[Federal Register Volume 69, Number 207 (Wednesday, October 27, 2004)]
[Rules and Regulations]
[Pages 62596-62602]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-24041]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-2004-0243; FRL-7371-6]


L-Glutamic Acid and Gamma Aminobutyric Acid: Order Denying 
Objections to Issuance of Tolerance

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final Order.

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SUMMARY: By this order, EPA denies the objections filed by the Truth In 
Labeling Campaign (TLC) and additional citizens to a final rule issued 
June 21, 2001. That rule exempts from the requirement of a tolerance 
under section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA) 
use of L-glutamic acid (LGA) and gamma aminobutyric acid (GABA) on all 
food commodities when applied/used in accordance with good agricultural 
practices. EPA is denying the objections because the Agency has 
evaluated these products and believes them to meet the statutory 
requirement of reasonable certainty of no harm.

DATES: This order is effective October 27, 2004.

FOR FURTHER INFORMATION CONTACT: Carol E. Frazer, Biopesticides and 
Pollution Prevention Division (7511C), Office of Pesticide Programs, 
Environmental Protection Agency, 1200 Pennsylvania Ave., NW., 
Washington, DC 20460; telephone number: (703) 308-8810; fax number: 
(703) 308-7026; e-mail address: <a href="/cdn-cgi/l/email-protection#5b3d293a213e2975383a2934371b3e2b3a753c342d"><span class="__cf_email__" data-cfemail="8fe9fdeef5eafda1eceefde0e3cfeaffeea1e8e0f9">[email protected]</span></a>.

ADDRESSES: EPA has established a docket for this action under Docket 
identification number OPP-2004-0243. All documents in the docket are 
listed in the EDOCKET index at http://www.epa.gov/edocket. Although 
listed in the index, some information is not publicly available, i.e., 
CBI or other information whose disclosure is restricted by statute. 
Certain other material, such as copyrighted material, is not placed on 
the Internet and will be publicly available only in hard copy form. 
Publicly available docket materials are available either electronically 
in EDOCKET or in hard copy at the Public Information and Records 
Integrity Branch (PIRIB), Rm. 119, Crystal Mall <greek-i>2, 1801 S. 
Bell St., Arlington, VA, Monday through Friday, excluding legal 
holidays. The Docket telephone number is (703) 305-5805.

SUPPLEMENTARY INFORMATION: 

I. General Information

A. Does This Action Apply to Me?

    This action is directed to the public in general. However, this 
action is of particular interest to TLC, the major objector to the use 
of LGA as a pesticide product and to Lucinda Larson, the only objector 
who specifically added GABA to her objection as well as LGA. Several 
other objectors expressed an objection to the Federal Register notice 
exempting the two chemicals from the requirement of a tolerance, 
without specifying either one. This action is also of interest to 
Emerald BioAgriculture Corporation, the manufacturer of 
AuxiGro<SUP>TM</SUP>, the only pesticide product that uses LGA and GABA 
as active ingredients, as well as users of AuxiGro<SUP>TM</SUP> 
products. Since various different entities may be interested in this 
action, the Agency has not attempted to describe all the specific 
entities that may be affected by this action. If you have any questions 
regarding the applicability of this action to a particular entity, 
consult the person listed in the FOR FURTHER INFORMATION CONTACT 
section.

B. How Can I Access Electronic Copies of this Document and Other 
Related Information?

    In addition to using EDOCKET (http://www.epa.gov/edocket/), you may 
access this Federal Register document electronically through the EPA 
Internet under the ``Federal Register'' listings at http://www.epa.gov/fedrgstr/. A frequently updated electronic version of 40 CFR part 180 
is available at E-CFR Beta Site Two at http://www.gpoaccess.gov/ecfr/.

II. Background and Statutory Findings

A. What Action Is the Agency Taking?

    From June 28, 2001 through January 14, 2002, TLC and others filed a 
series of objections to EPA's issuance of an exemption from the 
requirement of a tolerance under section 408 of the FFDCA for use of 
LGA and GABA on all food commodities when applied/used in accordance 
with good agricultural practices. EPA is denying the objections because 
it has reviewed all available data on these pesticides and maintains 
its conclusion that the uses of these pesticides are safe. None of the 
objectors filed a hearing request.

B. What Is the Agency's Authority for Taking This Action?

    Section 408 of the FFDCA authorizes the establishment by regulation 
of maximum permissible levels of pesticides in foods. Such regulations 
are commonly referred to as ``tolerances.'' Without such a tolerance or 
an exemption from the requirement of a tolerance, a food containing a 
pesticide residue is ``adulterated'' under section 402 of the FFDCA and 
may not be legally moved in interstate commerce. 21 U.S.C. 331, 342. 
Monitoring and enforcement of pesticide tolerances are carried out by 
the U.S. Food and Drug Administration (FDA) and the U.S. Department of 
Agriculture (USDA).
    Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a 
tolerance only if EPA determines that the tolerance is ``safe.'' 
Section 408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a 
reasonable certainty that no harm will result from aggregate exposure 
to the pesticide chemical residue, including all anticipated dietary 
exposures and all other exposures for which there is reliable 
information.'' This includes dietary exposure through food and drinking 
water and exposure other than dietary that occurs in non-occupational 
settings. In making safety determinations, EPA is required to consider, 
among other things, ``available information concerning the cumulative 
effects of the pesticide chemical residue and other substances that 
have a

[[Page 62597]]

common mechanism of toxicity.'' 21 U.S.C. 346a(b)(2)(D)(v). Section 
408(b)(2)(C) requires EPA to give special consideration to exposure of 
infants and children to the pesticide chemical residue in establishing 
a tolerance and to ``ensure that there is a reasonable certainty that 
no harm will result to infants and children from aggregate exposure to 
the pesticide chemical residue. . . .'' 21 U.S.C. 346a(b)(2)(C). For 
pesticides that pose a threshold effect, EPA is directed to apply ``an 
additional tenfold margin of safety . . . to take into account 
potential pre- and post-natal toxicity and completeness of the data 
with respect to exposure and toxicity to infants and children.'' 
[hereinafter referred to as ``the children's safety factor''] Id. This 
provision additionally specifies that EPA ``may use a different margin 
of safety for the pesticide chemical residue only if, on the basis of 
reliable data, such margin will be safe for infants and children.'' Id. 
The procedure for establishing tolerance regulations is generally 
initiated by pesticide manufacturers through the filing with EPA of a 
petition requesting the establishment of a tolerance. See 21 U.S.C. 
346a(d). EPA is required to publish notice of this petition as well as 
a summary of the petition prepared by the petitioner. Id. 346a(d)(3). 
After evaluation of the petition, EPA may issue a final tolerance 
regulation, a proposed tolerance regulation, or an order denying the 
petition. Id. 346a(d)(4). Once a final tolerance regulation is issued, 
any person may, within 60 days, file written objections to any aspect 
of this regulation and may also request a hearing on issues of fact 
raised by the objections. Id. 346a(g).
    EPA regulations specify that if a hearing is requested, the 
objections must include a statement of the factual issues on which a 
hearing is requested, the requestor's contentions on such issues, and a 
summary of any evidence relied upon by the requestor. 40 CFR 178.27. A 
request for a hearing will be granted if the Administrator determines 
that the material submitted shows the following: There is genuine and 
substantial issue of fact; there is a reasonable possibility that 
available evidence identified by the requestor would, if established, 
resolve one or more of such issues in favor of the requestor, taking 
into account uncontested claims or facts to the contrary; and 
resolution of the factual issues in the manner sought by the requestor 
would be adequate to justify the action requested. 40 CFR 178.32. EPA's 
regulations specify that if no hearing is requested, or a requested 
hearing is denied, EPA will publish in the Federal Register its 
determination on each objection submitted. 40 CFR 178.37(a).

III. Regulatory and Procedural History

    LGA and GABA are pesticides produced by Emerald BioAgriculture 
(formerly Auxein) Corporation. They are currently registered under the 
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), 7 U.S.C. 
136 et seq., for use on all food commodities (40 CFR 180.1187 and 
180.1188) and exemptions for the requirement of tolerances covering all 
uses have been established under the FFDCA.
    In 1987, EPA approved use of LGA as a plant nutrient inert for seed 
treatment [40 CFR 180.1001(d)].
    In August 1997, EPA published a notice of the first application for 
a new pesticide product containing both of these active ingredients (62 
FR 42782, August 8, 1997) (FRL-5735-1). This notice announced receipt 
of an application to register a pesticide product, AuxiGro WP (EPA File 
Symbol 70810-R) containing new active ingredients GABA: gamma 
aminobutyric acid at 29.2% and glutamic acid at 36.5%, not included in 
any previously registered product pursuant to the provisions of section 
3(c)(4) of the FIFRA, as amended. This product was a plant growth 
enhancer for use to increase yields and the quality of crop plants and 
early ripening in certain vegetables. EPA received no comments or 
objections to this application.
    In September 1997, in response to a petition submitted by Auxein 
Corporation, EPA issued temporary tolerances for glutamic acid (62 FR 
46882, September 5, 1997) (FRL-5741-3) and GABA (62 FR 46885, September 
5, 1997) (FRL-5741-4) on crops including: snap beans, peanuts, cotton, 
potatoes, tomatoes, lettuce, green peppers, spinach, broccoli, 
cauliflower and cabbage to enhance crop yields. These tolerances were 
scheduled to expire on October 1, 1999. Again, EPA received no comments 
or objections to the exemptions from the requirement for a tolerance.
    Later that same year, EPA published a proposed permanent exemption 
from the requirement of a tolerance to cover use of both active 
ingredients (62 FR 56168, October 29, 1997)(FRL-5751-3). Depending on 
the crop, the first application of AuxiGro was made at first bloom, 
first bud, at the 4 to 6 leaf stage, or other prescribed growth stage. 
A subsequent application, for a maximum of two applications, could be 
made 1 to 3 weeks later. The rate range is 0.10 - 0.75 pounds of 
formulated product/acre per treatment, not to exceed a maximum of 1.5 
lb/A per growing season. This equated to the application of 0.55 lb/A 
glutamic acid and 0.4 lb/A of GABA applied at the maximum use rate. EPA 
received no comments or objections to this proposal. EPA finalized this 
rule the following year (63 FR 679, January 7, 1998)(FRL-5764-4).
    On August 20, 1998, after the close of the objection period, Jack 
Samuels of the Truth in Labeling Campaign (TLC) wrote to EPA objecting 
to the approval of monosodium glutamate as a pesticide (Ref. 1). EPA 
responded to the letter on October 13, 1998 after Mr. Samuels' 
objections were reviewed (Ref. 2).
    In September 1998, EPA made a technical amendment to the 
nomenclature language of the tolerance exemption to change ``glutamic 
acid' to ``LGA'' (63 FR 51302, September 25, 1998)(FRL-6029-1).
    In 2000, Auxein petitioned EPA to modify 40 CFR 180.1187 and 40 CFR 
180.1188 by deleting the wording ``when used as a plant growth 
enhancer'' from the tolerance exemption then in place and, as a result 
broaden the scope of the tolerance exemption, and to correct the 
language of the tolerance exemption then in place by changing the term 
``raw agricultural commodities'' to ``food commodities'' (65 FR 76241-
76244, Dec. 06, 2000). EPA received no comments on the petition.
    Auxein submitted efficacy studies to support the broadened use 
patterns and EPA evaluated the data and determined that the new claims 
were supported by the data. As a result, in June 2001, EPA finalized 
the changes proposed by Auxein by modifying 40 CFR 180.1187 and 
180.1188 accordingly (66 FR 33195, June 21, 2001)(FRL-6785-6).
    On June 28, 2001, Dr. Adrienne Samuels of TLC submitted an 
Objection to the Exemption from the Requirement of a Tolerance and the 
group was joined individually by several of their members who also 
submitted objections.

IV. Response to Objections

A. Summary of Objections Received

    There were 57 objectors to the revised tolerance exemption for LGA 
and GABA. All objections addressed the perception that an exemption for 
LGA was equivalent to treating crops with ``monosodium glutamate'' or 
``processed free glutamic acid'' or ``processed free glutamic acid 
(MSG)'' or to ``what the Agency calls LGA.'' None of the objections 
specifically address ``LGA'' or provided scientific evidence or 
information linking dietary

[[Page 62598]]

consumption of LGA to adverse reactions. Similarly, none of the 
objections specifically cited consumption of GABA as the cause of 
adverse reactions or provided scientific evidence or information 
linking connection of dietary consumption of GABA to adverse reactions.
    Rather, many objections reported the individual's reactions or 
someone else's reactions to dietary intake of MSG, and/or to processed 
free glutamic acid (MSG). These included, with frequency of reaction 
cited, headache/migraine (12), nausea (5), abdominal cramps (5), 
allergy (5), shortness of breath (4), and accelerated pulse rate (3). 
Other symptoms mentioned once or twice included numbness, lethargy, 
stiffness, distorted vision, coughing, insomnia, and facial twitching. 
Eight objections noted individuals felt that ingestion of ``small'' or 
``tiny'' amounts of MSG elicited some reaction.

B. Agency Response to Summary Objections

    As to the general objections on LGA, there is no evidence, and 
objectors provide no support for a claim, that dietary consumption of 
LGA causes adverse human health effects. This is the case regardless of 
whether the dietary consumption is of raw or processed food containing 
LGA or whether the LGA is produced environmentally by natural events or 
in the laboratory. In fact, because LGA is a defined chemical structure 
and a constituent of protein, there is significant exposure to LGA via 
the diet unrelated to the pesticide use and it is also synthesized 
endogenously (Ref. 3). Objectors provide no scientific evidence or 
information to distinguish natural LGA from what objectors refer to as 
``processed'' LGA. This is because there is no difference in chemical 
structure, for example, between LGA found in nature or the human body 
and LGA produced for pesticide purposes. Where the chemical structure 
of two chemicals is the same in all contexts, there is no scientific 
basis to distinguish between the chemicals.
    With respect to the symptoms cited by objectors, these symptoms are 
representative of the ``acute, temporary, and self-limited reactions'' 
to oral ingestion of MSG, as delineated by an Expert Panel to the Food 
and Drug Administration (FDA) evaluating the safety of use of MSG (Ref. 
3). There has been a long history of inquiry into the safety of MSG as 
a flavor enhancer in foods. The Expert Panel to FDA concluded that 
``...[b]ased on scientifically verifiable evidence, there is a subgroup 
of presumably healthy individuals within the population that responds 
generally within one hour of exposure with manifestations of the MSG 
Symptom Complex to an oral bolus of [greater than or equal to] 3 grams 
in the absence of food.'' However, the Expert Panel also concluded 
(emphasis theirs) that ``...no evidence exists to support a role of 
ingested glutamate in the etiology or exacerbation of...any...long-term 
or chronic illness.'' Moreover, there is no evidence that dietary 
consumption of LGA elicits, or has elicited, the ``MSG Symptom 
Complex'' of reactions. None of the objections identify foods 
containing LGA as the cause of the reactions cited.

C. Specific Objections and Agency Responses

    1. First objection. TLC states that LGA naturally bound in protein 
or freed from protein via the natural human digestion process causes no 
adverse reactions (i.e., is safe). On the other hand, they state that 
foreign, unnatural substances are produced from protein containing 
glutamic acid stereoisomers (i.e., L-glutamic and D-glutamic acid) 
during natural fermentation, food preparation, and processing. 
Specifically mentioned are the production of D-glutamic acid and 
pyroglutamic acid when LGA is freed from protein via (microbial) 
fermentation, ``high heat (but not acid) hydrolysis,'' ``enzymolysis/
autolysis,'' and ``secretion.'' In addition, they state carcinogenic 
propanols are produced from acid hydrolysis, and carcinogenic 
heterocyclic amines may be produced from heat but not acid. They state 
that LGA freed from protein via these mechanisms, and containing the 
above contaminants causes ``adverse reactions.'' They call these 
mixtures of chemicals ``processed free glutamic acid'' or ``processed 
free glutamic acid (MSG).'' No data were presented on the oral or 
dietary toxicity of any of the contaminants, nor on the doses required 
to produce toxicity, if any, to humans. Neither did they provide any 
evidence that the components of ``processed free glutamic acid'' can or 
do elicit reactions associated with ``MSG Symptom Complex,'' at any 
level of dietary exposure. Further, TLC states ``...we have never 
stated these so called contaminants are the cause of adverse 
reactions.''(Ref. 4)
    EPA response. To the extent that objectors are concerned with 
contaminants that might be found in a pesticide product, EPA notes that 
its review of data/information submitted on the manufacturing process 
and on the chemical analyses of the technical grade of the active 
ingredient revealed none of the above mentioned contaminants. Thus, 
there is no scientific basis to support objectors' statements regarding 
the presence of the above mentioned contaminants and, to the extent 
that objectors' health-based statements are premised on the presence of 
these contaminants, there is no scientific basis to support objectors' 
statements. Had the contaminants been present in a pesticide product, a 
separate tolerance or exemption would typically be necessary to cover 
residues of such chemicals in or on food.
    In addition, as noted above, an apparent primary basis for 
objections by TLC (both at the EPA and FDA) appears to be derived from 
their belief that the LGA which is derived from a (or any) 
manufacturing process is somehow (and in an unspecified manner) 
different than if it were freed from protein via a mechanism of human 
digestion, and is somehow different from LGA that humans and other 
higher organisms synthesize in their bodies, and is somehow different 
from the LGA that is found in unadulterated, unprocessed, unfermented 
food. Further, according to TLC, the LGA in lower forms of life (like 
bacteria) is in some unspecified manner, not equivalent to the LGA 
found in higher organisms. Again, as noted above, there is no 
scientific basis to support such an argument. The chemical structure of 
LGA is the same regardless of the organism in which it is found or 
regardless of how it is freed from protein. To claim that people may 
react adversely to the same chemical structure solely on the basis of 
how it is produced is not a sound scientific proposition.
    Specifically, and as an example, when a hydrogen ion becomes 
disassociated from LGA, the compound is called L-glutamate. When a 
sodium ion becomes associated with L-glutamate the compound is called 
monosodium glutamate (MSG). When a potassium or ammonium ion becomes 
associated with L-glutamate the compounds are called respectively, 
monopotassium and monoammonium glutamate. When the monosodium, or 
monopotassium, or monoammonium salts of L-glutamate are dissolved in 
water the sodium, or potassium, or ammonium ions become disassociated 
from the glutamate molecule. Thus, ``...[G]lutamate entities from 
glutamic acid and glutamate entities from the three [ammonium, 
potassium, and sodium] salts are indistinguishable and, once added to 
food or water and eaten, glutamate from any source, whether naturally 
present in food or manufactured by bacteria, is metabolized in the same 
manner'' (Ref. 5). Likewise, upon release to the

[[Page 62599]]

environment (as in a pesticide product, for instance) glutamate 
entities from LGA or from the three salts would be metabolized in the 
same manner by organisms in the environment.
    2. Second objection. In granting the tolerance exemption, the EPA 
has ``...violated Section 408(c)(2)(A)(i), Section 408(c)(2)(ii), 
Section (408)(c)(2)(b), and Section 408(b)(2)(D) of the Federal Food, 
Drug, and Cosmetic Act (FFDCA).''
    EPA response. EPA does not agree with TLC that use of LGA or GABA 
as permitted by the registration and tolerance exemptions violates the 
specified sections of FFDCA in granting the tolerance exemption for 
LGA. TLC states that LGA bound in protein and freed via human digestion 
causes no ``adverse reactions.'' Since the chemical entity LGA is the 
same regardless of the source of protein or how it is freed from 
protein, it is the same as the ``truly natural glutamic acid'' referred 
to by TLC, and thus also would cause no adverse reactions. Further, 
none of the objectors registered any adverse reactions from dietary 
consumption of the chemical entity LGA as is normally found in foods. 
Finally, there is no evidence thus far submitted or thus far available 
to the Agency that dietary consumption of LGA has caused or will cause 
adverse effects in the U.S. population, and its subgroups. If such 
data/information became available, the Agency would then reassess its 
position with respect to the tolerance exemption for LGA (and also for 
GABA).
    In establishing the tolerance exemption for LGA, the Agency has 
considered the validity, completeness, and reliability of the extensive 
scientific data base on LGA, including in its monosodium form (MSG), 
and concluded that based on that data there is reasonable certainty of 
no harm resulting from all anticipated dietary exposures to LGA. The 
Agency considered information on the dietary consumption patterns of 
humans, as well as the sensitivities of major identifiable subgroups of 
consumers, including infants and children.
    In addition, the strength and weakness of the existing data base, 
which includes the reports and conclusions of authors cited by TLC, 
previously has been reviewed and summarized in detail by the 1995 
Expert Panel (Ref. 3). The Agency agrees with the conclusions of the 
subsequently issued summary report of Dr. Donald S. Stevenson (Ref. 6) 
that there is no scientific basis to support any argument that LGA, or 
glutamate, or MSG, plays any role in allergenicity including urticaria 
or anaphylaxis. ``It is illogical to propose that the human immune 
systems would form antibodies against our own amino acids....All amino 
acids are too small to be an antigen (allergen)'' (Ref. 6). EPA also 
agrees with the subsequent report conclusion of Dr. David G. Hattan 
(Ref. 7) that based on the scientific data ``...we do not concur with 
the Expert Panel that asthma is a predisposing medical condition 
associated with the ingestion of MSG.'' Finally, EPA agrees with the 
conclusions of the subsequently issued summary report of Dr. Roland N. 
Auer (Ref. 8) that ``[n]o causal relationship has been established 
between...diseases and oral MSG [or glutamate] ingestion in humans...'' 
There also is no evidence that ``...retinal diseases are caused, 
related to or accelerated by MSG [glutamate].''
    3. Third objection. ``The processed free glutamic acid (referred to 
in the 1998 Final Rule as LGA) that was granted an exemption from the 
requirement of a tolerance, is a neurotoxic endocrine disruptor that 
causes brain lesions [and] endocrine disorders'' which are manifested 
as growth disorders, learning/behavior/memory deficits, MSG-associated 
responses, schizophrenia, multiple sclerosis (MS), Parkinson's disease, 
amyotrophic lateral sclerosis (ALS), etc.
    EPA response. The Agency does not agree with the objection that LGA 
is a neurotoxic endocrine disruptor, and when consumed in the diet will 
lead to the stated disorders and associated diseases, and to the MSG 
symptom complex of reactions. As concluded by the Expert Panel to FDA, 
``...no evidence exists to support a role of ingested glutamate in the 
etiology or exacerbation of...any...long-term or chronic illnesses...'' 
including diseases such as Alzheimer's disease, Huntington's chorea, 
and amyotrophic lateral sclerosis (Ref. 3).
    The Agency is aware of the studies in which LGA, when delivered at 
high doses to laboratory animals (mice, rats, infant primates) by 
appropriate route (injection, high-volume force feeding) induces 
neuronal death-associated lesions at the hypothalamus (and, in rodents, 
the medulla oblongata). The Agency also is aware of concerns presented 
by some (Ref. 9) that such findings, if extrapolatable to dietary 
intake of LGA by humans could have health implications. Such 
speculations, however, are not supported since there is no scientific 
evidence to indicate that LGA or MSG as consumed in foods disrupts the 
neuroendocrine axis. No such glutamate-induced lesions of the 
hypothalamus or medulla oblongata ever have been seen or described in 
humans upon autopsy of millions of people - including children - over 
the years. (Ref. 8). ``Claims that orally ingested MSG [or glutamate] 
causes or contributes to Alzheimer's disease, Parkinsonism, 
Huntington's Chorea, amyotrophic lateral sclerosis, obesity, early or 
late puberty, stunting of growth, or infertility must be viewed with 
extreme skepticism until some evidence is provided.'' (Ref. 8).
    4. Other specific objection issues raised by TLC.--a. TLC knows of 
``...no white, practically free-flowing crystalline powder that is 
ubiquitous in nature.''
    Agency response. When organic materials, like amino acids,are 
purified from nature they take on the physical and chemical 
characteristics of the purified molecule. Upon release of this purified 
material to the environment, as a pesticide active ingredient for 
example, it will dissolve in water and will be indistinguishable from 
the LGA already in the environment.
    b. TLC states that EPA ``...falsely asserted that processed free 
glutamic acid has a long history of food uses''.
     Agency response. EPA never has used the term ``processed free 
glutamic acid.'' This term is used by TLC, and is not used by members 
of the scientific community. The terms ``LGA'' and ``monosodium 
glutamate'' define the chemical structures of specific organic 
molecules and are recognized terms.
    c. TLC cites three publications by J. W. Olney to support their 
conclusion that ``...there is growing recognition that the reactive 
component of monosodium glutamate is processed free glutamic 
acid...that causes adverse reactions...regardless of the names of the 
ingredients that contain it or the uses to which it is put.''
    Agency response. The scientific research results of J. W. Olney 
(e.g., Ref. 10) showing neuronal lesions in certain laboratory animals 
have been considered by EPA in its finding of safety from dietary 
exposure in humans to LGA. EPA believes Olney's research conclusions 
are based on effects due to the recognized molecules ``monosodium 
glutamate'' or ``LGA'' regardless of the source (e.g., natural or 
manufactured) and when delivered in highly purified form and at extreme 
dose levels.
    d. TLC cites a report by Martinez (Ref. 11) and concludes that the 
author ``...found a relationship between glutamate levels in the CSF 
[cerebrospinal fluid] of the central nervous system, not glutamate 
levels in the plasma, that were related to migraine headache.''
    Agency response. Martinez (Ref. 11) found that glutamic acid levels 
in CSF

[[Page 62600]]

[obtained by lumbar puncture during migraine attack] were lower than in 
CSF of a ``stress'' control population (e.g., pre-operative surgery 
patients, acute stroke sufferers, cancer patient, multiple sclerosis 
sufferers). He also found that glutamic acid levels in plasma of 
migraine sufferers during attack were lower than in plasma of the 
``stress'' control population. No conclusions on relationships between 
oral consumption of MSG and migraine can be drawn from the results, 
since the study was not designed to, or intended to, test such a 
relationship. The study results are best discussed with regard to 
possible physiological responses (e.g., glutamate release) to brain 
events (e.g., cortical blood flow, hypoxic ischemia) that occur during 
migraine.
    e. TLC states ``(i)ngestion of processed free glutamic acid causes 
adverse reactions in susceptible individuals - reactions known to occur 
as side effects of neurotropic drugs such as valium.''
    Agency response. The benzodiazepiene drug Valium (diazepam) is used 
to treat anxiety disorders, for skeletal muscle relaxation, and as a 
preoperative anesthetic. It interacts with part of the GABA receptor, 
in the presence of GABA to enhance GABA-induced changes in membrane 
potential, thereby augmenting inhibitory effects by stimulating various 
GABA-ergic pathways. Primary side effects are drowsiness and loss of 
balance. Thus Valium acts in concert with the neuroinhibitory 
physiological role of GABA, in apposition to the neuroexcitatory 
physiological role of L-glutamate.
    f. EPA omitted data from the literature on toxic and endocrine-
disrupting properties of processed free glutamic acid and its ability 
to cause adverse effects in humans.
    Agency response. TLC did not cite any studies done in humans that 
show adverse endocrine, neurological, learning, or locomotor effects 
from exposure to LGA, MSG, or to what TLC refers to as ``processed free 
glutamic acid.'' EPA believes it has considered all of the scientific 
literature.
    g. TLC states that certain human studies done with placebos induced 
reactions in control groups and thereby obscured the results of such 
studies when the control population was compared to the treated group. 
TLC cites a study by Strong (Ref. 12) who concluded that placebo 
materials (e.g., capsules) in some earlier human studies may give 
headaches to ``dietary migraine sufferers.''
    Agency response. Strong (Ref. 12) summarized results from six 
earlier published double-blind studies conducted to test patient 
sensitivity to tyramine and beta-phenylethylamine. His analysis of the 
results showed 18% of patients reported headaches from placebos which 
were concealed in gelatin capsules. In the current study by Strong 
(Ref. 12), the author was the sole subject in the study. The double-
blind component of the study apparently was done with water containing 
1 milligram/milliliter (mg/ml) tyramine or with some unspecified amount 
of unspecified placebo in 20 ml of water. Gelatin capsules were not 
used. The author suffered headache after consuming 5 of 6 of the 
tyramine samples, but not from placebo samples. The author self-
reported headache from consuming 400 mg of MSG in 15 grams (g) of 
cottage cheese, from 118 mg partially hydrolyzed vegetable protein in 
15 g of ricotta cheese, and 123 g gelatin capsule in potato chips. This 
part of the study apparently was not double-blinded. The Agency 
believes the results from an extensive study done by Geha et al. (Ref. 
13) represent the best available data in a multicenter, multiphase, 
double-blind, placebo-controlled study with MSG using 130 self-
reporting responders to MSG in the initial phase of the study. A 
citrus-based placebo beverage was used. The results suggested that 
``...large doses of MSG given without food may elicit more symptoms 
than a placebo in individuals who believe they react adversely to MSG. 
However, neither persistent nor serious effects from MSG ingestion are 
observed, and the responses were not consistent upon retesting.''
    h. TLC states ``[t]here is no evidence that surface residue from 
processed free glutamic acid will be gone prior to harvesting 
crops...and the applicant failed to note there would be residue in and 
on food crops.'' ``To be effective as a plant growth 
enhancer...processed free glutamic acid would have to be taken up by 
the plants.'' Also, all food crops ``[c]ould potentially be treated 
with processed free glutamic acid.''
    Agency response. The tolerance exemption for LGA is supported by a 
lack of dietary toxicity. Therefore, it is appropriate for the EPA to 
not require residue data for the pesticidal use of LGA.
    i. TLC states they have demonstrated that the glutamic acid in 
monosodium glutamate or other processed foods is not chemically 
identical to the LGA found in unadulterated/unprocessed/unfermented 
food. The glutamate industry has ``failed to distinguish between free 
glutamic and processed free glutamic acid...and only processed free 
glutamic acid causes adverse reactions in MSG-sensitive people who 
ingest amounts that exceed their tolerance levels.''
    Agency response. TLC has not demonstrated that the chemical entity 
LGA is somehow different when it is manufactured. The chemical 
structure of LGA is the same no matter how it is produced, or from the 
source from which it is derived.
    j. ``...EPA had the audacity to state in 1988 that `[t]he Agency 
has no information to suggest that glutamic acid will adversely affect 
the immune or endocrine systems'...and in 2001...EPA had the gall to 
ignore the subject of endocrine disruptors entirely.''
    Agency response. There is no evidence that dietary consumption of 
LGA or monosodium glutamate causes adverse effects to the immune or 
endocrine systems of humans including infants and children.
    k. TLC states that ``...monosodium glutamate and LGA are given 
hazard ratings of HR3 (most toxic) indicating an LD<INF>50</INF> below 
400 milligrams/kilogram (mg/kg)...in the sixth edition of `Dangerous 
Properties of Industrial Materials.'''
    Agency response. The oral LD<INF>50</INF> values for LGA are 
reported by the Registry of Toxic Effects of Chemical Substances 
(RTECS) as >30 g/kg in the rat and 2.3 g/kg in the rabbit. The oral 
LD<INF>50</INF> values for MSG are reported at 16.6 g/kg in the rat and 
11.4 g/kg in the mouse. These values are consistent with the least 
toxic category for pesticides, and would not require any precautionary 
statements for human hazard on the pesticide label. More relevant, is 
the long history of human dietary exposure to the naturally occurring 
amino acid, LGA, with no adverse effects - including lethality - ever 
being attributed, linked, or even expected from such exposures.
    l. TLC believes that EPA waived a requirement for a metabolism 
study with LGA because MSG has GRAS status.
    Agency response. A laboratory animal metabolism study (i.e., OPPTS 
Harmonized Guideline No. 870.7485) is not an EPA requirement for 
registration of biochemical pesticides (LGA and GABA are classified as 
biochemical pesticides). Thus, there is no need to waive a requirement 
for a metabolism study. Yet, the EPA could require such a study for 
biochemical pesticides if considered warranted. However, such a study 
in laboratory animals is not warranted because there is extensive 
knowledge on dietary exposure to, and subsequent metabolism of, LGA in 
humans without findings of toxicity. Likewise, the GRAS status of MSG

[[Page 62601]]

supports, and is consistent with, the Agency's finding for a tolerance 
exemption for LGA.
    m. TLC cites a multigeneration reproduction study (Ref. 14) where 
mice were fed MSG to support their contention that ``...failure to find 
differences in growth or adverse reactions of control and experimental 
groups may very well have been, in part, to the fact that control 
groups were receiving neurotoxic substances in their basal diets.'' The 
cited potential component of the basal diet was ``yeast food'' which 
TLC states ``...invariably contained either protease (which creates 
processed free glutamic acid during manufacture) or L-cysteine which 
produces neurotoxic effects...more extensive than the effects of 
processed free glutamic acid.''
    Agency response. In the above cited study, about 800 mice through 
the F0 to F3 generations were fed basal diet containing 1% MSG, and an 
additional 800 mice were fed basal diet containing 4% MSG. There were 
about 1800 mice in the control group, fed basal diet only. There were 
no observed adverse effects in animals from the control or treated 
groups. All parameters measured in the control and treated groups were 
within expected ranges for the mouse. No brain lesions or any other 
pathological changes were noted. Fertility index, gestation index, 
viability index, and lactation index were all high, in the MSG-treated 
animal and control groups. The hypothesis of TLC that neurotoxic 
components in the basal diet adversely affected the control group 
animals, and thus masked effects in the dosed group animals when the 
groups were compared is not supportable when no adverse effects were 
seen in any group, and all parameters were within expected ranges 
typical of the normal healthy mouse.
    n. TLC states certain animal feeding studies submitted to the 
Agency were flawed because while they ``...accounted for the amount of 
food consumed by experimental and control groups [they] did not account 
for the amount of processed free glutamic acid consumed as opposed to 
being left on the table.'' ``Every animal owner knows that animals are 
quite adept at ferreting out and rejecting (not eating) pills or other 
goodies hidden in their food.''
    Agency response. In dietary studies with rodents, test materials 
are uniformly blended with, and thus uniformly distributed in the food. 
Therefore, rejection of the diet due to aversion to the test material 
mixed in the food would be readily determined by a measured decrease in 
food consumption. Food consumption was accounted for in experimental 
and control groups in the studies cited, and was comparable among the 
groups.
    o. TLC states that the results from acute toxicity studies done 
with laboratory animals do not ``...mimic the real life situation 
wherein animals could be sprayed or otherwise come in contact with 
Auxigro.
    Agency response. The acute toxicity battery of studies were done at 
doses sufficiently high to allow placement of the test material in the 
least toxic category for pesticides. Considering the acute inhalation 
toxicity study as an example, rats were exposed in a chamber to 2.58 
mg/L for 4 hours. The only effects observed were piloerection, 
decreased activity, and red crust around the nose. These minor effects 
resolved by day 4 after exposure. Also, a very high dose of Auxigro 
(i.e., 5 g/kg) only caused slight and reversible redness to the 
animals' skin, and the minor eye irritation effects observed also were 
reversible. It can be concluded that if animals were sprayed with 
Auxigro during pesticide application and use, they would not be 
adversely affected.
    p. Agency summary response to objections by TLC on the tolerance 
exemption for LGA. TLC has not provided any scientific documentation 
that dietary consumption of LGA has caused harm, or will cause harm to 
humans, including to infants and children. They have not provided any 
evidence that LGA is allergenic, or when consumed by humans, adversely 
affects the endocrine system or the central and peripheral nervous 
system. They have provided no evidence that LGA is carcinogenic. They 
have not provided any scientific documentation that an oral bolus of 
MSG causes any adverse effects in humans beyond those typically 
associated with the MSG Symptom Complex. Even then, the pesticidal use 
of LGA represents an exposure scenario quite different than the food 
additive use of MSG as a flavor enhancer. Use of LGA as a pesticide is 
unlikely to contribute any significant addition of free glutamic acid 
already in the human diet, and even if use of LGA as a pesticide did 
significantly increase free glutamic acid in the diet there are no 
toxic endpoints that have been identified from dietary consumption of 
LGA. TLC has maintained that LGA is somehow different than the form 
found in nature when it is produced by microorganisms, or when it is 
released from protein by other than human digestive proteolytic 
enzymes. TLC calls this different material ``processed free glutamic 
acid'' and maintain that this is the material which causes numerous 
adverse effects. It mentions certain contaminants that may arise from 
certain processes that are used, or have been used, in deriving 
commercially available sources of LGA, but never states that it 
believes these contaminants are causing adverse effects, or provide any 
data on dose-response studies to support adverse effects from these 
materials. In fact, it has ``...never stated these so called 
contaminants are the cause of adverse reactions.'' Nevertheless, the 
tolerance exemption set forth under 40 CFR 180.1187 is for LGA, and is 
not for any other chemical.

D. Summary of Objections by Lucinda Larsen

    One objector, Lucinda Larsen, objected to the tolerance exemption 
for LGA and GABA on the ground that it would allow use of unrestricted 
amounts of ``potent neurotoxins'' which would interfere with 
``...almost all bodily functions.'' If supplemented in the diet, 
millions of consumers would suffer death or injury from ingestion of 
the slightest amount of ``processed free glutamic acid'' or 
``manufactured free glutamic acid.'' ``The glutamic acid found in 
nature is bound not freed and [is un]able to interfere with bodily 
functions.'' The objector believes the EPA has not considered and 
``...collect[ed] updated pertinent data from unbiased sources.''
    Agency response. The Agency has considered the strength and 
weakness of the existing scientific data base (e.g., see above) and has 
concluded that the tolerance exemptions for LGA and for GABA pose no 
unreasonable risk to human health. Free LGA is found in nature, in 
human bodies, and in the foods humans eat and it is the same glutamic 
acid as manufactured from microbial fermentation or by release from 
proteins. Likewise, free GABA, derived via enzymatic activity (i.e., 
decarboxylation reaction) from LGA, also is found in humans, plants, 
and microorganisms. LGA is the most important excitatory 
neurotransmitter in the central nervous system (CNS). GABA on the other 
hand is not an excitatory neurotransmitter, but rather is an important 
inhibitory neurotransmitter.

V. Order Responding to Objections

    The exemptions for the requirement of a tolerance for LGA and GABA 
on all food commodities to which TLC and other objectors filed 
objections are in force and will remain so.
    As detailed in Dr. Andersen's October 13, 1998 response to Mr. Jack 
Samuels and TLC's first objection to the exemption for LGA in August 
1998, EPA

[[Page 62602]]

scientists critically appraised all the data at that time and came to 
the conclusion that Mr. Samuels' objection was unwarranted (Ref. 2). 
However, EPA wishes to make sure all possible areas of disagreement are 
covered and has reviewed the latest information submitted by the 
objectors and believes nothing substantive has been added to the body 
of data known on these chemicals, and no change in the previous 
exemption is necessary.

VI. Regulatory Assessment Requirements

    As indicated previously, this action announces the Agency's final 
decision regarding an objection filed under section 408 of FFDCA. As 
such, this action is an adjudication and not a rule. The regulatory 
assessment requirements imposed on rulemakings do not, therefore, apply 
to this action.

VII. Congressional Review Act

    The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the 
Small Business Regulatory Enforcement Fairness Act of 1996, does not 
apply because this action is not a rule for purposes of 5 U.S.C. 
804(3).

VIII. References

    1. Letter from Jack L. Samuels to Sue Smith, The White House, Aug. 
20, 1998.
    2. Letter from J. Andersen to J. Samuels, Oct. 13, 1998.
    3. Raiten, D.J. et al., Analysis of Adverse Reactions to Monosodium 
Glutamate (MSG), American Institute of Nutrition, MD, 1995.
    4. e-Mail from J. Samuels to J. Andersen, 7/28/98.
    5. Kuznesof, P.M., Expert Report, undated.
    6. Stevenson, D.S. Expert Report, undated.
    7. Hattan, D.G. Expert Report, undated.
    8. Auer, R.N., Expert Report, undated.
    9. Olney, J. W. Excitotoxins in Foods. Neurotoxicology 15(3) 535-
544, 1994.
    10. Olney, J.W., et al., Cytotoxic effects of acidic and sulphur 
containing amino acids on the infant mouse central nervous system. Exp. 
Brain Res. 14:61-76, 1971.
    11. Martinez, F., et al. Neuroexcitatory amino acid levels in 
plasma and cerebrospinal fluid during migraine attacks. Cephalalgia. 
13:89-93, 1993.
    12. Strong, F.C., Why do some dietary migraine patients claim they 
get headaches from placebos? Clin. Experimental Allergy. 30:739-743, 
2000.
    13. Geha R. S. et al., Multicenter, double-blind, placebo-
controlled, multiple challenge evaluation of reported reactions to 
monosodium glutamate. J. Allergy Clin. Immunol. 106:973-980, 2000.
    14. Anantharaman, K., In utero and dietary administration of 
monosodium L-glutamate to mice: reproductive performance and 
development in a multigeneration study. In ``Glutamic Acid: Advances in 
Biochemistry.'' L. J. Filer, et al., eds. Raven Press, N.Y., 1979.

List of Subjects in 40 CFR Part 180

    Environmental protection, Administrative procedure, pesticides and 
pests.

    Dated: October 18, 2004.
James Jones,
Director, Office of Pesticide Programs.

[FR Doc. 04-24041 Filed 10-26-04; 8:45 am]
BILLING CODE 6560-50-S


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