Document ID: EPA-HQ-OPP-2012-0572-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-08-22T04:00Z

MacroButton macIb01 i  

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  >

<EPA Registration Division contact: [Roger Chesser, (703) 347-8516

Elizabeth Fertich, (703) 347-8560]>

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<[Diversey, Inc.]>

<[Petition Number 1E7843]>

<	EPA has received a pesticide petition ([1E7843]) from [Diversey,
Inc.], [8310 16th Street, Sturtevant, WI, 53177] proposing, pursuant to
section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21
U.S.C. 346a(d), to amend 40 CFR part 180 to establish an exemption from
the requirement of a tolerance for the residues of FD&C Red No. 40
(conforming to 21 CFR 21 CFR §74.340) if used as an inert ingredient
(colorant) in no-rinse, food contact surface sanitizer (sanitizer)
products.  <EPA has determined that the petition contains data or
information regarding the elements set forth in section 408 (d)(2) of 
FDDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of the
petition. Additional data may be needed before EPA rules on the
petition.>>

FD&C Red No. 40 is an azo dye with the structural formula listed below. 

The full chemical name of FD&C Red No. 40 is 2-NAPHTHALENESULFONIC ACID,
6-HYDROXY-5-[(2-METHOXY-5-METHYL-4-SULFOPHENYL)AZO]-, DISODIUM SALT, and
it has the CAS Registry Number 25956-17-6.  Commonly used synonyms are
Food Red No. 40 and FD&C Red No. 40 in the United States and Allura Red
AC in Europe.  The physical/chemical properties of the molecule have
been previously summarized (EPA, 2004).

<A. Residue Chemistry>

<	1. Plant metabolism.  >

<	2. Analytical method. [NA-Remove]>

<	3. Magnitude of residues. [Use of FD&C Red No. 40 in sanitizers will
not result in any residues on plants.  Residues of FD&C Red No. 40 are
exempt from the requirements of a tolerance when used as an inert
ingredient in pesticide formulations that are intended for application
on growing crops or on raw agricultural commodities after harvest (40
CFR 180.910).  The colorant cannot be used above 0.002% (20 ppm) by
weight in the formulation and must meet the certification requirements
specified in 21 CFR 74.340.  FD&C Red No. 40 is similarly approved for
use as a dye or coloring agent for seed treatment with a maximum
concentration of 2% by weight in the pesticide formulation (40 CFR
180.920).

The primary source of dietary exposure to FD&C Red No. 40 will most
likely occur from its existing use as a food and drug additive.   FDA
estimates that 95-97% of the certified color additives produced in the
United States are used domestically to manufacture food, drugs and
cosmetics (FDA, 2010).  An estimated 3%-5% of the domestic production is
exported.  Of these, approximately 73% is used in food, 10% in drugs and
3% in cosmetics.  Pesticidal uses were not mentioned but would fall
within the remaining 9-11% of use.  Accordingly, use of colorant in
sanitizers is expected to represent only a small percentage of the total
population exposure to the colorant.  

Sanitizers are used in commercial eating establishments and food and
dairy processing facilities to sanitize food contact surfaces after
cleaning.  The products are applied after the surface has been
thoroughly cleaned.  The sanitizer is not rinsed off and is allowed to
air dry, resulting in a small amount of colorant residue on the food
contact surface.  Accumulation of FD&C Red No. 40 residues is not
expected since the surfaces are extensively cleaned between sanitizer
applications.  

In the tolerance assessment for the use of FD&C Red No. 40 in
conventional pesticides, EPA noted that dyes are typically incorporated
into pesticide products at less than 0.1% (1000 ppm) based on
information in the PIRAT database (EPA, 2004). Most sanitizer products
are concentrates.  The product is diluted with water to produce the
use-solution, which is actually used to sanitize the surface. There are
some ready-to-use food contact surface sanitizing products available in
the consumer markets that do not require dilution, but these are
relatively rare.  

Dilutions rates for sanitizer concentrates typically vary from 1:64
(1.54%) to 1:1028 (0.01%).  Assuming the maximum concentration of FD&C
Red No. 40 in the concentrated product is 0.1% based on the information
in the PIRAT database, the expected amount of FD&C Red No. 40 in the
use-solutions will range from 15 ppm (0.0015%) to 0.1 ppm (0.00001%).  

 g FD&C Red No. 40 per cm2 of food contact surface.  The estimated
dietary exposures to FD&C Red No. 40 are discussed in section C.

EPA reviewed the environmental impact from use of FD&C Red No. 40 in
agricultural pesticides.  In agricultural use, the products are
discharged directly into the environment without treatment.  Based on
their review, EPA concluded that “modeling results indicate that
expected potential risks to aquatic organisms and soil and sediment
dwelling organisms resulting from the use of FD&C Blue No. 1, FD&C Red
No. 40, and FD&C Yellow No. 5 as inert ingredients in pesticide
formulations are low.” (EPA, 2004)

No-rinse food contact sanitizing solutions are typically indoor use
products.  These products are used at commercial facilities where there
is no direct discharge to the environment during recommended use.  The
used solutions are drained into the sanitary sewer of the facility,
where they are treated in accordance with permits issued under the Clean
Water Act.  After leaving the food processing facility, the
concentration of FD&C Red No. 40 in the waste-water will be reduced
further by dilution with other waste streams and by processing at the
waste water treatment facility.  Therefore, we would the ultimate
concentration of FD&C Red No. 40 discharged by a waste-water treatment
facility should be less than the concentration directly discharged to
the environment from agricultural uses.]>

<B. Toxicological Profile >

<	1. Acute toxicity.  [The European Food Safety Authority (EFSA) has
conducted the most recent (2009) full review of the toxicology of FD&C
Red No. 40.  This document relied heavily on the earlier reviews
conducted by the Joint FAO/WHO Expert Committee on Food Additives
(JECFA) which set the current, permanent Acceptable Daily Intake (ADI)
0-7 mg/kg-bw/day.(JECFA, 1981). For purposes of this petition, Diversey,
Inc. will summarize the key studies reported in these documents as the
basis for the toxicity discussion on FD&C Red No. 40.  The references
cited here correspond to the references in the EFSA, 2009 review.  No
compound related effects were observed when FD&C Red No. 40 (Allura Red
AC) was given to rats by gavage at doses varying from 215 to 10000
mg/kg.  Based on these studies, JECFA set the LD50 for rats at 10000
mg/kg-bw. Other studies in rabbits, dogs and mice produced LD50 values
of 10,000, 5000 and >2000 mg/kg, respectively.  Overall, the EFSA
concluded that “the acute oral toxicity of Allura Red AC  (FD&C Red
No. 40) is low.” ]>

<	2. Genotoxicity. [EFSA cited reviews by the European Scientific
Committee for Food (SCA), the JECFA and by TemaNord, to conclude that
FD&C Red No. 40 was determined to be non-mutagenic in a variety of in
vitro and in vivo based mutagenicity studies.  This determination is
consistent with EPA’s conclusion in the 2004 Tolerance Reassessment
for FD&C Red No. 40 (EPA, 2004). 

In their 2009 review, EFSA cited a study from 2001 conducted on FD&C Red
No. 40 using the Comet assay.  The study showed an increase in migration
of nuclear DNA in the glandular stomach and the colon of male mice
exposed to doses of FD&C Red No. 40 of 100 mg/kg-bw and 10 mg/kg-bw
respectively.  Since histopathology of the effected organs appeared
negative, the study authors concluded that observed effect was not
likely to be related to cytotoxicity.  In light of the negative in vivo
carcinogenicity studies conducted on FD&C Red No. 40 (see below), EFSA
concluded that the significance of the Comet assay results was
uncertain.]>

  

	3. Reproductive and developmental toxicity. [Relevant reproductive and
developmental toxicity studies cited in the EFSA document are summarized
in Table 1.   Blackmore, 1969, observed slight growth suppression in F1
and F2 pups exposed to 5.19% of FD&C Red No. 40 in the diet during a
multi-generation type reproduction study in rats.  This dose was
calculated to be equivalent to 2595 mg/kg/day.  The fetal No Adverse
Effect Level (NOAEL) was 1.39% in the diet; equivalent to 695 mg/kg/day.
 The maternal NOEAL was 5.19% in the diet, which was equivalent to 2595
mg/kg/day. No other significant anomalies were detected in growth,
litter size, pup weight, gross pathology, implantation sites, resorption
sites, live fetuses indices, appearance, anatomy and structure were
observed.  The ADI of 7 mg/kg-bw/day for FD&C Red No. 40 was partially
based on this study. 

Teratology studies in rats and rabbits showed no evidence of adverse
effects at 200 mg/kg-bw/day (gestation day (g.d.) 0-19) and 700
mg/kg/day (g.d. 6-18), respectively.

Reproductive toxicity endpoints were also monitored in three long-term
studies.  

In a lifetime study in mice, the animals were fed up to 5.19% of FD&C
Red No. 40 in the diet.  Animals were also exposed throughout gestation
and lactation.  At the highest dose level, lower body weights and
effects on organ weight and organ/body weight ratios were noted but
considered to be “inconsequential.”  (Serota et al., 1977a).  

In a nearly identical lifetime study with larger group numbers
(100/sex/group versus 50/sex/group in the original study), no compound
related adverse effects were observed.  The NOAEL’s in both studies
were determined to be 5.19% FD&C Red No. 40 in the diet, which was
calculated to be equivalent to 7300 and 8300 mg/kg-bw/day in male and
female mice, respectively.  (Reno et al., 1978)

Dietary administration of 5.19% FD&C Red No. 40 in rats was also studied
(Serota et al., 1977b).  Administration started throughout parental
breeding, gestation and lactation and continued for 118 and 121 weeks in
male and female rats, respectively.  For the female rats in the study,
mean body weights and growth rates were significantly lower in the high
dose group relative to controls.  No other significant adverse effects
were reported.  The NOAEL was 5.19% (2821 mg/kg-bw/day) in male rats and
1.3% (901 mg/kg-bw/day) in female rats.

A review conducted by TemaNord, 2002, discussed four additional
reproductive/developmental toxicity studies. 

Rats (group number not reported) were exposed to up to 10% of FD&C Red
No. 40 in the diet (calculated doses of 0, 1250, 2500 and 5000
mg/kg-bw/day).  Litter mortality was increased between 22-24 days of age
at a concentration of 10% in the diet.  Significantly decreased running
wheel activity was observed in all exposed groups.  Increased open-field
rearing was observed in the two highest dose groups.  The Low Adverse
Effect Level (LOAEL) was determined to be 1250 mg/kg-bw/day; a NOAEL
could not be determined from this study (Voorhees, et al., 1983). 

In a mouse study, animals (10/sex/group) were exposed to up to 1.68%
FD&C Red No. 40 in the diet over two generations (equivalent to 2400
mg/kg-bw/day). The study showed no significant, dose-related adverse
effects on reproduction or neurobehavioral endpoints following exposure
to FD&C Red No. 40 (Tanaka, 1994). 

In rats (group number not reported) dosed with FD&C Red No. 40 up to
0.7% in drinking water (equivalent to 939 mg/kg-bw/day) on g.d. 0-20, a
significant increase in the incidence of fetuses with reduced
ossification of the hyoid was observed at the highest dose level.  No
other fetal malformations were observed.  The NOAEL from this study was
determined to be 546 mg/kg-bw/day (Collins et al., 1989a).    

In rats dosed with FD&C Red No. 40 on g.d. 0-19 (group number not
reported), no significant, dose-related effects were observed at doses
up to 1000 mg/kg/day (Collins et al., 1989b).] 

  

<	4. Subchronic toxicity. [FD&C Red No. 40 was studied in rats, dogs and
pigs in the following short-term studies.

In rats, groups of 20 animals (10 males and 10 females per group) were
fed diets containing 0-2595 mg/kg-bw/day) for six weeks.  The NOAEL was
determined to be at least 2595 mg/kg-bw/day.  

Both of the dog studies were determined to be too limited to derive a
NOAEL.  

The pig study appeared to be a non-standard design.  Groups of 4 animals
(2 males and 2 females per group) were dosed with 1000 mg/kg-bw/day of
FD&C Red No. 40 for 21 days.  The dose was increased to 1500
mg/kg-bw/day for an additional 54 days.  No compound related effects
were reported.

>

<	5. Chronic toxicity. [The chronic toxicity/carcinogenicity of FD&C Red
No. 40 was studied in 5 key studies.  These are summarized in Table 2.  

In general, exposure to FD&C Red No. 40 did not result in significant
adverse effects.  In one mouse study, higher rates of early onset
lymphoma were observed in animals exposed to FD&C Red No. 40 (Serota et
al., 1977a).  However, this observation was not statistically
significant in this study and could not be replicated in a subsequent
study that used a higher number of animals per group (100 versus 50) and
an additional control group.  In general, the only significant effects
reported in these studies appeared to be growth suppression or body
weight reductions at high dietary doses used in these studies.]>

<	6. Animal metabolism. [The applicable studies were summarized in
JECFA, 1980.  In rats fed 5.19% FD&C Red No. 40 in the diet, only 0.1%
and 29% of the unmetabolized dye was found to be excreted in the urine
and feces, respectively.   Using 35S labeled FD&C Red No. 40, in dogs,
92-95% of the recovered radioactivity appeared in the feces and between
2.7 and 3.6% in the urine within 72 hours of administration.   In rats,
76-92% of the radioactivity was recovered in the feces and 5.7-19.8% in
the urine within the same timeframe.   Significant retention of the dye
was noted in the intestinal contents and in the washed intestines of
both species.  The total carcass and viscera of both species retained
only 0.4% of the total administered dose.  

FD&C Red No. 40 is absorbed to a limited extent and that the major route
of the excretion is through metabolic by-products eliminated through the
feces.  Urinary excretion is negligible.]>

<	7. Metabolite toxicology. [Cresidine-4-sulfonic acid was identified as
the major metabolite in the urine and feces of both rats and dogs along
with the parent compound and two unknown metabolites.  In the dog, an
additional unknown metabolite was observed in the feces and possibly the
urine.  Metabolism in the GI tract may occur though the reduction of the
azo group in the parent compound.]>

<	8. Endocrine disruption. [In the 2004 tolerance reassessment, EPA did
not make a formal determination as to whether FD&C Red No. 40 impacts
the endocrine system pending the outcome of assays under the Endocrine
Disrupter Screening Program.  Overt effects on the endocrine system were
not reported in the toxicological studies conducted on the FD&C Red No.
40.  

 M.  Aromatase catalyzes the conversion of androgens to estrogens and
presents a possible target for endocrine disrupting chemicals.  EFSA
concluded; however, that these data did not trigger a concern for FD&C
Red No. 40 since the chemical has limited systemic bioavailability and
that there was no evidence of related adverse effects in the various
reproduction studies conducted on the chemical.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [See below]>

<	i. Food. [Historically, FDA regulated sanitizer chemicals as indirect
food additives under the Federal Food, Drug and Cosmetic Act (codified
in 21 CFR §178.1010).  In 1993, FDA published guidance for assessing
dietary exposure to chemicals from sanitizing FDA described a tiered
assessment process for evaluating the safety of sanitizer solutions
based on where they are intended for use.  Solutions were approved for
use on food-contact surfaces in public eating places, dairy-processing
equipment and on food-processing equipment and utensils.  

The model developed for public eating facilities was considered
sufficiently conservative to assure the safe use of sanitizers on food
processing equipment in dairy and other industries [40 CFR §180.940 (b)
and (c)].  FDA considered this a worst-case assessment and if a chemical
was approved for use in public eating facilities, it could also be used
at similar concentrations on dairy processing equipment and food
processing equipment and utensils.

Upon passage of the Food Quality Protection Act in 1996, EPA assumed
responsibility for the regulation of sanitizers.  The regulations
governing the use of sanitizers are currently codified under 40 CFR
§180.940 and follow the basic FDA outline from 21 CFR §178.1010.

180.940 (a)- regulates chemicals used as ingredients in antimicrobial
pesticide formulation that are applied to food-contact surfaces in
public eating places, dairy-processing equipment, and food processing
equipment and utensils.

180.940 (b)-regulates chemicals used as ingredients in antimicrobial
pesticide formulations that are applied to dairy-processing equipment
and food processing equipment and utensils.

180.940 (c)-regulates chemicals used as ingredients in antimicrobial
pesticide formulations that are applied to food processing equipment and
utensils.

The exposure model published by FDA in 1993 was adopted by EPA in
modified form for dietary risk assessments conducted on antimicrobials
as part of Reregistration. For purposes of this assessment, we relied on
the dietary exposure models used by EPA in their review of Alkyl
Dimethyl Benzyl Ammonium Chloride (ADBAC) under Reregistration (Shamim,
2006). 

Public Eating Facilities

The EPA public eating facility model from the ADBAC Reregistration
Eligibility Decision (RED) is listed below. 

EDI (mg/p/day) = AR x RS x SA x F x 10-6

DDD (mg/kg/day) = AR x RS x SA x F x 10-6/BW 

EDI= Estimated Daily Intake 

DDD= Daily Dietary Dose

AR = Application rate (ppm)

RS = Residual solution (mg/cm2) = 1 mg/cm 2

SA = Surface area of the treated surface which comes into contact with
food (cm2)= 4000 cm2

F = Fraction of the pesticide transferred or migrated to food (unitless)
= 1

BW = Body weight (kg)

Consistent with FDA’s 1993 guidance, the model assumes that all of the
food consumed by a single individual in a day contacts 4000 cm2 of food
contact surface area.  This figure represents a total surface area of
dishes, eating utensils and drinking glasses used by a person eating 3
meals a day in an institutional or other public eating facility.  The
worst-case amount of sanitizer residue (use-solution) is presumed to be
1 mg/cm2.  

In the ADBAC RED, EPA slightly modified FDA’s original model to fit
their risk assessment requirements.  EPA converted the EDI to a “Daily
Dietary Dose” (DDD) by dividing the EDI by body weight.  The DDDs for
adult males (70kg), adult females (60 kg) and children (15 kg) were
determined.  EPA also incorporated a transfer factor (F), which is the
fraction of the chemical transferred or migrated to food. For ADBAC, the
Agency assumed that “F” equalled 10%.  

Countertops

In the ADBAC RED, EPA also includes a model for countertop exposures
from the use of these products as disinfectants at a higher
concentration of active ingredient.  This model is identical to the one
developed for public eating facilities except that it assumes that food
will come into contact with 2000 cm2 of countertop area per day. 
Diversey, Inc. incorporated this model into our assessment, assuming
that our products could be used to sanitize countertops that may
intentionally or inadvertently come into contact with food.

Dietary Exposure to FD&C Red No. 40 from Diversey, Inc. Products

Using EPA’s models as described in the ADBAC RED, we estimated the
dietary exposure to FD&C Red No. 40 from Diversey, Inc. sanitizer
products.  For purposes of this assessment, we assumed a concentration
of FD&C Red No. 40 of 20 ppm in the use-solution of the sanitizer
product.  For Diversey, Inc. products, the concentration of FD&C Red No.
40 in sanitizing use-solutions typically ranges from 0.1-0.4 ppm.  At
disinfecting concentrations (which require a potable water rinse), the
concentration range for FD&C Red No. 40 is from 0.2-3.1 ppm.

The use of 20 ppm is a worst-case scenario since it equals the maximum
amount present in the undiluted sanitizer product and is significantly
greater than the concentration of FD&C Red No. 40 in the actual
sanitizer use-solutions.

As our reference value, we relied on the ADI established by the
EFSA/FAO/WHO of 7 mg/kg-bw/day.  Since data were not available, we also
assumed that all of the FD&C Red No. 40 in the use-solution transferred
or migrated to food (F=1).]>

<	ii. Drinking water. [Sanitizer products are not intended to be added
to drinking water.  Therefore, direct exposure to FD&C Red No. 40 from
drinking water was not evaluated.  In the tolerance reassessment for
FD&C Red No. 40 published in 2004, EPA estimated that the amount of FD&C
Red No. 40 in the drinking water supply would be no greater than 1 ppb
from use of the colorant in conventional pesticides.  EPA concluded that
at this concentration in water, exposure to FD&C Red No. 40 would be
several orders of magnitude below current ADI’s.]>

<	2. Non-dietary exposure. [None expected.]>

<D. Cumulative Effects>

<	[When considering an exemption from the requirement of tolerance, the
Federal Food, Drug and Cosmetic Act requires consideration of the
cumulative effects of a particular pesticide residue under consideration
and in combination with other chemicals that share a common mechanism of
action.  EPA did not assume that FD&C Red No. 40 shared a common
mechanism of toxicity with any other substance in 2004, when the
tolerance for FD&C Red No. 40 in agricultural pesticides was reassessed.
 Currently, EPA has not made a common mechanism of toxicity finding for
FD&C Red No. 40 with any similar substances ( HYPERLINK
"http://www.epa.gov/pesticides/cumulative/"
http://www.epa.gov/pesticides/cumulative/ ).]>

<E. Safety Determination>

<	1. U.S. population. [Our analysis indicates that dietary exposure to
FD&C Red No. 40 at 20 ppm from use-solutions of sanitizers is only a
small fraction of the current ADI as established by FDA, the World
Health Organization and the European Food Safety Authority, for all
relevant age groups.   Our assessment is based on the FDA process,
modified by EPA, which has historically been used to assess dietary
exposure to sanitizer chemicals used in public eating establishments. 
The public eating establishment model is considered the worst-case
assessment of dietary exposure to sanitizer chemicals.  Therefore, these
results are also applicable to sanitizers containing FD&C Red No. 40,
when used on dairy-processing equipment and food processing equipment
and utensils.]>

<	2. Infants and children. [In the 2004 tolerance reassessment for FD&C
Red No. 40, EPA concluded that there was “no concern for potential
sensitivity to infants and children resulting from exposures to… FD&C
Red No. 40.” (EPA, 2004)

In 2007, a paper was published studying the effect on children of
dietary exposure to FD&C Red No. 40 in combination with three other
artificial food colors and the preservative, sodium benzoate, on
children. (McCann et al., 2007).  The authors reported increased
hyperactivity in the 8/9 year old children exposed to the food
dye/sodium benzoate mixture.  

In response, the Center for Science in the Public Interest (CSPI)
petitioned FDA in 2008 to ban eight of the nine approved food colorants
currently in use in the United States. The CPSI alleged that exposure to
food colorants causes hyperactivity and behavioral issues in some
children (CSPI, 2008).  

FDA initiated a review of the issue in response to the CSPI petition,
which culminated in a meeting of the Food Advisory Committee in March,
2011.  FDA prepared a comprehensive review of the available literature
on the possible effects of food colorants on children (FDA, 2010).  The
McCann study was also reviewed in detail (Sobotka, et al., 2010). 

Based on the information available, FDA concluded that a causal
relationship between exposure to color additives and hyperactivity in
children in the general population had not been established.  For
certain susceptible children with ADHD and other problem behaviors, the
FDA felt that the data suggested “these conditions may be exacerbated
by exposure to a number of substances in food, including, but not
limited to, artificial food colors.”  FDA also concluded that the
results of the cited studies indicate that the effects on behavior
appear to be due to “a unique intolerance to these substances and not
to any inherent neurotoxic properties.”   The Food Advisory committee
recommended that additional research be conducted on this subject. 

FDA’s decision is summarized in the background document prepared for
the March, 2011 meeting (FDA, 2011). EFSA also reviewed the overall
science (EFSA, 2010) on this topic and also conducted a detailed review
of the McCann study (EFSA, 2008).  Their conclusions were similar to
FDA.  In their 2008 review of the McCann study, EFSA drew the following
conclusions.  

The study provides limited evidence that the two different mixtures of
synthetic colors and sodium benzoate tested had a small and
statistically significant effect on activity and attention on some
children selected from the general population.

The effects were not observed for all children in all age groups and
were not consistent for the two mixtures.  

The clinical significance of the effects was unclear and it is not known
whether the small alterations in attention and activity would interfere
with schoolwork or other intellectual functioning.

Since only mixtures were studied, it is not possible to ascribe any of
the observed effects to any one of components of the mixture.  

The study was not sufficient to provide a basis to revise the existing
ADI (7 mg/kg-bw/day) based on the overall weight of evidence and the
relative weakness of the effects, and on the absence of information on
the clinical significance of the observed behavioral changes.

These conclusions were affirmed by EFSA in their overall reevaluation of
FD&C Red No. 40 as a food additive (EFSA, 2009).]>

<F. International Tolerances>

<	[United States Food and Drug Administration

FD&C Red No. 40 is permanently listed as a color additive for use in
food, drugs and cosmetics in the United States (21 CFR §74.340, Listing
of Color Additives Subject to Certification).  Certified versions of
this colorant are commercially available that meet FDA requirements as
specified under 21 CFR §70.25 (labelling), 21 CFR §80 (certification),
and 21 CFR §82.51 (specifications and labelling).

FDA does not specify an upper limit for the use of FD&C Red No. 40 in
food, only that it be used “generally in amounts consistent with good
manufacturing practices except that it may not be used to color foods
for which standards of identity have been promulgated under section 401
of the Act unless added color is authorized by such standards.”  

Consistent with other reviewing authorities (see below), FDA has
determined an ADI for FD&C Red No. 40 of 7 mg/kg-bw/day (FDA, 2011).

European Union (EU)

In the European Union, FD&C Red No. 40 is listed as Allura Red AC (E
129) on Annex 1 of Directive 94/36/EC, List of Permitted Food Colours. 
It is also approved for a number of specific food types under Annex III
of the Directive; “Foodstuffs to Which Only Certain Permitted Colours
may be Added.”(EU, 1994) 

Codex Alimentarius

The Codex Alimentarius is a joint program of the United Nations Food and
Agricultural Organization and World Health Organization.  The primary
goals of the Code are “protecting health of the consumers and ensuring
fair trade practices in the food trade, and promoting coordination of
all food standards work undertaken by international governmental and
non-governmental organizations.”  

The current approved food uses of FD&C Red No. 40 as listed in the code
are included in the attached reference (Codex, 2010). 

European Food Safety Authority

EFSA. Scientific Opinion on the re-evaluation of Allura Red AC (E 129)
as a food additive.  EFSA Journal.  7(11): 1327.  Accessed 1-24-2011 at 
HYPERLINK "http://www.efsa.europa.eu/en/efsajournal/pub/1327.htm"
http://www.efsa.europa.eu/en/efsajournal/pub/1327.htm  .

The EFSA, 2009 review on FD&C Red No. 40 is the most recent full
analysis of the safety of FD&C Red No. 40.  In their review, EFSA
reaffirmed the FAO/WHO acceptable daily intake of 0-7 mg/kg-bw/day.

2010- European Food Safety Authority (EFSA)- Scientific Opinion on the
appropriateness of the food azo-colours Tartrazine (E 102), Sunset
Yellow FCF (E 110), Carmoisine (E 122), Amaranth (E 123), Ponceau 4R (E
124), Allura Red AC (E129), Brilliant Black BN (E151), Brown FK (E 154),
Brown HT (E 155) and Litholrubine BK (E 180) for inclusion in the list
of food ingredients set up in Annex IIIa of Directive 2000/13/EC.  
Accessed 2-4-2011 at  HYPERLINK
"http://www.efsa.europa.eu/en/efsajournal/pub/1778.htm"
http://www.efsa.europa.eu/en/efsajournal/pub/1778.htm .

Upon the request of the European Commission, the EFSA was asked to
provide a scientific opinion on the potential of food azo-colors to
cause intolerance and/or allergic reactions in humans following oral
exposure.  The Panel concluded that “it is unlikely that oral
consumption of the food colours under consideration, either individually
or in combination would trigger severe adverse reaction in human
subjects at current levels of use.”  Based on their review of the
literature, they found no data linking FD&C Red No. 40 to any
sensitivity or intolerance reactions while acknowledging that lack of
clinical awareness may result in an unknown degree of under-reporting.

European Scientific Committee for Food (SCF)

Scientific Committee for Food.  Reports of the Scientific Committee for
Food.  Fourteenth Series.  EUR 8752 EN.  1983.  pp. 52-53.   Accessed
1-24-2011 at  HYPERLINK
"http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_14.pdf"
http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_14.pdf  .

The SCF established an ADI of 0-7 mg/kg-bw/day based on the review
conducted by the Joint FAO/WHO Expert Committee on Food Additives at
their 25th meeting (see below).

Scientific Committee for Food.  Reports of the Scientific Committee for
Food. Twenty-First Series.  EUR 11617 EN.  1989.  p. 4.  Accessed
1-24-2011 at  HYPERLINK
"http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_21.pdf"
http://ec.europa.eu/food/fs/sc/scf/reports/scf_reports_21.pdf  .

The SCF maintained the ADI of 0-7 mg/kg-bw/day established in 1983.

Joint FAO/WHO Expert Committee on Food Additives (JECFA)

Joint FAO/WHO Expert Committee on Food Additives.  (WHO Food Additive
Series 6). Toxicological Evaluation of Some Food Colours, Enzymes,
Flavour Enhancers, Thickening Agents, and Certain Food Additives.  WHO
Food Additives Series 6.  1975.  Accessed 1-24-2011 at  HYPERLINK
"http://www.inchem.org/documents/jecfa/jecmono/v06je07.htm"
http://www.inchem.org/documents/jecfa/jecmono/v06je07.htm  

In 1974, the JECFA conducted a review on FD&C No. 40 (Allura Red AC) but
was unable to determine an ADI because of gaps in the toxicology data
package.

Joint FAO/WHO Expert Committee on Food Additives (JECFA).  (WHO Food
Additive Series 15).  Allura Red AC.  Accessed 1-24-2011 at  HYPERLINK
"http://www.inchem.org/documents/jecfa/jeceval/jec_55.htm"
http://www.inchem.org/documents/jecfa/jeceval/jec_55.htm 

 HYPERLINK "http://www.inchem.org/documents/jecfa/jecmono/v15je02.htm"
http://www.inchem.org/documents/jecfa/jecmono/v15je02.htm 

Upon receipt of the data requested in their 1974 review, the JECFA
established a temporary ADI of 0-7 mg/kg-bw/day for FD&C Red No. 40
(Allura Red AC). 

Joint FAO/WHO Expert Committee on Food Additives (JECFA). Evaluation of
certain food additives.  Twenty-Fifth Report of the Joint FAO/WHO Expert
Committee on Food Additives.  WHO Technical Report Series 669.  1981. 
p. 18.   Accessed 1-24-2011 at  HYPERLINK
"http://whqlibdoc.who.int/trs/WHO_TRS_669.pdf"
http://whqlibdoc.who.int/trs/WHO_TRS_669.pdf  .

In this document, the JECFA made permanent the recommended ADI of 0-7
mg/kg-bw/day from WHO Food Additive Series 15.]>

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