[Federal Register Volume 86, Number 42 (Friday, March 5, 2021)]
[Notices]
[Pages 12993-12996]
[FR Doc No: 2021-04531]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-91231; File No. SR-CboeEDGX-2021-011]

Self-Regulatory Organizations; Cboe EDGX Exchange, Inc.; Notice
of Filing and Immediate Effectiveness of a Proposal To Permit the
Exchange To Look Back Only to July 2020 To Correct Certain Billing
Errors Which Were Discovered in October 2020

March 1, 2021.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(the ``Act''),\1\ and Rule 19b-4 thereunder,\2\ notice is hereby given
that on February 18, 2021, Cboe EDGX Exchange, Inc. (the ``Exchange''
or ``EDGX'') filed with

the Securities and Exchange Commission (the ``Commission'') the
proposed rule change as described in Items I, II, and III below, which
Items have been prepared by the Exchange. The Exchange filed the
proposal as a ``non-controversial'' proposed rule change pursuant to
Section 19(b)(3)(A)(iii) of the Act \3\ and Rule 19b-4(f)(6)
thereunder.\4\ The Commission is publishing this notice to solicit
comments on the proposed rule change from interested persons.
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    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
    \3\ 15 U.S.C. 78s(b)(3)(A)(iii).
    \4\ 17 CFR 240.19b-4(f)(6).
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I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    Cboe EDGX Exchange, Inc. (``EDGX'' or the ``Exchange'') is filing
with the Securities and Exchange Commission (the ``Commission'') a
proposal to permit the Exchange to look back only to July 2020 to
correct certain billing errors which were discovered in October 2020.
This rule change does not provide for any modifications to the text of
the Exchange's rules or fees schedule.
    The text of the proposal is also available on the Exchange's
website (http://markets.cboe.com/us/options/regulation/rule_filings/edgx/), at the Exchange's Office of the Secretary, and at the
Commission's Public Reference Room.

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

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

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

1. Purpose
    The Exchange recently amended its equities and options fees
schedules to adopt a provision relating to billing errors and fee
disputes.\5\ Specifically, the Exchange adopted a provision that
provides that all fees and rebates assessed prior to the three full
calendar months before the month in which the Exchange becomes aware of
a billing error shall be considered final. Particularly, the Exchange
will resolve an error by crediting or debiting Members and Non-Members
based on the fees or rebates that should have been applied in the three
full calendar months preceding the month in which the Exchange became
aware of the error, including to all impacted transactions that
occurred during those months.\6\ The Exchange will apply the three
month look back regardless of whether the error was discovered by the
Exchange or by a Member or Non-Member that submitted a fee dispute to
the Exchange. The Exchange's fees schedules also provide that all
disputes concerning fees and rebates assessed by the Exchange would
have to be submitted to the Exchange in writing and accompanied by
supporting documentation. The purpose of this policy is to provide both
the Exchange and Members and Non-Members subject to the Exchange's fee
schedule finality and the ability to close their books after a known
period of time. The Exchange further notes that several other exchanges
have adopted similar provisions in their rules.\7\
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    \5\ See Securities Exchange Act Release No. 90901 (January 11,
2021), 86 FR 4137 (January 15, 2021) (SR-CboeEDGX-2020-064).
    \6\ For example, if the Exchange becomes aware of a transaction
fee billing error on February 4, 2021, the Exchange will resolve the
error by crediting or debiting Members based on the fees or rebates
that should have been applied to any impacted transactions during
November, 2020, December 2020 and January 2021. The Exchange notes
that because it bills in arrears, the Exchange would be able to
correct the error in advance of issuing the February 2021 invoice
and therefore, transactions impacted through the date of discovery
(in this example, February 4, 2021) and thereafter, would be billed
correctly.
    \7\ See e.g. Securities Exchange Act Release No. 87650 (December
3, 2019), 84 FR 67304 (December 9, 2019) (SR-NYSECHX-2019-024);
Securities Exchange Act Release No. 84430 (October 16, 2018), 83 FR
53347 (October 22, 2018) (SR-NYSENAT-2018-23); and Securities
Exchange Act Release No. 79060 (October 6, 2016), 81 FR 70716
(October 13, 2016) (SR-ISEGemini-2016-11).
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    The Exchange proposes to apply the recently adopted billing policy
to transactions impacted by billing errors that were discovered in
October 2020. Particularly, in October 2020, the Exchange's affiliate,
Cboe BZX Exchange, Inc. identified a billing error relating to certain
fee codes. As a result of the discovery, the Exchange, along with its
affiliates, conducted a review of additional fee code configurations
across each Exchange, which review was only recently completed. The
review resulted in the discovery of additional billing errors relating
to Exchange fee codes. These errors resulted in various Members being
over-rebated or under-billed, and to a lesser extent over-billed, over
the course of several years. In the absence of applying the recently
adopted billing policy to transactions impacted by the October 2020
billing errors, the Exchange would be required to credit or debit
Members based on the fees or rebates that should have been applied to
all impacted transactions, regardless of how far back the transactions
occurred (which as noted above, is several years). If the Exchange were
permitted to apply the current rule language to the billing errors
discovered in October 2020 however, then the Exchange could limit its
look back in correcting those errors to only those transactions that
occurred in the three months preceding the discovery of the errors
(i.e., July 2020 through September 2020).\8\ Moreover, the benefit to
the Exchange of limiting the impact of these particular errors to three
months is much smaller as compared to the benefit that Members would
receive. Specifically, the nature of these particular billing errors is
such that in correcting the errors, more money would be owed to the
Exchange by Members due to over-rebating or under-billing than is owed
to Members by the Exchange due to overbilling. Accordingly, the
Exchange believes it's appropriate and equitable to apply the three-
month look back for corrective billing to the errors that were
discovered in October 2020.
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    \8\ The Exchange corrected errors in advance of issuing the
October 2020 invoice and therefore, transactions impacted through
the date of discovery and thereafter, were billed correctly.
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2. Statutory Basis
    The Exchange believes the proposed rule change is consistent with
the Securities Exchange Act of 1934 (the ``Act'') and the rules and
regulations thereunder applicable to the Exchange and, in particular,
the requirements of Section 6(b) of the Act.\9\ Specifically, the
Exchange believes the proposed rule change is consistent with the
Section 6(b)(5) \10\ requirements that the rules of an exchange be
designed to prevent fraudulent and manipulative acts and practices, to
promote just and equitable principles of trade, to foster cooperation
and coordination with persons engaged in regulating, clearing,
settling, processing information with respect to, and facilitating
transactions in securities, to remove impediments to and perfect the
mechanism of a free and open market and a national market system, and,
in general, to protect investors and the public interest. Additionally,
the Exchange believes the proposed rule change is consistent with

the Section 6(b)(5) \11\ requirement that the rules of an exchange not
be designed to permit unfair discrimination between customers, issuers,
brokers, or dealers.
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    \9\ 15 U.S.C. 78f(b).
    \10\ 15 U.S.C. 78f(b)(5).
    \11\ Id.
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    In adopting its currently policy, the Exchange noted that it
believed providing that all fees are final after 3 months is reasonable
as both the Exchange and Members have an interest in knowing when its
fee assessments are final and when reliance can be placed on those
assessments. Indeed, without some deadline on fee disputes and billing
errors, the Exchange and market participants would never be able to
close their books with any confidence. Furthermore, as noted above, a
number of Exchanges similarly consider their fees final after a similar
period of time.\12\ As discussed above, in October 2020, the Exchange
became aware of certain billings errors which resulted in various
Members being over-rebated or under-billed, and to a lesser extent
over-billed over the course of several years. The Exchange believes
it's appropriate that Members that were impacted by these billing
errors similarly be subject to the recently adopted billing policy to
not resolve billing errors past three months from the time a billing
error was discovered (in this case, not be invoiced for impacted
transactions that occurred prior to July 2020).\13\ The Exchange does
not think it is appropriate or equitable to have to correct billing
errors for transactions that occurred prior to July 2020. As discussed,
the Exchange believes it's reasonable and important for both Members
and the Exchange to rely on the finality of fees and rebates assessed.
Moreover, the proposed rule change would apply to all Members equally,
in that the Exchange would be precluded from invoicing any Member for
the correct amounts that should have been applied to trades that were
otherwise billed incorrectly before July 2020. The Exchange also
believes the proposal would be consistent with the protection of
investors and the public interest because it would allow impacted
market participants to benefit from the same rule recently adopted by
the Exchange. Additionally, as discussed, Members would receive a
greater benefit from the application of the current billing errors
policy as compared to the Exchange with respect to these particular
billing errors. Furthermore, the Exchange believes the proposal to
limit the time period it must correct billing errors does not raise any
new or novel issues that have not been already been considered by the
Commission. Particularly, the proposal to limit how far back an
exchange must go to correct billing errors is comparable to other
policies and practices that have long been established at other
exchanges.\14\
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    \12\ See supra note 7.
    \13\ Since the errors were discovered in October 2020, the three
preceding months that would be corrected are July, August, and
September 2020.
    \14\ See supra note 7.
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B. Self-Regulatory Organization's Statement on Burden on Competition

    The Exchange does not believe that the proposed rule change would
impose any burden on competition that is not necessary or appropriate
in furtherance of the purposes of the Act. First, the Exchange notes
the proposal is not intended to address any competitive issue, but
rather provide finality to Members with respect to billing errors that
were just recently discovered and extend to them the applicability of a
recently adopted billing practice that considers all fees final after
three months. Further, the Exchange does not believe that the proposed
rule change will impose any burden on intramarket competition that is
not necessary or appropriate in furtherance of the purposes of the Act
because the proposed changes apply equally to all Members. The Exchange
does not believe that the proposed rule change will impose any burden
on intermarket competition that is not necessary or appropriate in
furtherance of the purposes of the Act because the proposed change only
affects transactions that occurred on the Exchange. Additionally, other
exchanges have long established policies in which fees shall be
considered final after a specified period of time.

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

    No comments were solicited or received on the proposed rule change.

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

    Because the foregoing proposed rule change does not (i)
significantly affect the protection of investors or the public
interest; (ii) impose any significant burden on competition; and; (iii)
become operative for 30 days from the date on which it was filed, or
such shorter time as the Commission may designate, it has become
effective pursuant to Section 19(b)(3)(A) of the Act \15\ and Rule 19b-
4(f)(6) \16\ thereunder.
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    \15\ 15 U.S.C. 78s(b)(3)(A).
    \16\ 17 CFR 240.19b-4(f)(6). In addition, Rule 19b-4(f)(6)
requires a self-regulatory organization to give the Commission
written notice of its intent to file the proposed rule change at
least five business days prior to the date of filing of the proposed
rule change, or such shorter time as designated by the Commission.
The Exchange has satisfied this requirement.
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    At any time within 60 days of the filing of the proposed rule
change, the Commission summarily may temporarily suspend such rule
change if it appears to the Commission that such action is necessary or
appropriate in the public interest, for the protection of investors, or
otherwise in furtherance of the purposes of the Act. If the Commission
takes such action, the Commission will institute proceedings to
determine whether the proposed rule change should be approved or
disapproved.

IV. Solicitation of Comments

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

Electronic Comments

     Use the Commission's internet comment form (http://www.sec.gov/rules/sro.shtml); or
     Send an email to<EMAIL_ADDRESS>Please include
File Number SR-CboeEDGX-2021-011 on the subject line.

Paper Comments

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

All submissions should refer to File Number SR-CboeEDGX-2021-011. This
file number should be included on the subject line if email is used. To
help the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's internet website (http://www.sec.gov/rules/sro.shtml).
Copies of the submission, all subsequent amendments, all written
statements with respect to the proposed rule change that are filed with
the Commission, and all written communications relating to the proposed
rule change between the Commission and any person, other than those
that may be withheld from the public in accordance with the

provisions of 5 U.S.C. 552, will be available for website viewing and
printing in the Commission's Public Reference Room, 100 F Street NE,
Washington, DC 20549 on official business days between the hours of
10:00 a.m. and 3:00 p.m. Copies of the filing also will be available
for inspection and copying at the principal office of the Exchange. All
comments received will be posted without change; the Commission does
not edit personal identifying information from submissions. You should
submit only information that you wish to make available publicly. All
submissions should refer to File Number SR-CboeEDGX-2021-011 and should
be submitted on or before March 26, 2021.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\17\
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    \17\ 17 CFR 200.30-3(a)(12).
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J. Matthew DeLesDernier,
Assistant Secretary.
[FR Doc. 2021-04531 Filed 3-4-21; 8:45 am]
BILLING CODE 8011-01-P


° Additional data are required depicting carbaryl residues in/ on cotton gin byproducts derived from cotton treated at the maximum labeled rate and harvested 28 days after the final application using commercial equipment ( stripper and mechanical picker). At least three field trials representing each type of harvesting ( stripper and picker) are required. 128 ° The registrant does not intend to support carbaryl uses on avocados, barley, maple sap, oats, rye, and sweet sorghum; however, IR 4 has indicated ( Correspondence from K. Dorschner, IR 4 Project, 9/ 15/ 94) that they may fulfill the residue data requirements for some of these commodities. These data have not been submitted.

° The reregistration requirements for magnitude of the residue in livestock commodities are not fulfilled. Additional data are required to support dermal and poultry house uses.

Occupational/ Residential Exposure Data Gaps Residential Exposure ° For the postapplication risk assessments, there are no data on the amount of residues transferrable from treated pets to humans except for a low quality study that used collars. This study was used in the assessment but should be considered in context. Additional data for dust and liquid pet products would help refine the assessment. Residue data on turf specifically focused on hand tomouth and object to mouth toddler exposures would also help to refine those assessments.

Occupational Exposure ° For the occupational handler risk assessments, several exposure data gaps were identified, including: dust use for animal grooming and in agriculture; various specialized hand equipment application methods ( e. g., powered backpack, power hand fogger, and tree injection); and nursery operations such as seedling dips.

° For occupational postapplication risk assessments, several data gaps exist, such as an incomplete dislodgeable foliar residue database and a lack of exposure data on partially mechanized cultural practices where there is a potential for exposure.

° There are also many kinds of mechanized activities that do not involve foliar contact that have not been addressed in this risk assessment. The scenarios include: transplanting many crops including in the ornamental and forestry industry; thinning some crops such as hops; some partially mechanized operations that also involve human contact ( e. g., cotton harvesting where module builders and trampers are used); hand weeding some crops such as wheat; various operations with Christmas trees such as pruning or baling; and various operations with nut production such as sweeping for harvest. APPENDIX 1: Toxicology Profile Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100 90 Day oral toxicity rodents N/ A 870.3150 90 Day oral toxicity in nonrodents N/ A 870.3200 21/ 28 Day dermal toxicity with technical carbaryl 45630601( 2002) acceptable/ nonguideline 0, 20, 50, 100 mg/ kg/ day systemic NOAEL = 20 mg/ kg/ day systemic LOAEL = 50 mg/ kg/ day based on decreased RBC cholinesterase in males and females and brain cholinesterase in males dermal NOAEL = 100 mg/ kg/ day dermal LOAEL not established 870.3200 21/ 28 Day dermal toxicity with Sevin ® XLR Plus ( 44.82% a. i.) 45630602 ( 2002) unacceptable/ nonguideline 0, 20, 50, 100 mcL/ kg/ day ( 0, 9.6, 24, 48 mg/ kg/ day) systemic NOAEL = 50 mcL/ kg/ day ( 24 mg/ kg/ day) systemic LOAEL = 100 mcL/ kg/ day ( 48 mg/ kg/ day) based on decreased body weight gain dermal NOAEL = 100 mcL/ kg/ day ( 48 mg/ kg/ day) dermal LOAEL not established 870.3200 21/ 28 Day dermal toxicity with Sevin ® 80S ( 80.07% a. i.) 45630603 ( 2002) unacceptable/ nonguideline 0, 20, 50, 100 mg/ kg/ day systemic NOAEL = 20 mg/ kg/ day systemic LOAEL = 50 mg/ kg/ day based on decreased RBC cholinesterase in males and females dermal NOAEL = 100 mg/ kg/ day dermal LOAEL not established 870.3250 90 Day dermal toxicity N/ A 870.3465 90 Day inhalation toxicity N/ A 870.3700a Prenatal developmental in rats 44732901 ( 1998) acceptable/ guideline 0, 1, 4, 30 mg/ kg/ day ( oral gavage) Maternal NOAEL = 4 mg/ kg/ day LOAEL = 30 mg/ kg/ day based on clinical signs, decreased body weight gain ( BWG) and food consumption Developmental NOAEL = 4 mg/ kg/ day LOAEL = 30 mg/ kg/ day based on decreased fetal body weight and incomplete ossification of multiple bones 870.3700b Prenatal developmental in rabbits 44904202 ( 1999) Acceptable/ guideline 0, 5, 50, 150 mg/ kg/ day ( oral gavage) Maternal NOAEL = 5 mg/ kg/ day LOAEL = 50 mg/ kg/ day based on decreased BWG and plasma cholinesterase inhibition ( ChEI) Developmental NOAEL = 50 mg/ kg/ day LOAEL = 150 mg/ kg/ day based on decreased fetal weight Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3800 Reproduction and fertility effects 45448101 ( 2001) acceptable/ guideline 0, 75, 300, 1500 ppm ( 4.67, 31.34, and 92.43 mg/ kg/ day for F0 males; 0, 5.56, 36.32, and 110.78 mg/ kg/ day for F0 females; 0, 5.79, 23.49, and 124.33 mg/ kg/ day for F1 males; and 0, 6.41, 26.91, and 135.54 mg/ kg/ day for F1 females averaged over the premating period) Parental NOAEL = 300 ppm ( 23.49 31.34 mg/ kg/ day for males and 26.91 36.32 mg/ kg/ day for females) Parental LOAEL = 1500 ppm ( 92.43 124.33 mg/ kg/ day for males and 110.78 135.54 mg/ kg/ day for females) based on decreased body weight, weight gain, and feed consumption Reproductive toxicity NOAEL is $ 1500 ppm ( 92.43 124.33 mg/ kg/ day for males and 110.78 135.54 mg/ kg/ day for females) Reproductive toxicity LOAEL not be established Offspring NOAEL = 75 ppm ( 4.67 5.79 mg/ kg/ day for males and 5.56 6.41 mg/ kg/ day for females). Offspring LOAEL = 300 ppm ( 23.49 31.34 mg/ kg/ day for males and 26.91 36.32 mg/ kg/ day for females) based on increased numbers of F2 pups with no milk in the stomach and decreased pup survival.

870.4100a Chronic toxicity in rodents N/ A 870.4100b Chronic toxicity in dogs 40166701 ( 1987) 0, 125, 400, 1250 ppm ( 0, 3.1, 10, 31.3 mg/ kg/ day)

42022801 ( 1991) 0, 20, 45, 125 ppm ( 5 weeks) ( M: 0, 0.59, 1.43, 3.83; F: 0, 0,64, 1.54, 4.11 mg/ kg/ day) Together, the studies are Acceptable/ guideline MRID 40166701: NOAEL = not established in females LOAEL = 125 ppm based based on plasma and brain ChEI MRID 42022801: NOAEL = 45 ppm in males LOAEL = 125 ppm in males based on plasma ChEI 870.4200 Carcinogenicity in mice 42786901 ( 1993) Acceptable/ guideline 0, 100, 1000 or 8000 ppm ( M: 0, 14.73, 145.99, 1248.93 mg/ kg/ day; F: 0, 18.11, 180.86, 1440.62) systemic LOAEL = 1000 ppm based on increased intracytoplasmic droplets in bladder in males and females, chronic progressive nephropathy in males; NOAEL = 100 ppm RBC ChEI LOAEL for males = 1000 ppm , for females = 8000 ppm; NOAEL = 100 ppm for males, 1000 ppm for females plasma ChEI for males and females LOAEL > 8000 ppm; NOAEL $ 8000 ppm brain ChEI for males and females LOAEL = 8000 ppm; NOAEL = 1000 ppm increase in vascular tumors in all treated males and in females at 8000 ppm increase in adenomas, multiple adenomas, carcinomas of kidney in males at 8000 ppm increase in hepatic neoplasms ( adenomas, carcinomas, one hepatoblastoma) in females at 8000 ppm Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.4300 Chronic Toxicity/ Carcinogenicity in rats 42918801 ( 1993) Acceptable/ guideline 0, 250, 1500 & 7500 ppm ( M: 0, 10, 60.2, 349.5 mg/ kg/ day; F: 0, 12.6, 78.6, 484.6 mg/ kg/ day) systemic LOAEL = 1500 ppm in females based on decreased BW and BWG; 7500 ppm in males based on increased clinical signs, decreased BW, BWG and food consumption, increase in cataracts, clinical pathology changes, organ weight changes, nonneoplastic changes; NOAEL = 250 ppm in females and 1500 ppm in males plasma ChEI LOAEL = 7500 ppm in males and females; NOAEL = 1500 ppm RBC ChEI LOAEL = 1500 ppm in males and females; NOEL = 250 ppm brain ChEI LOAEL = 7500 ppm in males and females; NOEL = 1500 ppm at 7500 ppm, increase in liver adenomas in females, increase in benign transitional cell papillomas and transitional cell carcinomas in males and females, transitional cell carcinoma in kidney of one male, increase in benign thyroid follicular cell adenomas in males, follicular cell carcinoma in one male Bacterial reverse mutation test 870.5100 41370303 ( 1989) Acceptable/ guideline 5 1000 ug/ plate No evidence of mutagenicity in strains TA1535, TA 1537, TA1538, TA98 and TA100 with and without metabolic activation In vitro mammalian chromosome aberration test ( Chinese hamster ovary cells) 870.5385 41370304 ( 1989) Acceptable/ guideline without S9 activation: 5 100 ug/ mL, harvest at 20 hrs.; with S9 activation: 25 300 ug/ mL, harvest at 30 hrs Increase in chromosome aberrations with S9 activation In vitro mammalian chromosome aberration test 870.5385 41370302; 41420201 ( 1989) Unacceptable/ guideline S9 activation: 1 300 ug/ mL in 3 trials; without S9 activation: 1 300 ug/ mL in 2 trials Results provide no clear indication of a mutagenic response, however study had several deficiencies Mammalian erythrocyte micronucleus test 870. 5395 44069301 ( 1996) Unacceptable/ guideline single oral gavage dose of 50, 100, 200 mg/ kg Carbaryl did not induce a clastogenic or aneugenic effect, however there was no convincing evidence that MTD was achieved Unscheduled DNA synthesis 870.5550 41370301; 41810601 ( 1989) Acceptable/ guideline 0.5  25.0 ug/ mL Negative 870.6200a Acute neurotoxicity screening battery in rats MRID: 43845201 43845204 ( 1995) Acceptable/ guideline 0, 10, 50, 125 mg/ kg ( oral gavage) Separate study for ChEI: 0, 10, 30, 50 mg/ kg; ChEI done 1, 8, 24, 48 hrs postdosing Systemic LOAEL = 10 mg/ kg based on decreased RBC, plasma, blood, brain ChEI; NOAEL < 10 mg/ kg Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.6200b Subchronic neurotoxicity screening battery in rats MRID: 44122601 ( 1996) Acceptable/ guideline 0, 1, 10, 30 mg/ kg/ day ( oral gavage) LOAEL for neurotoxicity = 10 mg/ kg/ day based on increased FOB changes; NOAEL = 1 mg/ kg/ day LOAEL for ChEI = 10 mg/ kg/ day based on decreased plasma, blood, RBC, brain ChEI; NOAEL = 1 mg/ kg/ day 870.6300 Developmental neurotoxicity in rats 44393701 ( 1997) Acceptable/ guideline 0, 0.1, 1.0, 10 mg/ kg ( oral gavage) Maternal NOAEL = 1.0 mg/ kg/ day LOAEL = 10 mg/ kg/ day based on decreased BWG; FOB changes; RBC, plasma, whole blood, brain ChEI Offspring tentative NOAEL = 1.0 mg/ kg/ day tentative LOAEL = 10 mg/ kg/ day based on alterations in morphometric measurements ( measurements were not done at lower doses)

870.7485 Metabolism and pharmacokinetics in rats 43332101 ( 1994) Acceptable/ guideline 1 mg/ kg ( single and repeated oral doses; intravenous dose) and 50 mg/ kg ( single oral dose) Absorption was complete at all doses. At 168 hrs., post dose, negligible percentages of dose in any tissues. Kidney and blood contained highest concentrations of radioactivity. Excretion mostly through urine. A metabolic scheme with conjugated and non conjugated metabolites was proposed.

870.7485 Metabolism and pharmacokinetics in rats 44402501 ( 1997) Acceptable/ nonguideline 50 mg/ kg ( single oral radiolabeled dose); daily oral radiolabeled dose of 2 mg/ kg for 7 days followed by 83 daily unlabeled doses of 0, 250, 1500 or 7500 ppm; males only In all dosing regimens, urinary and fecal excretion was 93 103% of administered dose and tissue levels of radioactivity were minimal at 168 hrs. post dosing. Two major metabolites in tissues at 6 hrs. post dosing were naphthyl sulfate and naphthyl glucuronide, however quantitation was not possible. A total of 23 and 20 components were identified in the urine and feces, respectively. The sulfate conjugation pathway appears to be saturable following a 83 day feeding at 7500 ppm. BW and food consumption were decreased at 7500 ppm. Increases in kidney, spleen and thyroid weights were observed at 1500 and 7500 ppm. Non neoplastic changes in liver, thyroids and kidneys were observed at 7500 ppm.

870.7600 Dermal penetration in rats 43552901 ( 1995) 43.9% a. i. Acceptable 35.6, 403, 3450 ug/ cm2 % absorbed at 10 hrs.: 12.7, 7.44 and 1.93 at 35.6, 403 and 3450 ug/ cm2, respectively 870.7600 Dermal penetration in rats 43339701 ( 1994) 80.1% a. i. Acceptable 63, 626, 3410 ug/ cm2 % absorbed at 10 hrs: 8.90, 0.62 and 0.48 at 63, 626 and 3410 ug/ cm2, respectively Special studies in mice 43282201 ( 1994) Acceptable/ nonguideline male mice: single radiolabeled dose of 75 mg/ kg; pretreatment with 8000 ppm unlabeled carbaryl for 2 wks., then single radiolabeled dose of 75 mg/ kg Negative for DNA binding in liver Appendix 1/ Table 1: Toxicology Profile of Carbaryl Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Special studies in mice 43832601 ( 1994) Acceptable/ nonguideline continuation of MRID 43282201 in liver from mice treated at 8000 ppm, increase in microsomal protein, cytochrome P450, ethoxyresorufin O deethylase, pentoxyresorufin O depentylase, and testosterone hydrolases indicates phenobarbital type of induction of metabolizing enzymes Special study in mice 45281801, 45281802, 45236603 ( 1998 1999) Acceptable/ nonguideline 0, 10, 30, 100, 300, 1000 and 4000 ppm ( 0, 1.8, 5.2, 17.5, 51.2, 164.5 and 716.6 mg/ kg/ day) There was no evidence of neoplastic or preneoplastic changes in vascular tissue in heterozygous p53 deficient male mice treated with carbaryl for six months.

N/ A Not Available APPENDIX 2: Incident Review Conclusions/ Recommendations Based on Incident Review Data on incidents of adverse reactions in humans exposed to carbaryl were evaluated from several sources, including OPP's Incident Data System, Poison Control Centers, California Department of Pesticide Regulation, National Pesticide Telecommunications Network and the open literature. The data from the Incident Data System indicated that a majority of cases from carbaryl exposure involved dermal reactions. A number of cases involved asthmatics and people who experienced hives and other allergic type reactions. According to California data, about half of the cases involved skin and eye effects in handlers. About a quarter of the skin reactions were due to workers that were exposed to residues on crops. Reports from the literature are very limited but tend to support the finding that carbaryl has irritant properties.

The Poison Control Center cases involving non occupational adults and older children showed an increased risk in five of the six measures reported. These cases were almost twice as likely to require serious health care ( hospitalization or treatment in a critical care unit) and were two and a half times more likely to experience major medical outcome ( life threatening effects or significant residual disability) as compared to other pesticides. This pattern of increased risk was not seen among occupational reports or in young children. This may mean careless handling by non professionals is a particular hazard.

Five case reports suggested that carbaryl may be a cause of chronic neurological or psychological problems. Some of these effects appear to be consistent with those reported from organophosphate poisoning. However, unlike organophosphates, no controlled studies have been undertaken. If such effects occur as a result of over exposure to carbaryl, they appear to be relatively rare. The effects reported among the five case reports are too inconsistent to draw any conclusions, but do suggest the need for further study.

Carbaryl appears capable of causing dermal and allergic type reactions. Data support the need for personal protective equipment and eye protection for handlers for field workers who may have extensive exposure to carbaryl. Labels for products should advise that carbaryl can cause sensitizing effects in some people.

Based on an evaluation of limited incident data on domestic animals in IDS, it is recommended that all labels for carbaryl products used on cats contain the age restriction stated in PR Notice 96 6 ( should not be used in kittens less than 12 weeks of age).

A detailed discussion of the incident data is presented below.

Human Incident Data Review A review of the human incident data on carbaryl was prepared by Dr. Jerome Blondell and Ms. Monica Spann ( D267127 dated July 17, 2000).

The following data bases were consulted for the poisoning incident data on the active ingredient Carbaryl ( PC Code: 056801): 1) OPP Incident Data System ( IDS)  reports of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992.

2) Poison Control Centers  as the result of a data purchase by EPA, OPP received Poison Control Center data covering the years 1993 through 1998 for all pesticides. Most of the national Poison Control Centers ( PCCs) participate in a national data collection system, the Toxic Exposure Surveillance System which obtains data from about 65 70 centers at hospitals and universities.

3) California Department of Pesticide Regulation  California has collected uniform data on suspected pesticide poisonings since 1982. Physicians are required, by statute, to report to their local health officer all occurrences of illness suspected of being related to exposure to pesticides.

4) National Pesticide Telecommunications Network ( NPTN)  NPTN is a toll free information service supported by OPP. A ranking of the top 200 active ingredients for which telephone calls were received during calendar years 1984 1991 and 1995 1999 has been prepared for the categories human incidents, animal incidents, calls for information, and others.

Incident Data System There were approximately 500 reports in IDS concerning exposure of humans to carbaryl. At least 380 cases were considered minor ( minimal symptoms with no residual disability) and were not included in the review. The most frequently reported symptoms were of a dermatological nature, either dermal irritation or possibly a dermal manifestation of an allergic response ( e. g., hives, welts, rash, etc.). Clinical signs or symptoms less frequently reported were nausea, vomiting, diarrhea, respiratory irritation and difficulty breathing. Most of the incidents were associated with dermal exposure; however, a few resulted after inhalation of the product. There was one report of an attempted suicide. In 1993, a 21 year old man ingested about 75 ml of Beetle Bait ( 21.3% carbaryl, Registration Number 869 134). No information on the symptoms or outcome of the case were provided. There was also one death. In 1996, a woman with a history of chronic asthma experienced shock and severe respiratory distress after she used Mycodex Pet Shampoo ( 0.5% carbaryl, Registration Number 2097 8) on her dog. She was hospitalized but went into a coma and died five days later ( IDS 3694 1).

Poison Control Center ( PCC) Data  1993 through 1998 The PCC data base for 1993 through 1998 contained 174 cases involving occupational exposures in adults and older children ( outcome determined in 90 cases), 3033 nonoccupational exposures in adults and older children ( outcome determined in 1351 cases) and 2147 exposures in children under the age of six ( outcome determined in 1248 cases). Cases involving exposures to multiple products were excluded. The data from cases in which the outcome was determined were compared to all other pesticides using six measures: percent with symptoms, percent with moderate or more severe outcome, percent with life threatening or fatal outcome, percent of exposed cases seen in a health care facility, percent hospitalized and percent seen in an intensive care facility.

For occupational cases, carbaryl appears to be somewhat less hazardous than all pesticides combined, as determined by five of the six measures reported. Cases involving non occupational adults and older children showed an increased risk in five of the six measures reported. In particular these non occupational cases were nearly twice as likely to require serious health care ( hospitalization or treatment in a critical care unit) and were 2.5 times more likely to experience major medical outcome ( life threatening effects or significant residual disability). These data suggest that some consumers are using this chemical in a careless manner. For cases involving children under six years of age, carbaryl has a similar hazard profile to all other pesticides.

California Data  1982 through 1996 Detailed descriptions of 226 cases submitted to the California Pesticide Illness Surveillance Program ( 1982 1996) were reviewed. In 90 of these cases, carbaryl was used alone or was judged to be responsible for the health effects. Only cases with a definite, probable or possible relationship were reviewed. Carbaryl ranked 37th as a cause of systemic poisoning in California. The number of reports from California declined by over half from the first five years of the reporting period ( 1982 1986) to the last five years ( 1992 1996). It is difficult to determine whether some of this decline might be related to a decrease in usage because the method of collecting use information changed after 1989. Of the 90 persons reported to have illnesses, a total of 43 ( 48%) had systemic illnesses, 20 ( 22%) had eye irritation, 21 ( 23%) had skin irritation, 1( 1%) had respiratory illness and 5 ( 6%) had a combination of effects. A total of 26 workers were disabled ( took time off work, 1 for more than 10 days) as the result of carbaryl exposure. Seven required hospitalization ( 1 5 days). Applicators were associated with the majority of the exposures. Clinical signs/ symptoms in these workers included nausea, vomiting, skin rashes, sore throat, lip swelling, chemical conjunctivitis, dizziness, eye irritation, contact dermatitis, blurry vision, chest pains, and several other symptoms.

National Pesticide Telecommunications Network On the list of the top 200 chemicals for which NPTN received calls from 1984 1991 inclusively, carbaryl was ranked 5th with 503 incidents in humans reported and 85 incidents in animals ( mostly pets). For the years 1995 through 1998, carbaryl's rank ranged from 7th to 12th with 110 incidents in humans reported and 26 incidents in animals. Most of the decline in reported human cases from the earlier time period is due to the reduced level of incident reporting overall. However, even taking this into account, there does appear to be some reduction in carbaryl incidents which is also reflected in the lower rankings reported for the later years ( 1995 1998).

Literature Summary Thirteen epidemiological studies/ case reports from the open literature were reviewed. Five case reports suggested that carbaryl may cause long term neurological or 11Branch RA, Jacqz E ( 1986). Is carbaryl as safe as its reputation? Does it have a potential for causing chronic neurotoxicity in humans?. The American Journal of Medicine 80( 4): 659 664.

12Brewer B ( 2000). A rare cause of acute confusional state ( Letter to the Editor). Journal of Accidental Emergency Medicine 17( 1): 77.

13Devinsky O, Kernan J, Bear DM ( 1992). Aggressive behavior following exposure to cholinesterase inhibitors. Journal of Neuropsychiatry 4( 2): 189 194.

14Dickoff DJ, Gerber O, Turovsky Z ( 1987). Delayed neurotoxicity after ingestion of carbamate pesticide. Neurology 37( 7): 1229 1231.

15Wiener PK, Young RC ( 1995). Late onset psychotic depression associated with carbaryl exposure. American Journal of Psychiatry152( 4): 646 647.

16Savitz DA, Arbuckle T, Kaczor D, Curtis KM. ( 1997). Male pesticide exposure and pregnancy outcome. American Journal of Epidemiology 146( 12): 1025 1036.

17Whorton DM, Avashia BH, Hull EQ. ( 1979). Testicular function among carbaryl exposed employees. Journal of Toxicology and Environmental Health 5: 929 941.

18 Wyrobek AJ, Watchmaker G, Gordon L, Wong K, Moore D 2d, Whorton D ( 1981). Sperm shape abnormalities in carbaryl exposed employees. Environmental Health Perspectives 40: 255 265. psychologicalproblems. 11,12,13,14,15 Two of these cases involved attempted suicides in which large doses of carbaryl containing products were ingested. Some of the effects from carbaryl exposure are consistent with those reported from organophosphate poisoning. However, no controlled studies have been conducted. If such effects occur as a result of carbaryl overexposure they appear to be relatively rare. The effects observed in the case reports are too inconsistent to draw any conclusions, but do suggest the need for further study.

Other literature articles concerned epidemiology studies to evaluate the effects of pesticides on reproduction. In the 1979 Ontario Farm Family Study by Savitz et al16, the effects of activities and specific pesticides on male farmer's fertility were considered. The results suggested that thiocarbamates, carbaryl and other pesticides were most strongly associated with miscarriage. The adjusted odds ratio for carbaryl used on crops was 2.1 with a 95 percent confidence interval of 1.1 to 4.1 ( borderline significance). Use of carbaryl in the yard was not associated with a significantly increased risk of miscarriage and carbaryl was not a significant risk factor for preterm delivery or small for gestational age births. In a 1979 study of male workers who produced and packaged carbaryl, Whorton et al17 concluded that there was no evidence of sperm count suppression resulting from exposure to the chemical. Whorton et al. ( 1979) and Wyrobek et al18 ( 1981) used the same cohort in their studies to determine the effects on fertility by checking for infertile marriages and by measuring sperm counts and serum gonadotropins. The carbaryl exposed group included nearly three times as many oligospermic men as the control group. Wyrobek et al. ( 1981) concluded there was a non dose related, significant elevation in sperm head abnormalities compared to controls, that may not be reversible. Both of the studies had low participation rates, relied on self reporting of exposure levels, and used less than ideal control groups. 19Senthilselvan A, McDuffie HH, Dosman JA. 1992. Association of asthma with use of pesticides. Results of a cross sectional survey of farmers. Am Rev Respir Dis 146( 4): 884 887.

20Sharma VK, Kaur S. 1990. Contact sensitization by pesticides in farmers. Contact Dermatitis 23: 77 80. There were also two studies assessing carbaryl's potential to induce an allergic reaction. Senthilselvan et al. ( 1992) 19 reported on the association between self reported asthma and pesticide use in 1,939 farmers. The prevalence of asthma was significantly associated with the use of carbamate insecticides regardless of age, smoking pack years, and nasal allergic reactions. The authors concluded that the possibility of exposure to agriculture chemicals could be related to lung dysfunction in exposed farmers.

Sharma and Kaur ( 1990) 20 reported on 30 farmers that had contact dermatitis after using pesticides for several years. The farmers included 25 males and 5 females, between the ages of 28 and 70 years old. Patch testing was conducted on the upper back and readings were taken on the second, third, and seventh day. Allergic reactions to one or more pesticides were seen in 11 patients. One patient was sensitive to carbaryl and two patients to 3 each ( 2,4 D, thiram, carbaryl; pendimethalin, methyl parathion and carbofuran). Carbamates, including carbaryl, were the most frequent sensitizers. Allergic reactions did not occur in the twenty controls included in the study.

Unpublished Epidemiology Study Rhone Poulenc submitted an epidemiologic study of plant workers exposed to carbaryl titled " Standardized Mortality Ratio Analysis of Employees Exposed to Carbaryl at the Rhone Poulenc Institute, West Virginia Plant", which was reviewed by Dr. Jerome Blondell ( DP Barcode D194815). The results were part of a ten year vital status update undertaken by the National Institute of Occupational Safety and Health. The study included all individuals who were first hired between 1960 ( when the production of carbaryl started) and through 1978. The vital status of all workers was determined through 1988 using the National Death Index.

A total of 522 employees were identified as belonging to either the production, packing/ distribution, or maintenance facilities. Follow up through 1988 showed 25 deaths, including nine due to cancer. Significantly less deaths ( 50%) were seen compared to the number expected. No category of death resulted in a statistically significant excess. Those categories that exhibited an excess ( greater than the number of expected cases) were usually based on a single reported death with very wide confidence intervals. For brain cancer, there were two deaths ( 0.5 expected), but they had different histologic origin which reduces the likelihood that they were due to the same exposure. HED concluded that the epidemiologic study does not add significant new information concerning adverse health effects of carbaryl. The sample of workers was too small and the period of follow up to too short to permit definitive conclusions. Domestic Animal Incident Review The domestic animal incident review was prepared by Dr. Virginia Dobozy ( D266621 dated June 12, 2000). There are approximately 69 active products containing carbaryl with use sites for dogs and cats in OPP's Reference File System ( REFS). The majority of the products are 5 10% lawn and garden dusts, which may be registered for use on animal bedding and thus are included in the REFS search. Most of the powders for intentional application to dogs and cats for flea and tick control also contain 5 10% carbaryl, some in combination with pyrethrins and synergists. However, two products contain 12.5% carbaryl in combination with pyrethrins. Three products contain carbaryl ( 10 12.5%) in combination with 0.25% methoxylchlor. There is one shampoo which contains 0.5% carbaryl, two flea collars with either 9.5% ( cats) or 17% ( dogs) carbaryl and a dip for dogs with 60% carbaryl. In general, the use of powders, dips and sprays for flea and tick control in dogs and cats has been replaced within the last five years with oral ( FDA regulated) or spot on formulations. As there are no spot on carbaryl preparations, it can be assumed that the use of this chemical for flea and tick control has declined.

There are 213 reports in IDS for carbaryl for domestic animals from 1991 to May, 2000. Only those incidents from 1998 ( most recent year with complete data) were reviewed in order to provide an evaluation of current adverse reports in domestic animals. In 1998, there were 35 incidents in IDS involving 23 dogs, 9 cats and 1 pig. One incident involved two dogs and in three incidents, the species was not identified. Only two incidents involved products registered for use on dogs and cats. In one, an 8 week old kitten treated with Zodiac Flea and Tick Powder for Dogs developed vomiting and anorexia and died the next day. In the other, a dog was reported to have had a reaction to a shampoo with carbaryl; no other data were provided. The majority of the remaining incidents involved products containing a 5% carbaryl dust or a molluscicide which contains 2% metaldehyde and 5% carbaryl. A wide variety of clinical signs were reported. Most of the incidents were evaluated and classified as to causality ( doubtful, low, moderate or high suspicion) by the ASPCA/ National Animal Poison Control Center. All were classified as doubtful or low suspicion. A summary review of incidents for a 5% carbaryl powder from one registrant, along with the one report from 1998, provided some evidence that young kittens (< 12 weeks) may be susceptible to adverse reactions to carbaryl. It is recommended that all labels for carbaryl products used on cats contain the age restriction stated in PR Notice 96 6 ( should not be used in kittens less than 12 weeks of age).