Document ID: EPA-HQ-OPP-2012-0572-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-11-07T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                       
                                                                               
                                                                               
                                                     OFFICE OF CHEMICAL SAFETY 
                                                       AND POLLUTION PREVENTION
                                                                               
                                                                               
                                       

May 9, 2014

MEMORANDUM

SUBJECT:	Decision Document for Petition Number 1E7843:  FD&C Red No. 40 (CAS Reg. No. 25956-17-6); Human Health Risk Assessment and Ecological Effects Assessment for Proposed Exemption from the Requirement of a Tolerance When Used as an Inert Ingredient in Pesticide Formulations.

            PC Code:				911363
      DP Barcode: 				N/A
            Decision No.:				N/A
      Regulatory Action:			 Inert Tolerance Exemption
							40 CFR 180.940(a)
      Petition No.:				1E7843
      All CAS Reg. Nos:			25956-17-6
      Inert Tracking No			N/A

FROM:	Roger Chesser, Biologist
		Inert Ingredient Assessment Branch (IIAB)
		Registration Division (7505P)

THRU:	Kerry Leifer, Team Leader
      Inert Ingredient Assessment Branch (IIAB)
      Registration Division (7505P)

TO:		P.V. Shah, Chief
		Inert Ingredient Assessment Branch (IIAB)
		Registration Division (7505P)

Table of Contents

Executive Summary
I.	Background	4
II.	Inert Ingredient Profile	5
III.	Human Health Assessment	6
A.	Summary of Toxicity Data	6
B. Toxicity Endpoint Selection	13
C. Special Consideration for Infants and Children	13
IV. Exposure Assessment	13
V. Aggregate Risk and Determination of Safety	13
Acute Dietary Risk	13
Chronic Dietary Risk	14
Aggregate Cancer Risk for U.S. Population	14
Short-Term Aggregate Risk	14
Intermediate-Term Aggregate Risk	14
Determination of Safety	14
VI. Occupational Exposure / Risk Pathway	14
Occupational Handler Risk	15
Occupational Post-Application Risk	15
*	Exposure Scenarios	15
VII. Cumulative exposure	16
VIII. Environmental Justice Statement	16
IX. Environmental Fate Considerations	17
X. Ecotoxicity	17
XI. Risk Characterization	17
References	18

Executive Summary

      Diversey, Inc. (8310 16[th] Street, MS 707, Sturtevant WI 53177-1964)  submitted a petition (1E7843) to establish an exemption from requirement of a tolerance, pursuant to section 408 of the Federal Food, Drug, and Cosmetic Act, for the use of FD&C Red No. 40 as an antimicrobial pesticide formulation inert ingredient (colorant) in food contact surface sanitizer products under 40 CFR §180.940 (a) at a maximum level in the end-use concentration of 20 parts per million (ppm).  The majority of the data in this risk assessment decision document have been taken from the tolerance reassessment document for FD&C Red No. 40 dated December 21, 2004 (MRID 48779801) evaluating its use as an inert ingredient in pesticide formulations applied to growing crops and raw agricultural commodities after harvest (40 CFR 180.910), and to growing crops only (pre-harvest seed treatment) (40 CFR 180.920).
	  The reassessment document also summarized available information on the use, physical/chemical properties, toxicological effects, exposure profile, environmental fate, and ecotoxicity of FD&C Red No. 40, including data considered by the Joint Expert Committee on Food Additives of the Food and Agriculture Organization/World Health Organization (FAO/WHO) Expert Committee on Food Additives (JECFA) (MRIDs 48779804 and 48779805) as well as the European Food Safety Authority (EFSA) (MRID 48779803).    As summarized in that reassessment document, all toxicological studies were conducted at the limit dose or close to limit dose. No adverse toxicological effects were detected at these doses. A residential risk assessment was not performed since there are no residential uses.  No endpoint of concern was identified in the database.  

      FD&C Red No. 40 is a FDA permanently listed color additive used in food, drugs and cosmetics, including drugs and cosmetics for eye area. The FDA's color additive evaluation included the consideration of an extensive set of toxicological data on FD&C Red No. 40.  FDA concluded that this colorant was safe and established a maximum acceptable daily intake for FD&C Red No. 40 of 7 mg/kg-bw/day.  Similarly, JECFA and SCF have evaluated FD&C Red No. 40 for the purpose of establishing estimates of acceptable daily intake (ADI) as a food additive.   

      The JECFA and SCF evaluations of FD&C Red No. 40 included reviews of an extensive set of toxicological data including genotoxicity, chronic toxicity /carcinogenicity and reproductive and developmental toxicity.  Both evaluations concluded that the available data demonstrated that no adverse effects were seen in studies at limit dose levels. No hazard was identified in any of the data evaluated by JECFA for FD&C Red No. 40 at the limit dose of 1000 mg/kg/day to either parental animals or their offspring.  Acute oral toxicity was low based on studies with rats (LD50 > 10000 mg/kg bw). Based on other acute oral toxicity studies with rabbits and dogs, JECFA set the the LD50 values at > 10000 mg/kg bw and 5000 mg/kg bw, respectively.  The JECFA evaluation resulted in the establishment of an ADI of 7.0 mg/kg/day based on a chronic oral toxicity study in rats in which the no-observed-adverse-effect level (NOAEL) was 695 mg/kg/day (highest dose tested) with a safety factor of 100. (JECFA evaluation based upon Serota et al, 1977, as cited in JEFCA, 1980)  The JECFA and SCF evaluations of FD&C Red No. 40 established ADIs of 7.0 mg/kg/day based upon a chronic dietary toxicity study in rats in which the no-observed-adverse-effect level (NOAEL) was 750  mg/kg/day (highest dose tested) with a safety factor of 100.  
      
      More recently, the European Food Safety Authority (EFSA) has reevaluated FD&C Red No. 40 and concluded that the present database does not give reason to revise the ADI of 7.0 mg/kg bw/day.  As a result of these extensive evaluations of FD&C Red No. 40, in which either no adverse effects were noted, or the effects of single or repeated dosing were observed only at levels beyond the respective limit doses, EPA has utilized a qualitative approach to assessing human health risks from exposure to FD&C Red No. 40.  No hazard endpoint of concern was identified for the acute and chronic dietary assessment (food and drinking water), or for the short, intermediate, and long term residential assessments (via all exposure routes), therefore, acute and chronic dietary and short-, intermediate, and long-term residential exposure assessments were not performed.  
	
	Thus, due to its low potential hazard and the lack of a hazard endpoint, it has been determined that a quantitative risk assessment using safety factors applied to a point of departure protective of an identified hazard endpoint is not appropriate for FD&C Red No. 40 and an FQPA safety factor is not needed to protect the safety of infants and children.  
      
      Residues of concern are not anticipated for dietary exposure (food and drinking water) or for residential exposure from the use of FD&C Red No. 40 for the proposed use pattern as an inert ingredient in pesticide products. EPA expects aggregate exposure to FD&C Red No. 40 to pose no appreciable dietary risk given that the data on FD&C Red No. 40 show a lack of any systemic toxicity at limit dose levels and a lack of any apparent developmental effects (SIDS).  
      
      Taking into consideration all available information, EPA concludes that there is a reasonable certainty of no harm to the general population or to infants and children from aggregate exposure to FD&C Red No. 40 when used as an inert ingredient in pesticide formulations.  Therefore, the establishment of an exemption from the requirement of a tolerance under 40 CFR 180.940 (a) for FD&C Red No. 40 can be considered safe under section 408 of the FFDCA.  
      
I. Background

Diversey, Inc. (8310 16[th] Street, MS 707, Sturtevant WI 53177-1964) is requesting EPA to establish a tolerance exemption for FD&C Red No. 40, CAS #: 25956-17-6 for use as an antimicrobial pesticide formulation inert ingredient (colorant) in no-rinse, food contact surface sanitizer products under 40 CFR § 180.940(a) at a maximum level in the end-use concentration of 20 parts per million (ppm). 

In addition to the EPA approved uses as an inert ingredient in pesticides, FD&C Red No. 40  is approved by the Food and Drug Administration (FDA) as a color additive in food products as specified at 21 CFR §74.340, for use in drugs at 21 CFR §74.1340 and for use in cosmetics at 21 CFR §74.2340. It is permanently listed as safe for general use in these products.  

      EPA completed reassessment of the current established tolerance exemption FD&C Red No. 40 in December 2004. The Agency concluded that taking into consideration all available information, including the extensive toxicology database in which no adverse effects were noted, the low toxicity, the lack of risk concerns from usage as color additives, and the low exposures likely to result from uses as pesticide active ingredients, that there was reasonable certainty of no harm to any population subgroup from aggregate exposure to FD&C Red No. 40 , considering dietary and all other non-occupational exposures.  
      
      The European Food Safety Authority (EFSA); Panel on Food Additives and Nutrient Sources added to Food also reevaluated the safety of FD&C Red No. 40 as a food coloring additive and published their scientific opinion in 2009.  They concluded that no revisions to the current established ADI of 7 mg/kg/bw were needed.  
      
      Taking into consideration all available information, EPA concludes that there is a reasonable certainty of no harm to the general population or to infants and children from aggregate exposure to FD&C Red No. 40 when used as an inert ingredient in pesticide formulations.  Therefore, the establishment of an exemption from the requirement of a tolerance under 40 CFR 180.940(a) for FD&C Red No. 40 can be considered safe under section 408 of the FFDCA.  
II.	Inert Ingredient Profile

   A. Summary of  Uses
 FD&C Red No. 40 is 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).

   B. Physical and Chemical Properties
Some of the physical and chemical characteristics of FD&C Red No. 40, along with its structure and nomenclature follow:
      
      Source ChemIDplus Lite
            Chemical Name: FD&C Red No. 40
            CAS No.:  25956-17-6
            Molecular Formula: C18-H16-N2-O8-S2.2Na   
            Structure: 
      
      Source SRC, 2004:
            Molecular Weight:  496.427
            Water solubility: 2.25 x 10[5]  mg/L at 25° C (M)
            Octanol-water Partition Coefficient (Kow)  log Kow= -0.550 (E)
            
            Source:  (MPBPVPWIN EPI Suite, 2000 as cited by IACM, 2003)
            MP:  350 C  
            Vapor pressure: 1.25 x 10[5] mm Hg @  25° C
            Henry's Law Constant:  1 x 10-15 atm-m3/mole @ 25°C (estimated)
            
            Based on the above data, FD&C Red No. 40 has the following physicochemical profile:
               * Water soluble
               * Nonvolatile

III.	Human Health Assessment

   A. Summary of Toxicity Data

	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) of 07 mg/kg-bw/day.(JECFA, 1981).  
Acute oral toxicity. 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." 
 
 Dermal Toxicity Tests for dermal irritation in rabbits on intact and abraded skin showed no gross irritation at levels of .316, 1,03,16 abd 10 g/kg b/w of Allura Red. Daily applications of the color at rates of (JECFA, 1980 )

 Inhalation Toxicity. No studies available in the database.

 Primary Eye Irritation. No studies available in the database.
 
Table  1.    Acute Toxicity Profile of  FD&C Red No. 40 
                                       
                                  Study Type
                                       
                                    Results
                               Toxicity Category
                                       
                              MRIDs # /Reference
Acute Oral - rat
LD50 > 10,000 mg/kg bw 
                                      IV
                                48779804; JECFA
                                     1981
Acute Oral - rabbit
LD50 > 10,000 mg/kg bw 
                                      IV
                                48779804; JECFA
                                     1981
Acute Oral - dog
LD50 = 5,000 mg/kg bw 
                                      III
                                48779804; JECFA
                                     1981
Acute Oral - mice
LD50 > 2,000 mg/kg bw 
                                      IV
                                48779804; JECFA
                                     1981
Primary Skin Irritation - rabbit
Minimal to mild irritation 
                                      IV
                                48779804; JECFA
                                     1981

 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.

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).

 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.

 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.

  Metabolism and Pharmacokinetics. 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 the major route of excretion is through metabolic by-products eliminated through the feces.  Urinary excretion is negligible.

 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 through the reduction of the azo group in the parent compound.

 EFSA, 2009, reported that FD&C Red No. 40 was able to inhibit aromatase activity in an in vitro rat ovarian microsome system with an IC50 of 24M.  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.
 
Table 1: Summary of Reproductive and Developmental Toxicity Studies Conducted on FD&C Red No. 40 based on EFSA, 2009.
Reference
Study Type
Species
Duration
Dose
Summary
NOAEL
Blackmore et al., 1969
Reproduction (multi-generation)

Rat
10 male
10 female
Mating occurred after 27 weeks of exposure
0, 0.37, 0.72, 1.39 or 5.19 % in the diet.  Equivalent to 0, 185, 360, 695 and 2595 mg/kg-bw/day as recalculated by Borzelleca et al., 1991.)
Fertility indices for both filial generations were decreased in both treated and control groups.  Slight growth suppression was observed in high dose pups.  No other anomalies in regards to fertility, fetal development, teratology or pathology were observed.  
695 mg/kg- bw/day based on the slight growth suppression observed in F1 and F2 pups in the 2595 mg/kg- bw/day dose group.[a] 
Collins et al., 1974
Teratology
Rat
Gestation Day
0-19
0, 15,30, 100 and 200 mg/kg-bw/day
No compound related effects were observed.
200 mg/kg- bw/day
Reno, 1974
Teratology
Rabbit
Gestation Day
 6-18
0, 200 and 700 mg/kg-bw/day
No compound related effects were observed.
700 mg/kg- bw/day
Serota et al., 1977a; JECFA, 1980
Chronic
Mouse

50/sex/
group
Lifetime
0, 0.37, 1.39 and 5.19% in the diet 

(equivalent to 0, 507, 1877 and 7422 mg/kg-bw/day in male mice and 0, 577, 2043 and 8304 mg/kg-bw/day in female mice- as recalculated by Borzelleca et al., 1991).  
Animals were exposed through gestation and lactation.  At the highest dose levels, decreased body weight, organ weights and effects on organ/body weight were observed.   No significant compound related effects were observed.

The NOEAL was 5.19% in the diet, which is equivalent to: 
Males- 7422 mg/kg-bw/day
Females- 8304 mg/kg-bw/day
Reno, et al., 1978.  Later published in Borzelleca, 1991
Chronic
Mouse
100/sex/
group
Two negative control groups
Lifetime
0, 0.37, 1.39 and 5.19% in the diet (equivalent to 0, 492, 1821 and 7318 mg/kg-bw/day in male mice and 0, 526, 2057 and 8356 mg/kg-bw/day in female mice- as recalculated by Borzelleca et al., 1991). 
Sporadic changes in clinical signs, body weight, adrenal weights (both absolute and relative), food consumption and survival rates were observed.  None of the changes were significant or followed a dose-response relationship.

The NOEAL was 5.19% in the diet which is equivalent to Males- 7318 mg/kg-bw/day
Females- 8356 mg/kg-bw/day
Serota et al., 1977b; later published as Borzelleca et al., 1989)

Chronic with breeding
Rat
50/sex/
group
Lifetime- 118-121 weeks
0, 0.37, 1.39 and 5.19% Allura Red AC in the diet (equivalent to 180, 701 and 2829 mg/kg- bw/day for male and 0, 228, 901 and 3604 mg/kg-bw/day for female rats- as recalculated by Borzelleca et al., 1989)
Administration started throughout parental breeding, gestation and lactation, and lasted for 118 and 121 weeks for male and female rats, respectively.

In females, mean body weights and growth rates were significantly decreased (-12.5%) at 3604-m/kg bw/day.  

Some abnormalities in gross pathological and histopathological appearance of the kidney were observed in groups fed FD&C Red No. 40. There was no observed dose-response relationship. 

No compound-related adverse effects were observed, except for a reduction in body weight in high-dosed females at the end of the study. Borzelleca et al. (1989).
NOAELs in this study were 5.19% (2829 mg/kg-bw/day) for male rats and 1.39 % (901 mg/kg-bw/day) for female rats.[b]

Voorhees et al., 1983- from Tema Nord, 2004.
Multi-generation-2
Rat
Group number not recorded.
Not specified.
0, 2.5, 5 or 10%  FD&C Red No. 40 in the diet (equivalent to  0, 1250, 2500 and 5000 mg/kg-bw/day, respectively).  
Reproductive success (dams producing litters) was reduced at all dose levels but effect was not dose-related.  Litter mortality was increased between 22-24 days of age at a concentration of 10% in the diet.  Significantly decreased running wheel activity as observed in all exposed groups.  Increased open-field rearing was observed in the two highest dose groups. (Voorhees  et al., 1983). 

The LOAEL was determined to be 1250 mg/kg-bw/day. A NOAEL could not be determined from this study.
Tanaka, 1994
Multi-generation (2)
Mouse
10/sex/
group

0, 0.42, 0.84 or 1.68% in the diet (equivalent to 0, 600, 1200 and 2400 mg/kg-bw/day).  
Animals showed no significant, dose-related adverse effects on reproduction or neurobehavioral endpoints following exposure to FD&C Red No. 40.  
The NOAEL was determined to be 2400 mg/kg-bw/day.  No LOAEL could be determined.
Collins et al., 1989a
Teratology
Rat
Group number not recorded.
G.d. 0-20
0, 0.2, 0.4 or 0.7% in drinking water (equivalent to 0, 241, 546 and 939 mg/kg-bw/day). 
A significant increase in the incidence of fetuses with reduced ossification of the hyoid was observed at the highest dose level.  No other fetal or maternal effects were observed.  
The NOAEL from this study was determined to be 546 mg/kg-bw/day.    

Collins et al., 1989b
Teratology
Rat
G.d. 0-19
0, 30, 75, 150, 300, 600 and 1000 mg/kg-bw/day by gavage.
No significant, dose-related effects were observed at doses up to 1000 mg/kg-bw/day.  
The NOAEL from this study was determined to be 1000 mg/kg-bw/day.
 
B. Toxicity Endpoint Selection

No toxicological endpoints have been identified for FD&C Red No. 40 due to no adverse observable effects seen in toxicity studies at or above limit dose levels.  
C. Special Consideration for Infants and Children

      At this time, there is no concern for potential sensitivity to infants and children resulting from exposures to FD&C Red No. 40.  There is no reported quantitative or qualitative evidence of increased susceptibility of rat fetuses to in utero exposure to FD&C Red No. 40 in developmental toxicity studies in rats. No quantitative or qualitative evidence of increased susceptibility has been reported following the pre/postnatal exposure to rats in 2-generation reproduction toxicity studies in rats.  Given the lack of adverse toxicological effects at limit dose levels, a safety factor analysis has not been used to assess the risk.  For these reasons the additional tenfold safety factor is unnecessary.
IV. Exposure Assessment

      No hazard endpoint of concern was identified for the acute and chronic dietary assessment (food and drinking water), or for the short, intermediate, and long term residential assessments (via all exposure routes), therefore, acute and chronic dietary and short-, intermediate, and long-term residential exposure assessments were not performed for FD&C Red No. 40.  In addition, exposures to FD&C Red No 40 resulting from its use as an inert ingredient in pesticide formulations would be orders of magnitude less than the ADI's established for FD&C Red No. 40 by FDA/JECFA/SCF.

V. Aggregate Risk and Determination of Safety

      EPA determines whether acute and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the aPAD and cPAD.  The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate safety factors (SFs).  EPA calculates the aPAD and cPAD by dividing the POD by all applicable UFs.  For linear cancer risks, EPA calculates the probability of additional cancer cases given the estimated aggregate exposure.  Short-, intermediate, and chronic-term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the POD. The MOE is the product of all applicable UFs and should not be exceeded.  

Acute Dietary Risk  
         
An acute aggregate risk assessment takes into account exposure estimates from acute dietary consumption of food and drinking water using the exposure assumptions discussed in section IV for acute exposure and the use limitations in pesticide formulations. There was no hazard attributable to a single exposure seen in the toxicity database for FD&C Red No. 40; therefore an acute aggregate risk assessment is not required.   
 
Chronic Dietary Risk
          
A chronic aggregate risk assessment takes into account exposure estimates from chronic dietary consumption of food and drinking water using the exposure assumptions discussed in section IV for chronic exposure and the use limitations in pesticide formulations.  There was no hazard attributable to chronic exposures in the toxicity database for FD&C Red No. 40; therefore a chronic aggregate risk assessment is not required.

Aggregate Cancer Risk for U.S. Population
          
The Agency has not identified any concerns for carcinogenicity relating to FD&C Red No. 40; therefore, a cancer dietary exposure assessment was not performed and an aggregate risk assessment is not a concern.

Short-Term Aggregate Risk
         
 Short-term aggregate exposure takes into account short-term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). FD&C Red No. 40 is used as an inert ingredient in pesticide products that are currently registered for uses that could result in short-term residential exposure however no adverse effects were attributable to short-term exposure to FD&C Red No. 40 were seen in the toxicity database; therefore, a short-term aggregate risk assessment is not required. 

Intermediate-Term Aggregate Risk
         
Intermediate-term aggregate exposure takes into account intermediate-term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). FD&C Red No. 40 is used as an inert ingredient in pesticide products that are currently registered for uses that could result in intermediate-term residential exposure however no adverse effects were attributable to intermediate-term exposure to FD&C Red No. 40 were seen in the toxicity database; therefore, an intermediate-term aggregate risk assessment is not required. 

      Determination of Safety
         
 EPA concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to residues of FD&C Red No. 40.
VI. Occupational Exposure / Risk Pathway

The representative occupational scenarios selected by the Agency for assessment are evaluated based on likely maximum application rates for products which may contain the inert ingredient for the short-term exposure assessment, and average application rates for products likely to contain the inert ingredient for the intermediate- and long-term exposure durations.  Active ingredient application rates are corrected for the maximum amount of inert ingredient likely to be in the final formulations to determine exposure and risk from exposure to the inert ingredient by fungicide, insecticide or herbicide.  

RD traditionally considers a level of concern (LOC) for these risk assessments to be an MOE of 100 based on the standard 10X inter and 10X intra species extrapolation safety factors and additional uncertainty in the database.

Occupational Handler Risk
         
   * Exposure Scenarios

Due to the absence of dermal and inhalation toxicity endpoints, occupational handler risks are not of concern.  Therefore an occupational handler risk assessment was not performed.
      
Occupational Post-Application Risk
   * Exposure Scenarios

RD uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure. Inhalation exposures are not typically calculated for occupational post-application scenarios because inhalation exposures generally account for a negligible percentage of the overall body burden for most pesticide chemicals.  
	
Due to the absence of dermal and inhalation toxicity endpoints, occupational post-application risks are not of concern. Therefore an occupational post-application risk assessment was not performed.
VII. Cumulative exposure
 
Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity."

EPA has not found FD&C Red No. 40 to share a common mechanism of toxicity with any other substances, and that FD&C Red No. 40 does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that FD&C Red No. 40 does not have a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see EPA's website at http://www.epa.gov/pesticides/cumulative.
      
VIII. Environmental Justice Statement
      Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, RD estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.
IX. Environmental Fate Considerations

      FD&C Red No. 40 is water soluble, mobile and not readily biodegradable. It is essentially nonvolatile; volatilization from soils and water is not likely to be a transport process in the environment.
      
      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 Red No. 40 as an inert ingredient in pesticide formulations is 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, the ultimate concentration of FD&C Red No. 40 discharged by a waste-water treatment facility to the environment would be negligible 

X. Ecotoxicity

There are no available aquatic toxicity studies on FD&C Red No. 40 (ECOTOX, 2002), however, based on estimates of toxicity using physical and chemical property data, FD&C Red No. 40 would be of low concern for toxicity to fish, algae, and aquatic invertebrates as well as terrestrial/benthic organisms (ECOSAR, 2000).

XI. Risk Characterization

      No toxicological endpoints have been identified for FD&C Red No. 40 due to no adverse observable effects seen in toxicity studies at doses at or above limit dose levels . 

The toxicity database for FD&C Red No. 40 is adequate for FQPA assessment and the potential exposure is adequately characterized given the low toxicity of the chemical. No hazard was identified and there is no residual uncertainty regarding prenatal and/or postnatal toxicity.  No acute or subchronic neurotoxicity studies are available, but there were no clinical signs of neurotoxicity or any systemic toxicity observed in the available database at doses up to and exceeding limit dose levels.  No developmental or reproductive effects were seen in the available studies at doses at or above limit dose levels. Based on this information, there is no concern, at this time, for increased sensitivity to infants and children to FD&C Red No. 40 when used as a component of food contact sanitizing solutions applied to all food contact surfaces and a safety factor analysis has not been used to assess risk. For the same reason, EPA has determined that an additional safety factor is not needed.  The Agency believes that any exposure to FD&C Red No. 40 used as an inert ingredient in pesticide formulations would occur at a level much lower then an effect level noted in animal studies.  

      EPA has determined that the available data supports an exemption from the requirement of a tolerance for residues of FD&C Red No. 40 (CAS Reg. No 25956-17-6) as a pesticide inert ingredient (dye) in antimicrobial formulations in accordance with 40 CFR 180.940 (a) as requested by the petitioner. There is a reasonable certainty that no harm to any population subgroup will result from FD&C Red No. 40 when used as inert ingredient in pesticide antimicrobial formulations applied to food contact surfaces in public eating places, dairy processing equipment, food processing equipment and utensils, as result of aggregate exposure.  Therefore, it is recommended that a tolerance exemption for FD&C Red No. 40 (CAS Reg. No. 25956-17-6) be established for use as an inert ingredient (dye), limited to 20 ppm, in antimicrobial formulations under 40 CFR 180.940(a), which includes use on food contact surfaces in public eating places, dairy processing equipment and food processing equipment and utensils.  

References

ChemIDplus, 2004, ChemIDplus Advanced. U.S. National Library of Medicine. National Institutes of Health. Department of Health and Human Services. Online Search Database http://chem.sis.nlm.nih.gov/chemidplus/
Search terms: FD&C Red No. 40. (May 7, 2014)

ECOSAR. 2000.  Ecological Structure Activity Relationships Version 0.99g.  Environmental Protection Agency. 

ECOTOX.   U.S. Environmental Protection Agency. 2002. ECOTOX User Guide:  ECOTOXicology Database System. Version 4.0  http://www.epa.gov/ecotox/
Search terms: CAS Reg Nos: 25956-17-6 (July 9, 2013)

EFSA. 1980. Joint Food and Agriculture Organization (FAO) and World Health Organization (WHO) Committee on Food Additives. "JECFA Evaluation  -  Allura RED AC". MRID 48779805

EFSA. 1981. Joint Food and Agriculture Organization (FAO) and World Health Organization (WHO) Committee on Food Additives. "Evaluation of certain food additives".  MRID 48779804

EFSA. 2009. Scientific Opinion on the re-evaluation of Allura Red AC (E 129) as a food additive. MRID 48779803

EPA, ISK Biosciences Corporation (2011); Information Submitted to Support Petition Number 1E7843, Petition Proposing an Exemption from The Requirement of a Tolerance for Residues of FD&C Red No. 40 In or On Raw Agricultural Products and Food Products

EPI Suite. 2004. Estimation Programs Interface Suite Version 3.12 (August 17, 2004).
Environmental Protection Agency. http://www.epa.gov/opptintr/exposure/docs/episuite.htm

JECFA. 1980. Joint FAO/WHO Expert Committee on Food Additives.  Allura Red AC.  WHO Food Additive Series Vol. 15.  http://www.inchem.org/documents/jecfa/jecmono/v15je02..htm 

US Environmental Protection Agency (EPA), December 21, 2004, Action Memorandum, Dan Rosenblatt, Chief Minor Use, Inerts and Emergency Response Branch to Lois Rossi, Director Registration Division, Inert Ingredient Tolerance Reassessment  -  FD&C Blue No. 1, FD&C Red No. 40 and FD&C Yellow No. 5 (Tartrazine). MRID 48779801