[Federal Register Volume 85, Number 1 (Thursday, January 2, 2020)]
[Rules and Regulations]
[Pages 10-14]
[FR Doc No: 2019-28301]

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DEPARTMENT OF TRANSPORTATION

Federal Railroad Administration

49 CFR Part 243

[Docket No. FRA-2019-0095, Notice No. 2]
RIN 2130-AC86

Training, Qualification, and Oversight for Safety-Related
Railroad Employees

AGENCY: Federal Railroad Administration (FRA), Department of
Transportation (DOT).

ACTION: Final rule.

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SUMMARY: In response to a petition for rulemaking, FRA is amending its
regulation on Training, Qualification, and Oversight for Safety-Related
Railroad Employees by delaying the regulation's implementation dates
for all contractors, and those Class II and III railroads that are not
intercity or commuter passenger railroads with 400,000 total employee
work hours annually or more.

DATES: This regulation is effective December 30, 2019.

ADDRESSES: For access to the docket to read background documents or
submissions received, go to http://www.regulations.gov at any time or
to Room W12-140 on the Ground level of the West Building, 1200 New
Jersey Avenue SE, Washington, DC, between 9 a.m. and 5 p.m. Monday
through Friday, except Federal holidays.

FOR FURTHER INFORMATION CONTACT: Robert J. Castiglione, Staff
Director--Human Performance Division, Federal Railroad Administration,
4100 International Plaza, Suite 450, Fort Worth, TX 76109-4820
(telephone:<PHONE_NUMBER>); or Alan H. Nagler, Senior Attorney, Federal
Railroad Administration, Office of Chief Counsel, 1200 New Jersey
Avenue SE, Washington, DC 20590 (telephone:<PHONE_NUMBER>).

SUPPLEMENTARY INFORMATION:

I. Executive Summary

    On November 7, 2014, FRA published a final rule (2014 Final Rule)
that established minimum training standards for each category and
subcategory of safety-related railroad employees and required railroad
carriers, contractors, and subcontractors to submit training programs
to FRA for approval. See 79 FR 66459. The 2014 Final Rule was required
by section 401(a) of the Rail Safety Improvement Act of 2008 (RSIA),
Public Law 110-432, 122 Stat. 4883 (Oct. 16, 2008), codified at 49
U.S.C. 20162. The Secretary of Transportation delegated the authority
to conduct this rulemaking and implement the rule to the Federal
Railroad Administrator. 49 CFR 1.89(b).
    On May 3, 2017, FRA delayed implementation dates in the 2014 Final
Rule by one year. On April 27, 2018, FRA responded to a petition for
reconsideration of that May 2017 rule by granting the American Short
Line and Regional Railroad Association's (ASLRRA) request to delay the
implementation dates by an additional year.
    On June 27 and July 12, 2019, ASLRRA and the National Railroad
Construction and Maintenance Association, Inc. (NRC) (collectively
Associations) filed petitions for rulemaking that were docketed in
DOT's Docket Management System as FRA-2019-0050. The Associations'
petitions request that FRA delay implementation and make several
substantive changes to the part 243 regulation.
    On November 22, 2019, FRA published a notice of proposed rulemaking
(NPRM) describing the Associations' petitions and responding to the
request to delay implementation. 84 FR 64447. FRA proposed to delay the
implementation dates in the rule for all contractors, and those Class
II and III railroads that are not intercity or commuter passenger
railroads with 400,000 total employee work hours annually or more. In
the NPRM, FRA explained how its response is specifically targeted to
equalize the implementation dates for those employers most likely to
adopt model programs rather than develop their own programs. FRA also
announced that it is considering whether to initiate a separate
rulemaking which would be limited to amending FRA's training regulation
so that the regulatory text includes the latest guidance that is
intended to help small entities and other users of model training
programs. Although these two rulemakings would be separate, FRA
explained in the NPRM that they would be complementary in that, without
any changes to the implementation dates, the targeted employers might
not understand that the regulation contains more flexibility than is
commonly understood or they may not feel comfortable following the
guidance believing there is regulatory uncertainty.

II. Discussion of Comments and Conclusions

    FRA received six written comments in response to the NPRM. FRA did
not receive a request for a public hearing and none was provided.
    A comment was filed jointly by ASLRRA and NRC in support of

finalizing the proposed rule. The Associations believe the extension
and date alignment for Class II and III railroads and contractors will
reduce confusion, especially for those companies with multiple
operations. Additionally, the Associations express support for FRA to
take up other aspects of their petitions for rulemaking and propose
additional revisions to part 243 in future rulemakings.
    Several comments from interested citizens were submitted. The most
specific of these comments was against delaying the rule's
implementation dates for refresher training citing the importance of
the training. Other comments were more general in nature. A few
commenters supported the NPRM, or did not express an opinion about the
NPRM, while expressing a positive opinion about the part 243 training
regulation generally. Another commenter supported the rulemaking,
expressing that FRA should provide the flexibility necessary to best
accommodate railroad workers.

FRA's Response

    FRA initiated this rulemaking in response to ASLRRA and NRC's
petitions for rulemaking, and the comment from the Associations, along
with other commenters, expresses support for the NPRM. Moreover, none
of the other comments raise significant safety concerns which would
dictate against finalizing the proposed rule. Thus, FRA is amending
part 243 as proposed.
    As discussed further below, FRA is revising the part 243 regulation
to reclassify those employers that FRA anticipates will likely adopt a
model program so that they have the same implementation deadlines as
the small entities subject to the regulation. In this regard, the Class
II and III railroads and the contractors who will get relief provide
training and operations in a manner more similar to that of a small
entity than a Class I railroad. Treating this remainder group of
employers in the same manner as the small entities would therefore
reflect a more consistent approach to those employers adopting model
programs, thereby justifying the delay in the implementation schedule.
    The final rule's implementation date delays will not impact Class I
railroads, and those commuter and intercity passenger railroads with
400,000 total employee work hours annually or more. Because the first
implementation submission deadline for the entities affected by this
rule is January 1, 2020, it is imperative for this final rule to become
effective immediately, before that deadline is reached, to ensure the
intended regulatory relief is provided.

III. Section-by-Section Analysis

Subpart B--Program Components and Approval Process

Section 243.101 Employer Program Required
    FRA is amending the implementation date in Sec.  243.101(a)(1) so
that it is limited to Class I railroads, and those intercity or
commuter passenger railroads with 400,000 total employee work hours
annually or more. Also, FRA is amending this section so that all
employers not covered by Sec.  243.101(a)(1) will now be covered by
Sec.  243.101(a)(2), unless the employer is commencing operations after
January 1, 2020, and will be covered by Sec.  243.101(b). In other
words, Sec.  243.101(a)(1) will specifically except all contractors,
and those Class II and III railroads that are not intercity or commuter
passenger railroads with 400,000 total employee work hours annually or
more, from complying with the January 1, 2020, training program
submission implementation deadline. Instead, under Sec.  243.101(a)(2),
all contractors, and those Class II and III railroads that are not
intercity or commuter passenger railroads with 400,000 total employee
work hours annually or more, will be required to comply with a training
program submission deadline of May 1, 2021; these entities will thus
have an additional 16 months to submit a training program for their
safety-related railroad employees.
    Nonetheless, FRA understands that many regulated entities are on
schedule to meet the earlier, January 1, 2020, deadline, or submit
training programs well within the additional 16 months granted by this
final rule. For those regulated entities that are prepared to move
forward in advance of any deadline in part 243, there is certainly no
prohibition against doing so. FRA recognizes that implementing a
compliant training program earlier than required should benefit the
overall safety of those employers' operations.

Subpart C--Program Implementation and Oversight Requirements

Section 243.201 Employee Qualification Requirements
    FRA is amending the implementation dates in Sec.  243.101(a)(1) and
(e)(1) so that they are limited to Class I railroads, and those
intercity or commuter passenger railroads with 400,000 total employee
work hours annually or more. Also, FRA is amending this section so that
all employers not covered by Sec.  243.201(a)(1) and (e)(1) will now be
covered by Sec.  243.201(a)(2) and (e)(2). Please note that an employer
commencing operations after January 1, 2020, will still be covered by
Sec.  243.201(b) and will be expected to implement a refresher training
program upon commencing operations.

IV. Regulatory Impact and Notices

A. Executive Order 12866 and DOT Regulatory Policies and Procedures

    This final rule is a non-significant regulatory action within the
meaning of Executive Order 12866 and DOT policies and procedures. See
https://www.transportation.gov/regulations/2018-dot-rulemaking-order.
This rulemaking is a deregulatory action under Executive Order 13771,
``Reducing Regulation and Controlling Regulatory Costs.'' See 82 FR
9339, Jan. 30, 2017.
    As explained in the Supplementary Information section, FRA
published the 2014 Final Rule to fulfill a statutory mandate. On May 3,
2017, FRA delayed implementation dates in the 2014 Final Rule by one
year. On April 27, 2018, FRA responded to a petition for
reconsideration of that May 2017 rule by granting the ASLRRA's request
to delay the implementation dates an additional year. FRA is issuing a
final rule targeted to equalize the implementation dates for Class II
railroads, Class III railroads, and contractors regardless of their
annual employee work hours, with the exception of those intercity or
commuter passenger railroads with 400,000 total employee work hours
annually or more. With adoption of this final rule, these employers
will have until May 1, 2021, to submit a training program to FRA
instead of the previous January 1, 2020, deadline that was applicable
to railroads (regardless of whether they were Class II or III
railroads), and contractors with 400,000 annual employee work hours or
more.
    FRA believes that the final rule will reduce the regulatory burden
on the railroad industry by delaying the rule's implementation dates.
This final rule will extend the implementation deadlines for some
regulated entities by a total of 16 months. This final rule will be
beneficial for regulated entities by adding time for some railroads and
contractors to comply.
    FRA is amending the training rule in part 243 to reclassify those
employers that FRA anticipated in the 2014 Final Rule's Regulatory
Impact Analysis would likely adopt a model program so that the
regulation will reflect a more consistent approach to those employers

adopting model programs. Until the petitions for rulemaking were filed,
FRA did not appreciate that the Class II and III railroads and the
contractors who were not identified as small entities could be expected
to encounter the same types of obstacles to training program
implementation as that of a small entity. The final rule's
implementation date delay will not impact Class I railroads, and those
commuter and intercity passenger railroads with 400,000 total employee
work hours annually or more. However, this final rule will provide all
contractors, and those Class II and III railroads that are not
currently identified as small entities in part 243, or are not commuter
or intercity passenger railroads with 400,000 total employee work hours
annually or more, with an additional 16 months to submit a training
program for their safety-related railroad employees. FRA is also
amending part 243 so that those same employers get an additional 16
months to designate each of their existing safety-related railroad
employees by occupational category or subcategory, and only permit
designated employees to perform safety-related service in that
occupational category or subcategory. In addition, the final rule will
provide those same employers with one additional year to complete
refresher training for each of their safety-related railroad employees.
With this final rule, the training program submission date for Class II
railroads, Class III railroads, and contractors regardless of their
annual employee work hours, with the exception of those intercity or
commuter passenger railroads with 400,000 total employee work hours
annually or more, will be delayed from January 1, 2020, to a new
implementation date of May 1, 2021; the designation of employee date
will be delayed from September 1, 2020, to a new implementation date of
January 1, 2022; and, the deadline for the first refresher training
cycle will be delayed from December 31, 2024, to a new deadline of
December 31, 2025.
    By delaying the implementation dates, all contractors, and those
Class II and III railroads that are not intercity or commuter passenger
railroads with 400,000 total employee work hours annually or more, will
realize a cost savings. All contractors, and those Class II and III
railroads that are not intercity or commuter passenger railroads with
400,000 total employee work hours annually or more, will not incur
costs during the first 16 months of this analysis. Also, costs incurred
in future years will be discounted an extra 16 months, which will
decrease the present value burden. The present value of costs will be
less than if the original implementation dates were maintained. FRA has
estimated this cost savings to be approximately $3.0 million, at a 7%
discount rate, for impacted railroads and contractors that will
experience relief as a result of this final rule.

B. Regulatory Flexibility Determination

    The Regulatory Flexibility Act of 1980, 5 U.S.C. 601 et seq., and
Executive Order 13272, 67 FR 53461 (Aug. 16, 2002), require agency
review of proposed and final rules to assess their impact on small
entities. An agency must prepare an initial regulatory flexibility
analysis (IRFA) unless it determines and certifies that a rule, if
promulgated, would not have a significant impact on a substantial
number of small entities. Pursuant to the Regulatory Flexibility Act of
1980, 5 U.S.C. 605(b), the FRA Administrator certifies that this final
rule will not have a significant economic impact on a substantial
number of small entities.
    ``Small entity'' is defined in 5 U.S.C. 601 as including a small
business concern that is independently owned and operated, and is not
dominant in its field of operation. The U.S. Small Business
Administration (SBA) has authority to regulate issues related to small
businesses, and stipulates in its size standards that a ``small
entity'' in the railroad industry is a for profit ``linehaul railroad''
that has fewer than 1,500 employees, a ``short line railroad'' with
fewer than 500 employees, or a ``commuter rail system'' with annual
receipts of less than 15 million dollars. See ``Size Eligibility
Provisions and Standards,'' 13 CFR part 121, subpart A. Additionally, 5
U.S.C. 601(5) defines as ``small entities'' governments of cities,
counties, towns, townships, villages, school districts, or special
districts with populations less than 50,000. Federal agencies may adopt
their own size standards for small entities, in consultation with SBA
and in conjunction with public comment. Pursuant to that authority, FRA
has published a final statement of agency policy that formally
establishes ``small entities'' or ``small businesses'' as being
railroads, contractors, and hazardous materials shippers that meet the
revenue requirements of a Class III railroad as set forth in 49 CFR
1201.1-1, which is $20 million or less in inflation-adjusted annual
revenues, and commuter railroads or small governmental jurisdictions
that serve populations of 50,000 or less. See 68 FR 24891 (May 9,
2003), codified at appendix C to 49 CFR part 209. The $20-million limit
is based on the Surface Transportation Board's revenue threshold for a
Class III railroad. Railroad revenue is adjusted for inflation by
applying a revenue deflator formula in accordance with 49 CFR 1201.1-1.
FRA is using this definition for this rulemaking.
    The requirements of this final rule will apply to employers of
safety-related railroad employees that FRA previously determined were
not small entities. This final rule will have no direct impact on small
units of government, businesses, or other organizations. State rail
agencies are not required to participate in this program. State owned
railroads that are subject to the relief provided by this final rule
will receive a positive impact, if any impact. Therefore, the final
rule will not impact any small entities. Pursuant to the Regulatory
Flexibility Act, 5 U.S.C. 601(b), the FRA Administrator hereby
certifies that this final rule will not have a significant impact on a
substantial number of small entities.

C. Paperwork Reduction Act

    There are no new collection of information requirements contained
in this final rule and, in accordance with the Paperwork Reduction Act
of 1995, 44 U.S.C. 3501 et seq., the recordkeeping and reporting
requirements already contained in the 2014 Final Rule have been
approved by OMB. The OMB approval number is OMB No. 2130-0597. Thus,
FRA is not required to seek additional OMB approval under the Paperwork
Reduction Act.

D. Federalism Implications

    This final rule will not have a substantial effect on the States,
on the relationship between the national government and the States, or
on the distribution of power and responsibilities among the various
levels of government. Thus, in accordance with Executive Order 13132,
``Federalism'' (64 FR 43255, Aug. 10, 1999), preparation of a
Federalism Assessment is not warranted.

E. International Trade Impact Assessment

    The Trade Agreement Act of 1979 prohibits Federal agencies from
engaging in any standards or related activities that create unnecessary
obstacles to the foreign commerce of the United States. Legitimate
domestic objectives, such as safety, are not considered unnecessary
obstacles. The statute also requires consideration of international
standards and where appropriate, that they be the basis for U.S.
standards.

    This final rule is purely domestic in nature and is not expected to
affect trade opportunities for U.S. firms doing business overseas or
for foreign firms doing business in the United States.

F. Environmental Impact

    FRA has evaluated this final rule in accordance with its
``Procedures for Considering Environmental Impacts'' (FRA's Procedures)
(64 FR 28545, May 26, 1999) as required by the National Environmental
Policy Act (42 U.S.C. 4321 et seq.), other environmental statutes,
Executive Orders, and related regulatory requirements. FRA has
determined that this final rule is not a major FRA action, requiring
the preparation of an environmental impact statement or environmental
assessment, because it is categorically excluded from detailed
environmental review pursuant to section 4(c)(20) of FRA's Procedures.
See 64 FR 28547 (May 26, 1999).
    In accordance with section 4(c) and (e) of FRA's Procedures, the
agency has further concluded that no extraordinary circumstances exist
with respect to this final rule that might trigger the need for a more
detailed environmental review. As a result, FRA finds that this final
rule is not a major Federal action significantly affecting the quality
of the human environment.

G. Unfunded Mandates Reform Act of 1995

    Pursuant to section 201 of the Unfunded Mandates Reform Act of 1995
(Pub. L. 104-4, 2 U.S.C. 1531), each Federal agency shall, unless
otherwise prohibited by law, assess the effects of Federal regulatory
actions on State, local, and tribal governments, and the private sector
(other than to the extent that such regulations incorporate
requirements specifically set forth in law). Section 202 of the Act (2
U.S.C. 1532) further requires that before promulgating any general
notice of proposed rulemaking that is likely to result in the
promulgation of any rule that includes any Federal mandate that may
result in expenditure by State, local, and tribal governments, in the
aggregate, or by the private sector, of $100,000,000 or more (adjusted
annually for inflation) in any 1 year, and before promulgating any
final rule for which a general notice of proposed rulemaking was
published, the agency shall prepare a written statement detailing the
effect on State, local, and tribal governments and the private sector.
This final rule will not result in such an expenditure, and thus
preparation of such a statement is not required.

H. Energy Impact

    Executive Order 13211 requires Federal agencies to prepare a
Statement of Energy Effects for any ``significant energy action.'' 66
FR 28355 (May 22, 2001). FRA evaluated this final rule in accordance
with Executive Order 13211, and determined that this regulatory action
is not a ``significant energy action'' within the meaning of the
Executive Order.
    Executive Order 13783, ``Promoting Energy Independence and Economic
Growth,'' requires Federal agencies to review regulations to determine
whether they potentially burden the development or use of domestically
produced energy resources, with particular attention to oil, natural
gas, coal, and nuclear energy resources. 82 FR 16093 (Mar. 31, 2017).
FRA determined this final rule will not burden the development or use
of domestically produced energy resources.

I. Congressional Review Act

    Pursuant to the Congressional Review Act (5 U.S.C. 801 et seq.),
the Office of Information and Regulatory Affairs designated this rule
as not a ``major rule,'' as defined by 5 U.S.C. 804(2).

List of Subjects in 49 CFR Part 243

    Administrative practice and procedure, Penalties, Railroad
employees, Railroad safety, Reporting and recordkeeping requirements.

The Final Rule

    For the reasons discussed in the preamble, FRA amends part 243 of
chapter II, subtitle B of title 49 of the Code of Federal Regulations
as follows:

PART 243--TRAINING, QUALIFICATION, AND OVERSIGHT FOR SAFETY-RELATED
RAILROAD EMPLOYEES--[AMENDED]

0
1. The authority citation for part 243 continues to read as follows:

    Authority: 49 U.S.C. 20103, 20107, 20131-20155, 20162, 20301-
20306, 20701-20702, 21301-21304, 21311; 28 U.S.C. 2461, note; and 49
CFR 1.89.

Subpart B--Program Components and Approval Process

0
2. In Sec.  243.101 revise paragraph (a) to read as follows:

Sec.  243.101  Employer program required.

    (a)(1) Effective January 1, 2020, each Class I railroad, and each
intercity or commuter passenger railroad conducting operations subject
to this part with 400,000 total employee work hours annually or more,
shall submit, adopt, and comply with a training program for its safety-
related railroad employees.
    (2) Effective May 1, 2021, each employer conducting operations
subject to this part not covered by paragraph (a)(1) of this section
shall submit, adopt, and comply with a training program for its safety-
related railroad employees.
* * * * *

Subpart C--Program Implementation and Oversight Requirements

0
3. In Sec.  243.201, revise paragraphs (a)(1) and (2) and (e)(1) and
(2) to read as follows:

Sec.  243.201  Employee qualification requirements.

    (a) * * *
    (1) By no later than September 1, 2020, each Class I railroad, and
each intercity or commuter passenger railroad conducting operations
subject to this part with 400,000 total employee work hours annually or
more in operation as of January 1, 2020, shall declare the designation
of each of its existing safety-related railroad employees by
occupational category or subcategory, and only permit designated
employees to perform safety-related service in that occupational
category or subcategory. The Associate Administrator may extend this
period based on a written request.
    (2) By no later than January 1, 2022, each employer conducting
operations subject to this part not covered by paragraph (a)(1) of this
section in operation as of January 1, 2021, shall declare the
designation of each of its existing safety-related railroad employees
by occupational category or subcategory, and only permit designated
employees to perform safety-related service in that occupational
category or subcategory. The Associate Administrator may extend this
period based on a written request.
* * * * *
    (e) * * *
    (1) Beginning January 1, 2022, each Class I railroad, and each
intercity or commuter passenger railroad conducting operations subject
to this part with 400,000 total employee work hours annually or more,
shall deliver refresher training at an interval not to exceed 3
calendar years from the date of an employee's last training event,
except where refresher training is specifically required more
frequently in accordance with this chapter. If the last training event
occurs before FRA's approval of the employer's training program, the
employer shall provide refresher training either within 3 calendar
years

from that prior training event or no later than December 31, 2024. Each
employer shall ensure that, as part of each employee's refresher
training, the employee is trained and qualified on the application of
any Federal railroad safety laws, regulations, and orders the person is
required to comply with, as well as any relevant railroad rules and
procedures promulgated to implement those Federal railroad safety laws,
regulations, and orders.
    (2) Beginning May 1, 2023, each employer conducting operations
subject to this part not covered by paragraph (e)(1) of this section
shall deliver refresher training at an interval not to exceed 3
calendar years from the date of an employee's last training event,
except where refresher training is specifically required more
frequently in accordance with this chapter. If the last training event
occurs before FRA's approval of the employer's training program, the
employer shall provide refresher training either within 3 calendar
years from that prior training event or no later than December 31,
2025. Each employer shall ensure that, as part of each employee's
refresher training, the employee is trained and qualified on the
application of any Federal railroad safety laws, regulations, and
orders the person is required to comply with, as well as any relevant
railroad rules and procedures promulgated to implement those Federal
railroad safety laws, regulations, and orders.

    Issued in Washington, DC, on December 27, 2019.
Brett A. Jortland,
Acting Chief Counsel, Federal Railroad Administration.
[FR Doc. 2019-28301 Filed 12-30-19; 11:15 am]
BILLING CODE 4910-06-P


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 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 asymptomatic. 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 49 of 69 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 was probably not correct since according to the investigators at least two of these controls were symptomatic as well as some test and control subjects also exhibited some atypical lymphocytes of unknown origin.

The WOE document stated " 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 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 any 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 was not known if this was an omission as the report did not state that there were no symptoms or signs. Hematological, clinical chemistry 50 of 69 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 stated " 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 said that the test group plasma values were significantly different than the placebo group values.

It appeared 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."

A Report from EPA, Office of Pesticide Programs, Health Effects Division, Hazard Identification and Assessment Review Committee ( HIARC) dated 4/ 1/ 98 stated 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 51 of 69 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 was much lower than that expected from the animal studies, however, the second study informed the first and provided 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 ( 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 Board concluded that the scientific quality of either the ethephon 28 day oral toxicity study or the ethephon 16 day human oral toxicity study was not adequate on its own. The 16 day study can be used to inform the ethephon 28 day human oral toxicity study. The Board approved the 28 day study for use in EPA risk assessments, emphasizing 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 would result in greater protection for exposed human populations.

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 asked 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 was 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 52 of 69 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 Carley ( 2006f, g). 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 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 provided 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 selfreport any adverse clinical symptoms. There was no mention in the documents reviewed by the Board that the investigators made provisions 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 ethephonexposure 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 were 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 53 of 69 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 selfreported after hours and on weekends. Laboratory analyses were performed on days 1, 9, and 16, and two weeks following last dose. Surprisingly, the report failed 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 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 pre physical 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. 54 of 69 HSRB Consensus and Rationale The Board concluded that:

a) 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 were 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 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 did 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. Sodium 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 had concluded that the clinical trial was 55 of 69 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 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. Bloodcyanide 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 56 of 69 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 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 sodium 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 asked 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 was not clear and convincing evidence that the conduct of the research was fundamentally unethical; and whether there was 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 57 of 69 Two related studies were 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 did 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 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 58 of 69 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 sodium 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 acute and chronic oral exposures in addition to dermal and inhalation exposures of various durations. For oral exposure, the Agency had concluded that the combined results from the single oral dose study and human metabolism study established a dose response relationship in human subjects and that the single oral dose study was appropriate for developing a point of departure for acute and chronic dietary risk, 59 of 69 short term oral exposure, and inhalation exposures of various durations. The Agency had further concluded that the human dermal study was 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 established a dose response relationship in human subjects, and that the single oral dose study was 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 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 were more sensitive than males. The study investigators concluded that humans were more sensitive to amitraz than were other species included in the metabolism study. 60 of 69 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 were adequate to characterize a " no effect" level in regard to neurotoxicity for amitraz.

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 and 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 61 of 69 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 was deficient in its description of the psychomotor performance testing, and in the rationale for selecting these tests. There was no description of the specific procedures followed, 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 were adequate to characterize a " no effect" level in regard to neurotoxicity for amitraz.

The primary deficiency of this study was that it did 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 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 62 of 69 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 were informed by the human metabolism study such that the single oral dose study is appropriate for developing a point of departure for acute dietary risk.

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 were 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 no 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 postdose Excretion of radio labeled metabolites was incomplete ( 62%) at 24 hours. The proposed NOAEL is only one half the dose used in the 1984 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 did 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 were equivalent. 63 of 69 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 requested 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 appeared 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 asked 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 was not clear and convincing evidence that the conduct of the research was fundamentally unethical.

Whether there was 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 radio labeled isotope technology, a 1992 oral dosing study, and a 1998 dermal absorption study. 64 of 69 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 doubleblind 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 was 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 ( 2006i). Specifically, there was 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 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 ( 2006i). 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 ( 2006k). Although concern had 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. 65 of 69 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, however 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, and 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 included 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.

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. 66 of 69 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 Ethephon Human Study. REF: Weir RJ ( 1977). Final Report: Evalution of Ethephon in Human Volunteers: LBI Project No. 2416. Unpublished study prepared by Litton Bionectics Inc ( MRID 66931).

Carley J. 2006g. Initial Ethics Review of Ethephon Human Study. REF: Reese W H Jr. ( 1972) Final Report Phase II: Evaluation of Ethrel in Human Volunteer: BRL Project No. 7223. Unpublished study prepared by Litton Bionetics Inc. ( MRID 36510).

Carley J. 2006h. 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. 2006i. 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. 67 of 69 Unpublished study performed by FBC Ltd., Chesterford Park Research Station, UK, under project number Metab/ 84/ 01. 20 Pages Carley J. 2006j. 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 Carley J. 2006k. 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.

Emanuel E, Wendler D and Grady C. 2000. What Makes Clinical Research Ethical? JAMA 283: 701 2711.

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 A. 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 A. 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 68 of 69 Health Risk Assessment. DP Barcode: 314342, PC Code 099801, Reregistration Case 0382, MRID Several TXR No. 0053509. 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 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. 69 of 69 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 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 Science Policy on the Use of Cholinesterase Inhibition in Risk Assessment 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. 2000. Dermal absorption of pesticides in the rat. American Industrial Hygiene Association Journal. 61: 473 483.


[Federal Register Volume 79, Number 113 (Thursday, June 12, 2014)]
[Proposed Rules]
[Page 33711]
[FR Doc No: 2014-13705]

========================================================================
Proposed Rules
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.

========================================================================

Federal Register / Vol. 79, No. 113 / Thursday, June 12, 2014 /
Proposed Rules

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 860

[Docket No. FDA-2013-N-1529]

Medical Device Classification Procedures; Extension of Comment
Period

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; extension of comment period.

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

SUMMARY: The Food and Drug Administration (FDA) is extending the
comment period for the proposed rule that appeared in the Federal
Register of March 25, 2014. In the proposed rule, FDA requested
comments on its proposal to amend its regulations governing
classification and reclassification of medical devices to conform to
the applicable provisions in the Food and Drug Administration Safety
and Innovation Act (FDASIA), to update its regulations by proposing
changes unrelated to the new FDASIA requirements, and to codify the
procedures and criteria that apply to classification and
reclassification of medical devices and to provide for classification
of devices in the lowest regulatory class consistent with the public
health and the statutory scheme for device regulation. The Agency is
taking this action in response to requests for an extension to allow
interested persons additional time to submit comments.

DATES: FDA is extending the comment period on the proposed rule
published March 25, 2014 (79 FR 16252). Submit either electronic or
written comments by September 22, 2014.

ADDRESSES: You may submit comments, identified by Agency name and
Docket No. FDA-2013-N-1529, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name
and Docket No. FDA-2013-N-1529 for this rulemaking. All comments
received may be posted without change to http://www.regulations.gov,
including any personal information provided. For additional information
on submitting comments, see the ``Comments'' heading of the
SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Marjorie Shulman, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 1536, Silver Spring, MD 20993-0002, 301-
796-6572; or Stephen Ripley, Center for Biologics Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
71, Rm. 7301, Silver Spring, MD 20993-0002,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of March 25, 2014 (79 FR 16252), FDA
published a proposed rule with a 90-day comment period to request
comments on the Agency's regulations governing classification and
reclassification of medical devices to conform to the applicable
provisions in FDASIA and proposed changes unrelated to the new FDASIA
requirements to update its regulations governing classification and
reclassification of medical devices. Comments on the proposed rule will
inform FDA's rulemaking to establish regulations for governing
classification and reclassification of medical devices to conform to
the applicable provisions in FDASIA and proposed changes unrelated to
the new FDASIA requirements to update its regulations governing
classification and reclassification of medical devices.
    The Agency has received requests for an extension of the comment
period for the proposed rule. Each request conveyed concern that the
current 90-day comment period does not allow sufficient time to develop
a meaningful or thoughtful response to the proposed rule. The Agency
believes that a 90-day extension allows adequate time for interested
persons to submit comments without significantly delaying rulemaking on
these important issues.

II. Request for Comments

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

    Dated: June 6, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-13705 Filed 6-11-14; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register Volume 76, Number 171 (Friday, September 2, 2011)]
[Notices]
[Page 54764]
[FR Doc No: 2011-22504]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

 [Docket No. ER11-3627-000]

Southwest Power Pool, Inc.; Notice of Filing

    Take notice that, on August 24, 2011, Southwest Power Pool, Inc.
filed to supplement its May 24, 2011 filing of revisions to its Open
Access Transmission Tariff, in the above-captioned docket, pursuant to
the Commission's request. Such filing serves to reset the filing date
in this proceeding.
    Any person desiring to intervene or to protest this filing must
file in accordance with Rules 211 and 214 of the Commission's Rules of
Practice and Procedure (18 CFR 385.211, 385.214). Protests will be
considered by the Commission in determining the appropriate action to
be taken, but will not serve to make protestants parties to the
proceeding. Any person wishing to become a party must file a notice of
intervention or motion to intervene, as appropriate. Such notices,
motions, or protests must be filed on or before the comment date.
Anyone filing a motion to intervene or protest must serve a copy of
that document on the Applicant and all the parties in this proceeding.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper using the ``eFiling'' link at http://www.ferc.gov. Persons unable to file electronically should submit an
original and 14 copies of the protest or intervention to the Federal
Energy Regulatory Commission, 888 First Street, NE., Washington, DC
20426.
    This filing is accessible on-line at http://www.ferc.gov, using the
``eLibrary'' link and is available for review in the Commission's
Public Reference Room in Washington, DC. There is an ``eSubscription''
link on the Web site that enables subscribers to receive e-mail
notification when a document is added to a subscribed docket(s). For
assistance with any FERC Online service, please e-mail
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For
TTY, call<PHONE_NUMBER>.
    Comment Date: 5 p.m. Eastern Time on September 14, 2011.

    Dated: August 25, 2011.
Kimberly D. Bose,
Secretary.
[FR Doc. 2011-22504 Filed 9-1-11; 8:45 am]
BILLING CODE 6717-01-P