade the original DER.

Khasawinah. United States Environmental Protection Agency. Supplement to HED Document No. 001405, 007214  DER for MRID No. MRID: 00066931. Ethephon  Oral Study   Humans. This supplement provides an Executive Summary to upgrade the original DER.

Kent R. 2006. United States Environmental Protection Agency. Final Weight of Evidence Comparison of Human and Animal Toxicology Studies And Endpoints for Ethephon Human Health Risk Assessment. DP Barcode: 314342, PC Code 099801, Reregistration Case 0382, MRID Several TXR No. 0053509. 5 15 Pages Langford H. 1997. Amitraz ( Code AE B049974) Human Volunteer Double Blind Dermal Tolerance Study. AgrEvo USA Company. Study No. TOX 97228, AgrEvo Report Reference C00350. 243 Pages Litton Bionetics, Inc. 1977. Final Report, Evaluation of Ethepnon in Human Volunteers LBI Project no. 2416. AMCHEM Products, Inc. 62 Pages. William H. Reese, Jr. March, 1972 86 of 87 Evaluation of Ethrel in Human Volunteers Amchem Products, Inc. Study No. 7223. 8 Pages McFarlane, P.; Freestone, S. 1999a. A Randomised Double Blind Ascending Oral Dose Study with Oxamyl: Lab Project No. HLO 1998 01505. Unpublished study prepared by Inveresk Clinical Research. MRID 44912301, pp. 96.

McFarlane P and Freestone S. 1999b. A Randomised Double Blind Placebo Controlled Study with Azinphos Methyl to Determine The No Effect Level on Plasma and RBC Cholinesterase Activity After Repeat Doses. Inveresk Clinical Research Limited File 8889, ICR 013580 634 Pages.

McFarlane, P.; Sanderson JB and Freestone, S. 1998. A Randomised Double Blind Ascending Oral Dose Study with Methomyl: Lab Project No. HLO 1998 00969. Unpublished study prepared by Inveresk Clinical Research. MRID 44721401.

Moertel, CG et al. 1981 A Pharmacologic and Toxicological Study of Amygdalin. JAMA, Vol. 245, No. 6: 591 594, MRID # 46769601, published.

Moertel, C,; Fleming, T.; Rubin, J.; et al. 1982. A Clinical Trial of Amygdalin ( laetrile) in the Treatment of Human Cancer. The New England Journal of Medicine: 306( 4): 201 206. MRID 46769602.

Moyer J, Milanez S and Ross R. 1998, Toxicology & Hazard Assessment Group Life Sciences Division. November, 1998. Methomyl/ 90301 Non Guideline Study Study Type: Ascending Acute Oral Toxicity Study in Humans MRID 44721401 Health Effects Division Office of Pesticide Programs.

Moyer J and Milanez S. Toxicology and Hazard Assessment Group Life Sciences Division. Oxamyl/ 103801 Non Guideline Study. Study Type: Ascending Oral Toxicity Study in Humans. MRID 44912301. Health Effects Division Office of Pesticide Programs USEPA. 13 Pages Nolan RJ, Rick DL, Freshour NL, Saunders JH. 1984. Chlorpyrifos: pharmacokinetics in human volunteers. Toxicol Appl Pharmacol. 73: 8 15.

NRC 2001. Intentional Human Dosing Studies for EPA Regulatory Purposes. National Academy Press.

Reese, W. 1972. Oral Study   Humans; None Guideline Citation: Reese, W. H ( 1972) Final Report  Phase II: Evaluation of Ethrel in Human Volunteers: BRL Project No. 7223. Prepared by Litton Industries, submitted by Union Carbide Agricultural Products, Co. CDL: 093946 D March 3, 1972. MRID 00036510 87 of 87 Sette W. 1992. Aldicarb Oral Toxicity Study in Humans. Data Evaluation Report. United States Environmental Protection Agency.

USEPA. 2000. Office of Pesticide Programs Science Policy on The Use of Data on USEPA. 1997. Exposure Factors Handbook. U. S. Environmental Protection Agency.

Weir. 1997. Oral Study   Humans: Non Guidline   Citation: Weir, R. J. ( 1977) Final Report; Evaluation of Ethephon in Human Volunteers: LBI Project No. 2416. Prepared by Litton Bionetics, Inc. MRID 00066931.

Wyld, PJ., Watson CE, Nimms, WS and Watson N. 1992. A Safety and Tolerability Study of Aldicarb at Various Dose Levels in Healthy Male and Female Volunteers. Inveresk Clinical Research Report No. 7786. Project No. 003237. 372 Pages.

Zendzian RP. 2001. Dermal absorption of pesticides in the rat. American Industrial Hygiene Association Journal. 61: 473 483.


[Federal Register Volume 77, Number 54 (Tuesday, March 20, 2012)]
[Notices]
[Pages 16217-16218]
[FR Doc No: 2012-6633]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Combined Notice of Filings 1

    Take notice that the Commission received the following electric
rate filings:

    Docket Numbers: ER10-1781-001.
    Applicants: Northern Indiana Public Service Company.
    Description: Amendment to Triennial Updated Market Power Analysis
Filing Letter of Northern Indiana Public Service Company.
    Filed Date: 3/12/12.
    Accession Number: 20120312-5240.
    Comments Due: 5 p.m. ET 4/2/12.

    Docket Numbers: ER11-3322-002.
    Applicants: PJM Interconnection, LLC.
    Description: Compliance Filing per the February 24, 2012 Order in
Docket ER11-3322-001 to be effective 11/7/2011.
    Filed Date: 3/12/12.
    Accession Number: 20120312-5236.
    Comments Due: 5 p.m. ET 4/2/12.

    Docket Numbers: ER11-4272-003.
    Applicants: ITC Midwest LLC.
    Description: Filing of a Compliance Filing to be effective 10/10/
2011.
    Filed Date: 3/12/12.
    Accession Number: 20120312-5161.
    Comments Due: 5 p.m. ET 4/2/12.

    Docket Numbers: ER12-1244-000.
    Applicants: RLD Resources, LLC.
    Description: RLD Resources MBR Tariff Filing to be effective 3/26/
2012.
    Filed Date: 3/12/12.
    Accession Number: 20120312-5183.
    Comments Due: 5 p.m. ET 4/2/12.

    Docket Numbers: ER12-1245-000.
    Applicants: Interstate Power and Light Company.
    Description: Amended IPL & ITC Operations Services Agreement to be
effective 1/1/2011.
    Filed Date: 3/12/12.
    Accession Number: 20120312-5191.
    Comments Due: 5 p.m. ET 4/2/12.

    The filings are accessible in the Commission's eLibrary system by
clicking on the links or querying the docket number.
    Any person desiring to intervene or protest in any of the above
proceedings must file in accordance with Rules 211 and 214 of the
Commission's Regulations (18 CFR 385.211 and 385.214) on or before 5
p.m. Eastern time on the specified comment date. Protests may be
considered, but intervention is necessary to become a party to the
proceeding.
    eFiling is encouraged. More detailed information relating to filing

requirements, interventions, protests, service, and qualifying
facilities filings can be found at: http://www.ferc.gov/docs-filing/efiling/filing-req.pdf. For other information, call<PHONE_NUMBER>
(toll free). For TTY, call<PHONE_NUMBER>.

    Dated: March 13, 2012.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2012-6633 Filed 3-19-12; 8:45 am]
BILLING CODE 6717-01-P


[Federal Register Volume 79, Number 184 (Tuesday, September 23, 2014)]
[Notices]
[Pages 56853-56854]
[FR Doc No: 2014-22516]

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DEPARTMENT OF TRANSPORTATION

Pipeline and Hazardous Materials Safety Administration

[Docket No. PHMSA-2014-0093]

Pipeline Safety: Information Collection Activities

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

ACTION: Notice and request for comments.

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SUMMARY: In accordance with the Paperwork Reduction Act of 1995, PHMSA
published a notice with request for comments in the Federal Register on
June 26, 2014; 79 FR 36378 on an information collection under Office of
Management and Budget (OMB) Control No. 2137-0622, titled ``Pipeline
Safety: Public Awareness Program.'' PHMSA received no comments. PHMSA
is now forwarding the information collection request to OMB and
providing an additional 30 days for comments.

DATES: Interested persons are invited to submit comments to OMB on or
before October 23, 2014.

ADDRESSES: You may submit comments identified by the docket number
PHMSA-2014-0093 by any of the following methods:
     Fax: 1-202-395-5806.
     Mail: Office of Information and Regulatory Affairs (OIRA),
Records Management Center, Room 10102 NEOB, 725 17th Street NW.,
Washington, DC 20503, ATTN: Desk Officer for the U.S. Department of
Transportation\PHMSA.
     Email: Office of Information and Regulatory Affairs, OMB,
at the following email address<EMAIL_ADDRESS>Requests for a copy of the Information Collection should be directed to
Angela Dow by telephone at<PHONE_NUMBER>, by fax at<PHONE_NUMBER>, by
email at<EMAIL_ADDRESS>or by mail at U.S. Department of
Transportation, PHMSA, 1200 New Jersey Avenue SE, PHP-30, Washington,
DC 20590-0001.

FOR FURTHER INFORMATION CONTACT: Angela Dow by telephone at 202-366-
1246, by fax at<PHONE_NUMBER>, or by mail at U.S. Department of
Transportation, PHMSA, 1200 New Jersey Avenue SE, PHP-30, Washington,
DC 20590-0001.

SUPPLEMENTARY INFORMATION: Section 1320.8(d), Title 5, Code of Federal
Regulations, requires PHMSA to provide interested members of the public
and affected agencies an opportunity to comment on information
collection and recordkeeping requests. This notice identifies an
information collection request that PHMSA will be submitting to OMB for
renewal and extension. The information collection expires October 31,
2014, and is identified under Control No. 2137-0622, titled: ``Pipeline
Safety: Public Awareness Program.'' The following information is
provided for this information collection: (1) Title of the information
collection; (2) OMB control number; (3) Type of request; (4) Abstract
of the information collection activity; (5) Description of affected
public; (6) Estimate of total annual reporting and recordkeeping
burden; and (7) Frequency of collection. PHMSA will request a three-
year term of approval for this information collection activity. PHMSA
requests comments on the following information collection:
    Title: Pipeline Safety: Public Awareness Program.
    OMB Control Number: 2137-0622.
    Type of Request: Renewal of a currently approved information
collection.
    Abstract: The Federal Pipeline Safety Regulations require each
operator to develop and implement a written continuing public education
program that follows the guidance provided in the American Petroleum
Institute's Recommended Practice RP 1162. Upon request, operators must
submit their completed programs to PHMSA or, in the case of an
intrastate pipeline facility operator, the appropriate state agency.
The operator's program documentation and evaluation results must also
be available for periodic review by appropriate regulatory agencies (49
CFR 192.616 and 195.440).
    Affected Public: Operators of natural gas and hazardous liquid
pipelines.
    Estimated number of responses: 22,500.
    Estimated annual burden hours: 517,480 hours.
    Frequency of collection: Annual.
    Comments are invited on:
    (a) The need for the proposed collection of information for the
proper performance of the functions of the agency, including whether
the information will have practical utility;
    (b) The accuracy of the agency's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used;
    (c) Ways to enhance the quality, utility, and clarity of the
information to be collected; and
    (d) Ways to minimize the burden of the collection of information on
those who are to respond, including the use of appropriate automated,
electronic, mechanical, or other technological collection techniques.

    Authority:  The Paperwork Reduction Act of 1995; 44 U.S.C.
Chapter 35, as amended.

    Issued in Washington, DC on September 17, 2014.
John A. Gale,
Director, Office of Standards and Rulemaking.
[FR Doc. 2014-22516 Filed 9-22-14; 8:45 am]
BILLING CODE 4910-60-P