# 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 ]**  **INSTRUCTIO**

**NS: 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. Simp ly 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 16**  **th 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 r esidues of**  **F D&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 e lements set forth in section 408 (d)(2) of FDDCA; however, EPA has not full y 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 Num ber 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** 2

**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 a s 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 m eet 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 pri mary 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 foo d, 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 sani** **tize 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. Ac**  **cumulation 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 in**  **corporated 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 sani** **tize 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**3

**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%). The primary dietary exposure to FD&C Red No. 40 will occur from the transfer of**  **the chemical residues from the food contact surface into food during processing. Both FDA and EPA assume, in the absence of the other data, that the**  **am ount of**  **residue left behind after sanitizing and draining is 1 mg of use -**  **solution per cm 2**  **of food contact surface. Assuming 20 ppm of FD&C Red No. 40 in the use**  **- solution,**  **this corresponds to a maximum residue concentration of 2 g FD&C Red N**  **o. 40 per cm**  **2 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 dis charged 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 N o. 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 i s 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 disc**  **harged 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 t he 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 referen ces 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. Othe** **r 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.” ]** 4

2. Genotoxic i ty. **[ EF**  **SA cited reviews by th e 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 con clusion 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 relat**  **ed 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. **[ Rele** **vant 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 typ**  **e 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 25 95 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 e**  **ffects 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)**5

**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 o f 0, 1250, 2500 and 5000 mg/kg** **- bw/day). Litter**  **mo rtality 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 o**  **bserved 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 d ose 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 -**  **stan dard 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**6

**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, high er 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 num ber 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. A nimal 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 35**  **S 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 s ame 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 abs**  **orbed 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**  **metab olite 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. EFSA, 2009, reported that FD&C Red No. 40 was able to inhibit aromatase activity**  **in an in vit** 

**ro rat ovarian microsome system with an IC**  **50 of 24**  **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**7

**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 equipme nt 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 p**  **assage 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) -**  **regula tes 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 assessmen t, 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** 8

**The EPA public eating facility model from the ADBAC Reregistration El igibility**  **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/cm**  **2 ) = 1 mg/cm**  **2 SA = Surface area of the treated surface which comes into contact with food (cm**  **2 )=**  **4000 cm 2**  **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 al l of the food**  **consumed by a single individual in a day contacts 4000 cm 2**  **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/cm**  **2**

**. In the ADBAC RED, EPA slightly modified FDA’s original model to fit their risk**  **assessment requirements. EPA converted the EDI to a “Da ily 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 mig rated 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 mo del is identical to the one developed for public eating facilities except that it**  **assumes that food will come into contact with 2000 cm 2**  **of countertop area per day. Diversey, Inc. incorporated this model into our assessment, assuming that our**  **products cou ld 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),** 9

**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. The refore, 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 c hemicals 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 (**  **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 r elevant 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. ]** 10 2. Infan ts 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 CPS**  **I 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 Mar**  **ch, 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 c oncluded 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 su ggested “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 pre**  **pared for the March, 2011 meeting (FDA, 2011).**  **EF SA 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**  **McC ann 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 childre**  **n 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**11 **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 conc**  **lusions 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 us e 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 (labellin g),**  **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 th**  **at 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**  **A DI 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 spec**  **ific 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 -**  **governm ental 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**12

**1. 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**  **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.**  **2. 2010**  **- European Food Safety Authority (EFSA)**  **- Scientific Opinion on the**  **appropriateness of the food azo -**  **colours Tart razine (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 ingredien**  **ts set up in Annex IIIa of Directive 2000/13/EC. Accessed 2 -**  **4 -**  **2011 at**  **http://www.efsa.europa.eu/en/efsajournal/pub/1778.htm .**  **Upon the request of the European Commission, the EFSA was as ked 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 consideratio n, 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 whi le**  **acknowledging that lack of clinical awareness may result in an unknown degree of under** **- reporting.**  **European Scientific Committee for Food (SCF) 1.**  **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 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 c**  **onducted by the Joint FAO/WHO Expert Committee on Food Additives at their 25**  **th meeting (see**  **below). 2.**  **Scientific Committee for Food. Reports of the Scientific Committee for Food. Twenty** **- Fi**  **rst Series. EUR 11617 EN. 1989. p. 4. Accessed 1 -**  **24 -**  **2011 at**  **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) 1.**  **Joint FAO/WHO Expert Committee on Food Additives. (WHO Food Additive Series 6). Toxicological Evaluation of Some Food Colours, Enzymes,** 13 **Flavour Enhancers, Thickening Agents, and Certain Food Additives. WHO Food Additives Series 6. 1975. Accesse**  **d 1 -**  **24 -**  **2011 at 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 becau**  **se of gaps in the toxicology data package. 2.**  **Joint FAO/WHO Expert Committee on Food Additives (JECFA). (WHO Food Additive Series 15). Allura Red AC. Accessed 1**  **- 24**  **- 2011 at**  **http://www.in chem.org/documents/jecfa/jeceval/jec_55.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). 3.**  **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 Tec hnical Report Series 669.**  **1981. p. 18. Accessed 1 -**  **24 -**  **2011 at 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 f rom WHO Food Additive Series 15.**  **]**