


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

EPA Registration Division contact: Kerry Leifer 202-566-2812


United States Department of Agriculture, Animal and Plant Health Inspection Service 

IN-11661

	EPA has received a pesticide petition IN-11661 from United States Department of Agriculture, Animal and Plant Health Inspection Service, 4700 River Road, Unit 149, Riverdale, MD 20737 requesting, 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

2. to establish an exemption from the requirement of a tolerance for 

Iron Oxide (Fe3O4) (CAS No. 1317-61-9) for use as an inert ingredient in feral swine toxicant pesticide formulations at no more than 2,000 ppm in the final formulation, in accordance with 40 CFR §180.930. 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.

A. Residue Chemistry

	1. Plant metabolism. NA-Remove

	2. Analytical method. EPA Method 3050B "Acid digestion of sediments, sludges, and soils" is an analytical method to measure total iron in an environmental sample that could be used to measure iron oxides. 

	3. Magnitude of residues. NA-Remove

B. Toxicological Profile

	1. Acute toxicity.  Acute toxicity testing in rats indicates that iron oxides are of low acute oral toxicity. 

Summary of acute oral toxicity data for iron oxides 
Study
Toxicity Value
Chemical 
Oral LD50 (rat)
15000 mg/kg
Unspecified iron oxides
Oral LD50 (rat)
> 10000 mg/kg
FeO(OH)·H2O
Oral LD50 (rat)
> 10000 mg/kg
Fe2O3
Oral LD50 (rat)
> 5000 mg/kg
Fe2O3
Oral LD50 (rat)
> 10000 mg/kg
(FeO·Fe2O3)

	2. Genotoxicty. There are several studies that have evaluated in vitro genotoxicity testing with different iron oxides (Fe2O3 and FeO·Fe2O3) and indicate that there is genotoxic concern. However, all in vitro studies that presented positive genotoxicity results were only observed at dose levels coincident with oxidative stress and/or cytotoxicity. Cytotoxicity and oxidative stress are considered indirect threshold-based modes-of-action for genotoxicity. Therefore, doses that are protective of those indirect outcomes and associated modes-of-action are also expected to be protective of genotoxicity. 

Given that microsized iron oxide does not show any indication of systemic toxicity at limit doses in in vivo studies (>1000 mg/kg/day), there is no indication the residues of iron oxide have the potential for genotoxicity in animals or humans. Furthermore, a chromosomal aberration and micronucleus in vivo study in rats, aligned with OECD Test Guidelines 474 and 475, presented no adverse genotoxicity outcome at up to 2000 mg/kg/day.

In summary, based on the available evidence, it can be concluded that residues of iron oxide are non-genotoxic.

Summary of genotoxicity results for iron oxides 
Study
Dose Levels
Cytotoxic Concentration
Results
In vitro
Ames Test
2000  -  50000 ug/plate with and without metabolic activation
N/A
Non-mutagenic
Comet assay (nanosized and microsized red iron oxide)
0, 10, 25, 50, and 250 μg/mL
>= 10 μg/mL (nano); >= 50 μg/mL (micro)
Increased in genotoxicity only at cytotoxic levels >= 50 μg/mL
Comet assay (red iron oxide)
10 and 50 μg/cm[2] for 24 hours
50% and 40% at 10 and 50 μg/cm[2]
ROS-associated DNA oxidative damage in the presence of decreased cell viability
Comet assay (nanosized and microsized black and red iron oxide)
20 and 40 μg/cm[2] for 4 hours
Not reported by EFSA
Increase in oxidative DNA damage all doses for microsized; increase in oxidative DNA damage at 40 ug/cm[2] for nanosized
Comet assay
(nanosized and microsized iron oxide)
0 (control), 5, 10, and 50 ug/cm[2]
Increase in ROS at 10 ug/cm[2] (nanosized)
Non-genotoxic
Micronucleus assay
(nanosized and microsized iron oxide)
0 (control), 5, 10, and 50 ug/cm[2]
Increase in ROS at 10 ug/cm[2] (nanosized)
Non-genotoxic
Micronucleus assay
(nanosized red iron oxide)
6.0 x 10[10], 6.0 x 10[11], and 6.0 x 10[12] nanoparticles/mL
No cytotoxic effects
Non-significant increase in micronucleated leukocytes
Chromosomal aberration assay
(black iron oxide)
6.25, 12.5, and 25 μg/mL with and without metabolic activation
25 μg/mL in the presence of metabolic activation
Non-genotoxic
Forward mutation assay
(black iron oxide)
6, 9, 12, 18, 24, and 36 μg/mL with and without metabolic activation
N/A
Non-genotoxic
In vivo
Unscheduled DNA synthesis
(red iron oxide)
Intratracheal
3.75 mg/kg/day
N/A
Non-genotoxic
Chromosomal aberration and micronucleus (red iron oxide)
Oral
0, 500, 1000, and 2000 mg/kg bw.
N/A
Non-genotoxic

	3. Reproductive and developmental toxicity. Teratogenic evaluations of relevant read-across iron compounds do not indicate any adverse outcomes. An oral teratogenic evaluation of ferrous sulfate in mice and rats presented no adverse effects on maternal toxicity, embryotoxicity, or teratogenicity. An oral teratogenic evaluation of ferric sodium pyrophosphate (FeNaO7P2) in mice and rats presented no adverse effects on maternal toxicity, embryotoxicity, or teratogenicity. 

In an unpublished eight-generation rat reproduction study, no signs of toxicity were evident in rats that consumed more than 50 mg/kg/day of iron oxide. Note that this reproductive study is considered the basis for the ADI of 0.5 mg/kg/day. As such, the ADI should be considered a conservative value to use for risk assessment for iron oxide, as there were no reproductive effects at the highest dose tested, and there are more recent repeat-dose studies with iron oxides that have established NOAELs of 1000 mg/kg/day as described previously.

In summary, based on the available evidence, it can be concluded that residues of iron oxide are not developmental or reproductive toxicants.

Summary of developmental and reproductive results for iron oxides
Study
Species
Route/Dose Levels
(mg/kg/day)
Results
Developmental
(ferrous sulfate)
Mouse
Oral
0 (control), 1.6, 7.4, 34.5, and 160.0
No adverse outcomes
Developmental
(ferrous sulfate)
Rat
Oral
0 (control), 2.0, 9.3, 43.1, and 200
No adverse outcomes
Developmental
(ferric sodium pyrophosphate)
Mouse
Oral
0 (control), 15.0, 74.3, 345, and 1600
No adverse outcomes
Developmental
(ferric sodium pyrophosphate)
Rat
Oral
0 (control), 15.0, 74.3, 345, and 1600
No adverse outcomes
Reproductive
(iron oxide)
Rat
Oral
50
No adverse outcomes

	4. Subchronic toxicity. Repeat-dose oral studies indicated iron oxide-mediated effects are contingent on the size of the particles, with only non-relevant (with regards to residues of iron oxide) iron oxide nanoparticles demonstrating adverse effects. As previously discussed, the data from red iron oxide can be bridged to black iron oxide due to the convergence of the ferric and ferrous forms of iron within the GI digestion and absorption pathway. 

In a 28-day study, rats were dosed with 30, 300, and 1000 mg/kg/day with either iron oxide nanoparticles (Fe2O3-30 nm) or bulk particles (<5 uM). The following endpoints were evaluated: body weight, biochemistry, and histopathology (liver, kidney, spleen, heart, and brain). Nano red iron oxide (Fe2O3-30 nm) caused reduced body weight and feed intake, severe toxic symptoms and several disturbances in biochemical parameters and adverse histopathological changes in the liver, kidney, and spleen with a NOAEL of 300 mg/kg/day. Microsized red iron oxide (Fe2O3-Bulk) did not induce any significant adverse effects in either biochemical parameters or histopathology in rats given the highest dose. 

In a 13-week study aligned with OECD Test Guideline 408, rats were treated were treated with red iron oxide (Fe2O3, 60-118 nm) at 250, 500, and 1000 via gavage. The following endpoints were evaluated: body weights, food consumption, urinalysis, ophthalmoscope examination, hematology, serum biochemistry, macroscopic examination, organ weights (heart, liver, lung, spleen, thymus, kidney, adrenal gland, testis, ovary, brain and pituitary gland), and histopathological assessment (aligned with standard tissue battery). Further, in a parallel distribution study, iron concentrations in sampled blood, organs, urine and feces were measured. There were no treatment-related adverse outcomes on any endpoints. In all tissues tested, including liver, kidney, spleen, lung, and brain, the concentrations of iron showed no dose-associated response in comparison to the respective control groups, even in the high-dose group. The iron concentrations in the blood of the Fe2O3 nanoparticle-treated rats showed no significant increase compared with the respective control groups. Lastly, although not statistically significant, the concentrations of iron in the feces in the Fe2O3 nanoparticle-treated animals were found to be higher than that of the control groups.

The repeat-dose data indicates toxicity from iron oxide is contingent on particle size, with only particles at 30 nm or less presenting treatment-related outcomes related to liver and renal toxicity. Iron oxide particles at 60-118 nm or higher showed no treatment-related adverse outcomes at any endpoint up to 1000 mg/kg/day. The residues of iron oxide have a size range of 150 to 200 nm.

In summary, based on the available evidence, it can be concluded there is no repeat-dose toxicological endpoint of concern for the residues of iron oxide as described in this subject document.

Summary of repeated dose toxicity testing results for iron oxides
Study
Dose Levels
NOAEL
Critical effects
28 days in rats (oral)
0, 30, 300, and 1000 mg/kg/day  
Fe2O3-Bulk: 1000 mg/kg/day
Fe2O3-30 nm: 300 mg/kg/day
Fe2O3-Bulk: No adverse effects
Fe2O3-30 nm: Liver and kidney histopathology; alterations in liver enzymes at 1000 mg/kg/day
13 weeks in rats (oral)
250, 500, and 1000 mg/kg/day
Fe2O3-60 nm: 1000 mg/kg/day
Fe2O3-60 nm: No adverse effects

	5. Chronic toxicity. Repeat-dose oral studies indicated iron oxide-mediated effects are contingent on the size of the particles, with only non-relevant (with regards to residues of iron oxide) iron oxide nanoparticles demonstrating adverse effects. As previously discussed, the data from red iron oxide can be bridged to black iron oxide due to the convergence of the ferric and ferrous forms of iron within the GI digestion and absorption pathway.

In a 28-day study, rats were dosed with 30, 300, and 1000 mg/kg/day with either iron oxide nanoparticles (Fe2O3-30 nm) or bulk particles (<5 uM). The following endpoints were evaluated: body weight, biochemistry, and histopathology (liver, kidney, spleen, heart, and brain). Nano red iron oxide (Fe2O3-30 nm) caused reduced body weight and feed intake, severe toxic symptoms and several disturbances in biochemical parameters and adverse histopathological changes in the liver, kidney, and spleen with a NOAEL of 300 mg/kg/day. Microsized red iron oxide (Fe2O3-Bulk) did not induce any significant adverse effects in either biochemical parameters or histopathology in rats given the highest dose. 

In a 13-week study aligned with OECD Test Guideline 408, rats were treated were treated with red iron oxide (Fe2O3, 60-118 nm) at 250, 500, and 1000 via gavage. The following endpoints were evaluated: body weights, food consumption, urinalysis, ophthalmoscope examination, hematology, serum biochemistry, macroscopic examination, organ weights (heart, liver, lung, spleen, thymus, kidney, adrenal gland, testis, ovary, brain and pituitary gland), and histopathological assessment (aligned with standard tissue battery). Further, in a parallel distribution study, iron concentrations in sampled blood, organs, urine and feces were measured. There were no treatment-related adverse outcomes on any endpoints. In all tissues tested, including liver, kidney, spleen, lung, and brain, the concentrations of iron showed no dose-associated response in comparison to the respective control groups, even in the high-dose group. The iron concentrations in the blood of the Fe2O3 nanoparticle-treated rats showed no significant increase compared with the respective control groups. Lastly, although not statistically significant, the concentrations of iron in the feces in the Fe2O3 nanoparticle-treated animals were found to be higher than that of the control groups.

The repeat-dose data indicates toxicity from iron oxide is contingent on particle size, with only particles at 30 nm or less presenting treatment-related outcomes related to liver and renal toxicity. Iron oxide particles at 60-118 nm or higher showed no treatment-related adverse outcomes at any endpoint up to 1000 mg/kg/day. The residues of iron oxide have a size range of 150 to 200 nm.

In summary, based on the available evidence, it can be concluded there is no repeat-dose toxicological endpoint of concern for the residues of iron oxide as described in this subject document.

Summary of repeated dose toxicity testing results for iron oxides
Study
Dose Levels
NOAEL
Critical effects
28 days in rats (oral)
0, 30, 300, and 1000 mg/kg/day  
Fe2O3-Bulk: 1000 mg/kg/day
Fe2O3-30 nm: 300 mg/kg/day
Fe2O3-Bulk: No adverse effects
Fe2O3-30 nm: Liver and kidney histopathology; alterations in liver enzymes at 1000 mg/kg/day
13 weeks in rats (oral)
250, 500, and 1000 mg/kg/day
Fe2O3-60 nm: 1000 mg/kg/day
Fe2O3-60 nm: No adverse effects

	6. Animal metabolism. The available data indicate that absorption of iron from iron oxide particles is low. A 2015 study indicated that repeat-dose administration of up to 1000 mg/kg/day of red iron oxide did not substantially alter iron levels in the liver, spleen, lung, or brain, or in the urine or blood. Further it should be the noted that the water solubility of the residues of iron oxide is 0.5%, which further supports that very little of the residue of iron will be bioavailable following ingestion. In other reports it has been noted in rats that 0.01 - 2.3% of the total oral dose of microsized red iron oxide (Fe2O3) was absorbed and distributed in different organs or excreted in urine. Low absorption of iron (0.01%) from red iron oxide was observed in humans receiving a diet containing red iron oxide, whereas a higher absorption of yellow iron oxide (1.5 - 2.4%) was described in similar populations.

The primary downstream metabolite of concern with any form of iron oxide would be the soluble iron that is released from the parent compound, which again, is expected to be minimal given iron oxide's relative insolubility. Any soluble Fe[2+] is expected to be rapidly oxidized to Fe[3+] at physiological pH before being converted back to Fe[2][+] during digestion. The lumen Fe[3+] transforms to Fe[2+] via the low pH of the proximal duodenum (small intestine) as well as intestinal lumen enterocyte enzymes. The Fe[2+] is the preferred state for intestine absorption and is also the key biological form for downstream biological processes, e.g., ferritin and hemoglobin. 

Overall, residues of iron oxides are expected to have very low solubility and uptake in the gastrointestinal tract, and in conjunction with its low hazard potential, support the conclusion that there is a reasonable certainty of no harm.

	7. Metabolite toxicology. The primary downstream metabolite of concern with any form of iron oxide would be the soluble iron that is released from the parent compound, which again, is expected to be minimal given iron oxide's relative insolubility. Any soluble Fe[2+] is expected to be rapidly oxidized to Fe[3+] at physiological pH before being converted back to Fe[2+] during digestion. The lumen Fe[3+] transforms to Fe[2+] via the low pH of the proximal duodenum (small intestine) as well as intestinal lumen enterocyte enzymes. The Fe[2+] is the preferred state for intestine absorption and is also the key biological form for downstream biological processes, e.g., ferritin and hemoglobin. 

Overall, residues of iron oxides are expected to have very low solubility and uptake in the gastrointestinal tract, and in conjunction with its low hazard potential, support the conclusion that there is a reasonable certainty of no harm.

	8. Endocrine disruption. No endocrine disruption data was located for iron oxide in a search of regulatory databases and literature references. The proposed food-use end use product will be a feral swine bait. Iron oxide consumed in the bait product may remain in the stomach of the feral swine. A small amount may be digested and metabolized into soluble iron that is released from the parent compound, which again, is expected to be minimal given iron oxide's relative insolubility, at which point becoming incorporated into the feral swine tissue. Any undigested product would remain in the stomach of the target pest.

C. Aggregate Exposure

	1. Dietary exposure. Exposure to iron oxide could potentially occur during consumption of feral swine that was hunted and consumed shortly after ingesting the bait. There were no dose-associated responses in iron concentration in tissues across dose groups in a 13-week study aligned with OECD Test Guideline 408. However, in order to be conservative, an unlikely high end dietary exposure was estimated and results can be found in Table "Conservatively Estimated Residue of Iron Oxide in Feral Swine". This estimated worst case secondary residue of 107 mg/kg (or 107 ppm) assumed equal distribution throughout the animal.

Conservatively Estimated Residue of Iron Oxide in Feral Swine
Inert Ingredient
% in formulation
Single Feeding (kg)
Inert per Feeding (mg)
Feral Swine Weight (kg)

Estimated Residue (mg/kg or ppm)

Iron oxide


0.2%

3.75

7500

70

107


This residue value (107 ppm) was included under the category of "meat, game" within the Dietary Exposure Evaluation Model - Food Commodity Intake Database (DEEM-FCID) version 4.02 and evaluated for all relevant population subgroups with results found in Table "Dietary Exposure and Risk Assessment". Dietary exposure accounted for only 0.03% to 0.15% of the ADI of 0.5 mg/kg/day.  Please note that the "meat, game" category in DEEM-FCID includes all animals and not just swine and thus the results should be considered conservative. As mentioned previously, EPA had evaluated iron oxide yellow for the use as strip in beehives, and therefore these exposures were aggregated with the proposed use and also presented in Table "Dietary Exposure and Risk Assessment". Aggregate exposure and risk accounted for just 0.06% to 0.17% of the ADI of 0.5 mg/kg/day. Finally, a maximum feral swine residue was calculated by subtracting the iron oxide yellow exposure from 100% of the ADI and dividing this value by the exposure contribution of consumption of swine with results found in Table "Dietary Exposure and Risk Assessment". Maximum theoretical feral swine residue ranged from 71000 ppm to 400000 ppm illustrating that even if iron oxide concentrates in certain tissues the possibility of these residues being exceeding is very unrealistic. 

Dietary Exposure and Risk Assessment
Population
Chronic Exposure and Risk for Consumption of Game at 107 ppm[1]
EPA Iron Oxide Yellow
(EPA, 2016)
Aggregate Exposure and Risk[2]
Maximum Feral Swine Residue to be <=100% of ADI (ppm)[3]

(mg/kg/day)
% of ADI
(mg/kg/day)
% of ADI
(mg/kg/day)
% of ADI

Total US Population:
0.000591
0.12%
0.000076
0.02%
0.000667
0.02%
91000
All Infants:
0.000133
0.03%
0.000167
0.03%
0.000300
0.04%
400000
Children 1-2:
0.000448
0.09%
0.000115
0.02%
0.000563
0.03%
120000
Children 3-5:
0.000471
0.09%
0.000102
0.02%
0.000573
0.03%
110000
Children 6-12:
0.000408
0.08%
0.000069
0.01%
0.000477
0.02%
130000
Youth 13-19:
0.000409
0.08%
0.000056
0.01%
0.000465
0.02%
130000
Adults 20-49:
0.000755
0.15%
0.000075
0.02%
0.000830
0.02%
71000
Adults 50-99:
0.000536
0.11%
0.000075
0.02%
0.000611
0.02%
100000
Female 13-49:
0.000494
0.10%
0.000074
0.01%
0.00568
0.02%
110000
1 107 ppm was evaluated for "meat, game" in DEEM-FCID version 4.02
2 Aggregate exposure combines exposure from both uses of iron oxide and evaluates them against the ADI of 0.5 mg/kg/day
[3] Maximum Feral Swine Residue to be <=100% of ADI (ppm) = 107 ppm x (100% - [% of ADI from EPA iron oxide yellow use] / [% of ADI from consumption of game at 107 ppm])

	i. Food. Same as above.

	ii. Drinking water. Iron oxides are insoluble in water. Iron oxide consumed as the bait product may remain in the stomach of the feral swine or be digested and metabolized into soluble iron that is released from the parent compound, which again, is expected to be minimal given iron oxide's relative insolubility, at which point becoming incorporated into the feral swine tissue and therefore not exposed to groundwater or ultimately, drinking water.

	2. Non-dietary exposure. Pesticide applicator exposure to iron oxide in the bait formulations could potentially occur during filling of the target pest bait station. The NOAEL of 50 mg/kg/day was used to perform a quantitative assessment for applicators of the refillable bait stations. Occupational handler exposures were estimated for refillable bait stations using dermal (single layer with gloves) and inhalation (no respirator) unit exposures, which express the anticipated exposure per pound of ingredient handled. A single applicator could potentially apply bait at multiple different bait sites per day. The body weight of an adult is assumed to be 80 kg. A very conservative dermal absorption value of 100% was assumed. Occupational handler Margins of Exposure (MOEs) were 170 for dermal, 31000 for inhalation, and 170 for total (MOE (total) = 1 / (1/MOE dermal + 1/MOE inhalation)). MOEs greater than the LOC of 100 indicate that the occupational exposures for the proposed uses are not of concern.   

D. Cumulative Effects

For the proposed use of iron oxide as an inert ingredient in a feral swine toxicant end-use product, human exposure to iron oxide could occur when applicators are filling the bait stations or during eventual consumption of feral swine that was hunted and consumed shortly after it ingested the bait. However, neither exposure scenario is expected to produce significant exposure and there are no repeat-dose toxicological endpoints of concern for the residues of iron oxide. 

E. Safety Determination

	1. U.S. population. There are no repeat-dose toxicological endpoints of concern for the residues of iron oxide as described in this subject document, particularly for particles with the size of 0.2 um (200 nm) and 0.15 um (150 nm). Overall, there is lack of acute toxicological effects, repeat-dose toxicological effects, genotoxicity, carcinogenicity, developmental, and reproductive toxicity in the database. 

In 2016, EPA conducted a human health risk assessment for the use of yellow iron oxides (as noted in this petition, an associated chemical in the same family as the iron oxide that is the subject of this petition) as a food use inert ingredient from miticidal plastic strips to be placed at the entrance of beehives, in which the Agency concluded that no toxicological endpoint of concern was identified in the literature. The EPA (2016) review of yellow iron oxides did utilize the JECFA ADI of 0.5 mg/kg/day for risk assessment, and therefore that is what we used herein for occupational and dietary risk assessment.

	2. Infants and children. Iron is an essential nutrient and critical for basic mammalian physiological functions. As an essential nutrient it has been well studied by the NAS which has Recommend Daily Allowance (RDA) levels of iron of 8 mg/day for all age groups of men and postmenopausal women and an RDA for premenopausal women is 18 mg/day. The NAS has also established a Tolerable Upper Intake Level for adults and children of 45 mg/day of iron based on gastrointestinal distress as an adverse effect.

Exposure to iron oxide could also occur during consumption of feral swine that was hunted and consumed shortly after ingesting the bait. There were no dose-associated responses in iron concentration in tissues across dose groups in a 13-week study aligned with OECD Test Guideline 408. However, in order to be conservative, an unlikely high end dietary exposure was estimated, and the results can be found in the Table "Conservatively Estimated Residue of Iron Oxide in Feral Swine". This estimated worst case secondary residue of 107 mg/kg (or 107 ppm) assumed equal distribution throughout the animal.

Conservatively Estimated Residue of Iron Oxide in Feral Swine

Inert Ingredient
% in formulation
Single Feeding (kg)
Inert per Feeding (mg)
Feral Swine Weight (kg)

Estimated Residue (mg/kg or ppm)

Iron oxide


0.2%

3.75

7500

70

107


This residue value (107 ppm) was included under the category of "meat, game" within the Dietary Exposure Evaluation Model - Food Commodity Intake Database (DEEM-FCID) version 4.02 and evaluated for all relevant population subgroups with results found in Table "Dietary Exposure and Risk Assessment". Dietary exposure accounted for only 0.03% to 0.15% of the ADI of 0.5 mg/kg/day. Please note that the "meat, game" category in DEEM-FCID includes all animals and not just swine and thus the results should be considered conservative. As mentioned previously, EPA had evaluated iron oxide yellow for the use as strip in beehives, and therefore these exposures were aggregated with the proposed use and also presented in Table "Dietary Exposure and Risk Assessment". Aggregate exposure and risk accounted for just 0.06% to 0.17% of the ADI of 0.5 mg/kg/day. Finally, a maximum feral swine residue was calculated by subtracting the iron oxide yellow exposure from 100% of the ADI and dividing this value by the exposure contribution of consumption of swine with results found in Table "Dietary Exposure and Risk Assessment". Maximum theoretical feral swine residue ranged from 71000 ppm to 400000 ppm illustrating that even if iron oxide concentrates in certain tissues the possibility of these residues being exceeding is very unrealistic. 

Dietary Exposure and Risk Assessment
Population
Chronic Exposure and Risk for Consumption of Game at 107 ppm[1]
EPA Iron Oxide Yellow
(EPA, 2016)
Aggregate Exposure and Risk[2]
Maximum Feral Swine Residue to be <=100% of ADI (ppm)[3]

(mg/kg/day)
% of ADI
(mg/kg/day)
% of ADI
(mg/kg/day)
% of ADI

Total US Population:
0.000591
0.12%
0.000076
0.02%
0.000667
0.02%
91000
All Infants:
0.000133
0.03%
0.000167
0.03%
0.000300
0.04%
400000
Children 1-2:
0.000448
0.09%
0.000115
0.02%
0.000563
0.03%
120000
Children 3-5:
0.000471
0.09%
0.000102
0.02%
0.000573
0.03%
110000
Children 6-12:
0.000408
0.08%
0.000069
0.01%
0.000477
0.02%
130000
Youth 13-19:
0.000409
0.08%
0.000056
0.01%
0.000465
0.02%
130000
Adults 20-49:
0.000755
0.15%
0.000075
0.02%
0.000830
0.02%
71000
Adults 50-99:
0.000536
0.11%
0.000075
0.02%
0.000611
0.02%
100000
Female 13-49:
0.000494
0.10%
0.000074
0.01%
0.00568
0.02%
110000
1 107 ppm was evaluated for "meat, game" in DEEM-FCID version 4.02
2 Aggregate exposure combines exposure from both uses of iron oxide and evaluates them against the ADI of 0.5 mg/kg/day
[3] Maximum Feral Swine Residue to be <=100% of ADI (ppm) = 107 ppm x (100% - [% of ADI from EPA iron oxide yellow use] / [% of ADI from consumption of game at 107 ppm])

F. International Tolerances

	The CODEX General standard for food additives permits the use of iron oxide, black as a colorant with no maximum use level. There are specific maximum use levels for iron oxides (black, red and yellow) on various food categories ranging from 20-10000 mg/kg. 

Iron Oxides Permitted for Use Under Specified Conditions in Certain Food Categories or Individual Food Items  
IRON OXIDES
INS
172(i)
Iron oxide (iron oxide, black)
Functional Class Colour
INS
172(ii)
Iron oxide, red
Functional Class Colour
INS
172(iii)
Iron oxide, yellow
Functional Class Colour


Food Cat. No.

Food Category

Max. Level

Notes[1]

Year Adopted

01.1.4
Flavoured fluid milk drinks
20 mg/kg
52 & 402
2017
01.6.2.2
Rind of ripened cheese
100 mg/kg

2005
01.6.4
Processed cheese
50 mg/kg

2005
01.7
Dairy-based desserts (e.g. pudding, fruit or flavoured yoghurt)
100 mg/kg

2005
02.4
Fat-based desserts excluding dairy-based dessert products of food category 01.7
350 mg/kg

2005
03.0
Edible ices, including sherbet and sorbet
300 mg/kg

2005
04.1.1.2
Surface-treated fresh fruit
1000 mg/kg
4 & 16
2008
04.1.2.4
Canned or bottled (pasteurized) fruit
300 mg/kg
267
2018
04.1.2.5
Jams, jellies, marmelades
200 mg/kg

2005
04.1.2.6
Fruit-based spreads (e.g. chutney) excluding products of food category 04.1.2.5
500 mg/kg

2005
04.1.2.7
Candied fruit
250 mg/kg

2005
04.1.2.9
Fruit-based desserts, including fruit-flavoured water-based
200 mg/kg

2005

desserts



05.2
Confectionery including hard and soft candy, nougats, etc. other than food categories 05.1, 05.3 and 05.4
200 mg/kg
XS309R
2017
05.3
Chewing gum
10000 mg/kg
161
2009
05.4
Decorations (e.g. for fine bakery wares), toppings (non-fruit) and sweet sauces
100 mg/kg

2005
06.3
Breakfast cereals, including rolled oats
75 mg/kg

2005
06.5
Cereal and starch based desserts (e.g. rice pudding, tapioca pudding)
75 mg/kg

2005
07.2
Fine bakery wares (sweet, salty, savoury) and mixes
100 mg/kg

2005
08.4
Edible casings (e.g. sausage casings)
1000 mg/kg
72
2005
09.2.5
Smoked, dried, fermented, and/or salted fish and fish products, including mollusks, crustaceans, and echinoderms
250 mg/kg
22, XS167, XS189, XS222, XS236, XS244
& XS311
2018
09.3.3
Salmon substitutes, caviar, and other fish roe products
100 mg/kg
XS291
2018
09.3.4           
Semi-preserved fish and fish products, including mollusks,
crustaceans, and echinoderms (e.g. fish paste), excluding
products of food categories 09.3.1 - 09.3.3
50 mg/kg
95
2010
09.4                
Fully preserved, including canned or fermented fish and fish
products, including mollusks, crustaceans, and echinoderms
50 mg/kg
95, XS3, XS37, XS70, XS90, XS94 & XS119
2018
10.1                  
Fresh eggs
GMP
4
2005
10.4
Egg-based desserts (e.g. custard)
150 mg/kg

2010
12.2.2
Seasonings and condiments
1000 mg/kg

2005
12.5
Soups and broths
100 mg/kg
XS117
2015
12.6
Sauces and like products
75 mg/kg
XS302
2018
13.6
Food supplements
7500 mg/kg
3
2009
12.1.4
Water-based flavoured drinks, including "sport," "energy," or
"electrolyte" drinks and particulated drinks
100 mg/kg

2005
15.1
Snacks - potato, cereal, flour or starch based (from roots
and tubers, pulses and legumes)
500 mg/kg

2005
15.2
Processed nuts, including coated nuts and nut mixtures
(with e.g. dried fruit)
400 mg/kg

2005

Additionally, Health Canada's Pest Management Regulatory Agency (PMRA) includes iron oxide (Fe3O4, CAS No. 1317-61-9) on List 4a which includes inert ingredients are approved use in food and non-food use pesticide formulations.


