Document ID: EPA-HQ-OPP-2006-0479-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-04-02T04:00Z

February 22, 2008

MEMORANDUM

SUBJECT:	Decision Document for Petition Number 6E7062; 

	Ferric Citrate (CAS Reg. No. 2338-05-8) 

FROM:	Kathleen Martin, Chemist 

		Inert Ingredient Assessment Branch (IIAB)

		Registration Division (7505P)

TO:		Deborah McCall, Acting Chief

		Inert Ingredient Assessment Branch (IIAB)

		Registration Division (7505P)

  SEQ CHAPTER \h \r 1 

OVERVIEW	 

The Shepherd Chemical Company is requesting that ferric citrate be
exempt from the requirement of tolerance in or on raw agricultural
commodities under 40 CFR 180.910 when these substances are used as inert
ingredients in pesticide formulations.  After considering the available
toxicity and exposure data, EPA recommends that the requested exemption
from the requirement of tolerance be granted.  

EXECUTIVE SUMMARY  

	The Shepherd Chemical Company is requesting an exemption from tolerance
for ferric citrate (CAS Reg. No. 2338-05-8).  The toxicity data are from
the published literature and an EPA Reregistration Eligibility Document
(RED).  For exposure, standard models were used along with available
data.  

	In summary, ferric citrate has low acute oral toxicity.  In subchronic
and chronic toxicity in rodents, no effects were noted.  Ferric citrate
has not been shown to be mutagenic or carcinogenic.  Finally, no
developmental and reproductive effects have been shown.  Based on this
information there is no concern, at this time, for increased sensitivity
to infants and children to ferric citrate when used as an inert
ingredient in pesticide formulations.  For the same reason, a safety
factor analysis has not been used to assess risk and, therefore, the
additional tenfold safety factor for the protection of infants and
children is also unnecessary.

	Ferric citrate will be used as an inert ingredient in pesticide
formulations applied to raw agricultural commodities.  In addition to
exposure through the pesticide application, individuals may be exposed
to iron through their diet (iron is an essential nutrient); and as a
pharmaceutical (to treat iron deficiency).  Application of pesticide
formulations containing ferric citrate is not expected to result in
residues of concern; modeled exposure estimates are low.  Iron is an
essential nutrient that, by definition, must be obtained through the
diet.  Foods rich in iron include:  beef, chicken, oysters, soybeans,
lentils, and spinach.  Iron occurs naturally in ground and surface
waters.  Any contribution from application of ferric citrate is expected
to be minimal.  Considering the environmental fate of related iron
compounds, ferric citrate is not expected to be mobile but rather will
remain mostly in soil where it is not expected to contribute
significantly to the chemistry and fate of the compounds existing
naturally in the environment.  As a pharmaceutical, about a quarter of
the U.S. population is estimated to ingest iron daily to ensure that
they are ingesting adequate amounts of iron.  

Taking into consideration all available information on ferric citrate,
it has been determined that there is a reasonable certainty that no harm
to any population subgroup will result from aggregate exposure to ferric
citrate when used as an inert ingredient in pesticide formulations when
considering dietary exposure and all other nonoccupational sources of
pesticide exposure for which there is reliable information.  Therefore,
the exemption from the requirement of a tolerance requested by the
petitioner, The Shepherd Chemical Company, for residues of ferric
citrate, can be considered assessed as safe under section 408(q) of
FFDCA (or the Federal Food, Drug, and Cosmetic Act).

	 

	

I.	BACKGROUND

	Under a Notice of Filing (NOF) published on June 7, 2006 (71 FR 32955)
the Shepherd Chemical Company is requesting that ferric citrate be
exempt from the requirement of tolerance in or on raw agricultural
commodities when used as an inert ingredient in pesticide formulations. 
That is, the Shepherd Chemical Company is requesting that ferric citrate
be exempt from the requirement of tolerance under 40 CFR 180.910 as a
stabilizing agent.  No comments were received in response to the NOF.  

II.	PHYSICAL AND CHEMICAL PROPERTIES

	“Ferric Citrate occurs as brown granules or as thin, transparent,
garnet red scales.  It is more readily soluble in hot water than in
cold, but it is insoluble in alcohol” (Committee on Food Chemicals
Codex 2003).  It appears to decompose on heating or exposure to light. 
Some other physical and chemical properties are provided in Table 1:  

Table 1.  Physical and Chemical Properties of Ferric Citrate

Parameter	Value	Source

Structure		NIH 2004

CAS #	2338-05-8	NIH 2004

Molecular Weight	244.943	NIH 2004

Common Names	iron citrate; iron(III) citrate 	NIH 2004

III.	HUMAN HEALTH ASSESSMENT

	Iron is one of the most common elements on Earth and it is essential to
nearly all known organisms.  It can exist in oxidation states ranging
from -2 to +6 but in biological systems three states are commonly found:
 ferrous (+2); ferric (+3); and ferryl (+4) (IOM 2001).  The iron of
ferric citrate is in the +3 oxidation state.  

	Iron in the body is bound to proteins such as transferrin, hemoglobin,
myoglobin, ferritin, and hemosiderin; most of the iron in the body, 60
to 70 percent, is found in the hemoglobin molecule.  Ingested iron is
absorbed from the gastrointestinal (GI) tract and a small amount is
excreted.  An adult male needs to absorb only about 1 mg/day to maintain
iron balance.  In total, there is about 3 to 5 g of iron in the body. 
Within the body the disposition of iron is regulated by a complex
mechanism to maintain homeostasis which involves transfer among the
liver, spleen, bone marrow, and blood.  (Klaasen et al 1986; IOM 2001)

	Iron is an essential nutrient; it plays a vital role in the transport
of oxygen throughout the body.  Too little may result in anemia—iron
deficiency anemia is the most common nutritional deficiency in the
world, resulting in fatigue and impaired cognitive development and
productivity.  However, the prevalence of iron deficiency in the United
States is low (NRC 1989).  Too much iron can cause adverse effects. 
(Klaasen et al 1986; IOM 2001)  Klaasen et al (1986) point out that
“acute iron toxicity is nearly always due to ingestion of
iron-containing medicines…” and that chronic iron toxicity (iron
overload) is actually a more common problem.  Iron overload can result
from health-based problems (need for blood transfusions; idiopathic
hemochromotosis) or from excess dietary iron (Klaasen et al 1986).  The
Institute of Medicine (IOM), in developing its Dietary Reference Intakes
(DRI), determined an upper level of exposure to iron; it is based on GI
manifestations (IOM 2001).  

Acute Toxicity 

	No acute toxicity studies per se were identified for ferric citrate. 
In 2002 the Agency reassessed the tolerance exemptions for the mineral
acids and their salts (USEPA 2002).  Among the chemicals assessed were
the iron sulfates.  Acute toxicity values included:  

1oral LD50 rat:	1,487 to 2,102 mg/kg

2oral LD50 mice:	1,520 mg/kg

1dermal LD50 rabbit:	>2,000 mg/kg

1inhalation LC50 rat:	>1.10 mg/L

1Eye Irritation:	corrosive

1Dermal Irritation:	corrosive

1Dermal Sensitization:	negative

1Conducted with ferric (III) sulfate; 2Conducted with iron (II)
heptahydrate

	IOM (2001) discusses reports of acute toxicity resulting from overdoses
of medicinal iron, especially in young children.  Accidental iron
overdose is the most common cause of poisoning deaths in children under
six years of age in the U.S.  The severity of iron toxicity is related
to the amount of elemental iron absorbed.  Gastrointestinal
manifestations occur following the ingestion of 20 mg/kg bw and systemic
toxicity may occur following the ingestion of 60 mg/kg bw.  Vomiting and
diarrhea characterize the initial stages of iron intoxication while
later systemic effects can include those involving the heart, central
nervous system, kidney, liver, and blood.  The Institute of Medicine
(IOM 2001) reports that in studies with adults, GI effects were seen at
50 mg/day of elemental iron; this finding is supported by other studies
showing similar effects. 

Subchronic Toxicity

	Inai et al (1994) administered ferric citrate in the drinking water of
male and female mice at doses of:  1; 0.5; 0.25; 0.12; or 0.06% (which
is equivalent to 0; 600; 1,200; 2,500; 5,000; or 10,000 ppm) for 13
weeks.  The investigators determined that the maximum tolerated dose is
0.12%.  No “specific findings induced by the oral administration of
ferric citrate could be detected.  

	Mutagenicity

	Ishidate et al (1984) conducted the Ames test (with S. typhimurium
strains TA92, TA 1535, TA100, TA1537, TA94, and TA98) and chromosomal
aberration testing (with Chinese hamster fibroblasts).  In the Ames test
using 25 mg/plate of ferric citrate (the maximum dose), no significant
increases in the number of revertant colonies were detected in any S.
typhimurium strains.  In the chromosomal aberration testing using 0.5
mg/mL(the maximum dose), polyploidy was observed in 3% of the cells
after 48 hours and structural aberration was observed in 1% of the cells
after 48 hours; the investigators concluded that these results were
negative for chromosomal aberration.  

Chronic Toxicity  

	Ferric citrate was orally administered at concentrations of 0.12%
(maximum tolerated dose), 0.06%, or 0% in the drinking water to male and
female B6C3F1 mice (for males, 0.12% ferric citrate in drinking water is
equivalent to 0.22 mg/kg/day and 0.06% is equivalent to 0.10 mg/kg/day;
for females, 0.12% ferric is equivalent to 0.16 mg/kg/day and 0.06% is
equivalent to 0.07 mg/kg/day).  These concentrations were chosen on the
basis of the results of the subchronic testing.  Treatment was continued
for 13 weeks.  There was no significant difference between treated and
control groups in the tumor incidence or in the distribution of
different types of tumor.  Thus the long-term oral administration of
ferric citrate to mice did not yield any evidence of chronic toxicity or
tumorigenicity. (Inai et al 1994)

	Developmental and Reproductive Toxicity

	To determine if toxic fetal serum iron levels are reached when maternal
serum iron concentrations rise above what the body can homeostatically
maintain, investigators (Curry et al 1990) dosed pregnant sheep with
toxic doses of iron.  Specifically, four gravid ewes were dosed with
ferric chloride at 2 mg/kg/bw via intravenous administration over 60
minutes; this route was chosen over the oral route because only a small
amount of iron is absorbed from the GI tract after overdose.  A
significant rise was observed in the maternal serum iron concentration
but not in that of the fetuses.  The investigators concluded that the
fetus is protected from elevated maternal serum iron concentrations
during the third trimester of pregnancy, a period when the fetus
acquires most of the iron that it needs during the gestational period. 

	Summary

	From what is known about the sulfates of iron (as opposed to the
citrate), it appears that ferric citrate is not acutely toxic via the
oral route.  In subchronic toxicity using mice, no effects were noted at
the maximum tolerated dose, which was 0.12% ferric citrate in distilled
water (this is approximately equivalent to 0.17 mg/kg/day).  In chronic
toxicity testing, no effects were seen at 0.22 mg/kg/day.  Ferric
citrate has not been shown to be mutagenic or carcinogenic.  Finally, no
developmental and reproductive effects have been shown.  

Based on this information there is no concern, at this time, for
increased sensitivity to infants and children to ferric citrate when
used as an inert ingredient in pesticide formulations.  For the same
reason, a safety factor analysis has not been used to assess risk and,
therefore, the additional tenfold safety factor for the protection of
infants and children is also unnecessary. 

IV.	Environmental Fate Characterization and Drinking Water
Considerations 

Environmental Fate

	In 1993 (USEPA 1993) the Agency assessed the environmental fate of the
iron sulfates.  Because specific information on the fate of iron citrate
is not available, the Agency is relying on the iron sulfate assessment
(USEPA 1993) to describe the fate of the iron moiety of iron citrate. 
This is reasonable given that the concentration of iron citrate in the
formulation will be low (1%) and the iron moiety of the sulfate salts
and citrate is expected to behave in a similar fashion.  Provided below
is the summary and conclusion for the environmental fate assessment for
the iron salts (USEPA 1993):  

	In summary, the fate and transport of Fe(II) and Fe(III) salts in the
environment is dominated by three major processes:  (1) the pH-redox
potential dependent oxidation of Fe(II) to Fe(III); (2) the formation of
insoluble oxides and hydroxides that are also well known components of
soils; and (3) the distinct surface chemistry of the oxides and
hydroxides of iron that control the adsorption of anions, cations and
organic material or the adsorption of iron species onto the surfaces of
mineral and organic components of soils, contributing to the aggregation
of soil particles into larger units.

	In terrestrial environments, the use of Fe(II) and Fe(III) sulfates is
expected to produce iron oxides and hydroxides that are no different
from the iron oxides and hydroxides found in soils and which are
responsible for their brown and red colors.  Although certain bacteria
can reduce Fe(III) to the more mobile Fe(II), reoxidation and
reprecipitation to Fe(III) oxides and hydroxides will rapidly immobilize
any free Fe(II) that may form.

	Therefore, the use of the iron salts as herbicides to control moss in
residential outdoor ornamentals (herbaceous and woody plants; lawns and
turf) or as fertilizers to correct chlorosis in plants is not expected
to contribute significantly to the chemistry and fate of the compounds
existing naturally in the environment.

So, based on what is known on the salts of iron in the environment, EPA
does not expect that iron citrate will pose environmental risks of
concern.  

Drinking Water

	Iron occurs naturally in ground and surface waters.  The Agency sets
nonenforceable standards for certain contaminants that may cause
cosmetic effects (such as skin or tooth discoloration) or aesthetic
effects (such as taste, odor, or color) in drinking water.  EPA
recommends secondary standards to water systems but does not require
systems to comply.  However, states may choose to adopt them as
enforceable standards.  These standards are referred to as National
Secondary Drinking Water Regulations.  For iron, the standard is 0.3
mg/L.  

	Iron concentrations in groundwater have been reported to range <0.5 to
100 mg/L; higher values have been found in the absence of oxygen and in
the presences of organic matter.  In surface waters, iron concentrations
can vary widely, ranging from 61 to 2,680 mg/L. (NIH 2005b)

V. 	Aggregate Exposure Assessment

	In examining aggregate exposure, FFDCA section 408 directs EPA to
consider available information concerning exposures from the pesticide
residue in food and all other nonoccupational exposures, including
drinking water (ground water or surface water) and exposure through
pesticide use in gardens, lawns, or buildings (residential and other
indoor uses).  

EPA does not have information available to assess the potential for
exposure to ferric citrate in consumer products.  Nevertheless, given: 
the natural and ubiquitous occurrence of iron-containing compounds in
the environment; iron’s known role in human physiology; and its
presence in various foods such as beef, soybeans, lentils, and spinach
(NIH 2005a), it is unlikely that residential exposures of concern would
result from the use of ferric citrate in nonpesticide products and as an
inert ingredient in pesticides.  Therefore, no further aggregate
assessment is necessary.

™ (USEPA 2007b).  DEEM™, or Dietary Exposure Evaluation Model, is a
generic screening model that assumes that the inert ingredient is used
on all commodities and that 100 percent of crops are treated with the
inert ingredient.  Further, it assumes finite residues for every
consumed commodity (including meat, milk, poultry, and eggs) included in
the model.  DEEM™ does not include a weight fraction input, but
instead is based on a group of active ingredients that are typically
found in agricultural food-use products at concentrations ranging from
>50% to 100% of the formulation.  Provided in Table 2 are the estimated
generic chronic exposures for the U.S. population and several subgroups
along with the ferric citrate exposures (which happen to be the same as
the generic exposures).  Please note that these estimates are unrefined
and very conservative in nature.  

Table 2.	Estimated Chronic Dietary Exposure for Ferric Citrate Use in 
Glyphosate (USEPA 2007)

Population Subgroup1	Estimated Exposure (mg/kg/day)2

	Generic	Ferric Citrate	Ferric Citrate as 1% in Formulation

U.S. Population (total)	0.120	0.120	0.0012

All infants (<1 year)	0.245	0.245	0.0025

Children (1-2 years)	0.422	0.422	0.0042

Children (3-5 years)	0.310	0.310	0.0031

Children (6-12 years)	0.174	0.174	0.0017

Youth (13-19 years)	0.100	0.100	0.0010

Adults (20-49 years)	0.087	0.087	0.0009

Adults (50+ years)	0.086	0.086	0.0009

Females (13-49 years)	0.087	0.087	0.0009

1Only representative population subgroups are shown.

2Exposure estimates are based on highest tolerance-level residues of
high-use active ingredients for all food forms including meat, milk,
poultry, and eggs.

	In addition to exposure from use in pesticides, individuals are exposed
to iron through the diet.  Iron is an essential nutrient that, by
definition, must be obtained through the diet.  Foods rich in iron
include:  beef, chicken, oysters, soybeans, lentils, and spinach (NIH
2005a).  To ensure health, The National Academy of Sciences (NAS)
recommends that adults consume 8 mg of iron per day (or about 0.11
mg/kg/day); this is the Recommended Daily Allowance or RDA (IOM 2001). 
Data from nationally representative U.S. surveys show that the median
daily intake of dietary iron by men is about 16 to 18 mg/day (or 0.23 to
0.26 mg/kg/day) and women about 12 mg/day (or 0.17 mg/kg/day). (IOM
2001)  In addition to food, cookware containing iron, such as stainless
steel or cast iron, can be a source of iron in the diet (NIH 2005b).  

	Finally, salts of iron (e.g., ferrous sulfate) are used as
pharmaceuticals.  About 21 to 25 percent of women and 16 percent of men
were reported to take a daily iron supplement; on average it is
estimated to contain about 1 mg of iron/day (or 0.014 mg/kg/day).  (IOM
2001)

VI.	Cumulative Exposure

	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." 

	Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to ferric citrate and any other
substances and, this material does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, EPA has not assumed that ferric citrate has
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 the policy statements released by EPA's Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA's website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

VII.	Ecological Exposure Assessment

A.	Ecological Data

	In 1993 the Agency assessed the hazards posed to nontarget terrestrial
and aquatic organisms resulting from their exposure to iron sulfates
(USEPA 1993).  Because information specific to iron citrate is not
available, EPA is relying on the iron sulfate ecological hazard
assessment (USEPA 1993) to describe ecological hazards resulting from
exposure to iron.  This is reasonable given that the concentration of
iron citrate in the formulation will be low (1%) and the iron moiety of
the sulfate salts and citrate is expected to behave in a similar
fashion.  Provided below is the summary and conclusion for the
environmental fate assessment for the iron salts (USEPA 1993):  

	No adverse effects to avian, mammalian or aquatic populations are
anticipated from the use of iron salts.  Iron is one of the most
abundant elements and will be immobilized at the environmentally
important pH range of 5-9.  There is very little likelihood for runoff
to aquatic systems since the parent compounds convert very rapidly to
less soluble forms in the environment.  Furthermore, these oxidized iron
compounds bind tightly to soil under turf.  

VIII.	Risk Characterization  

A.	Human Health	

	The Shepherd Chemical Company is requesting that ferric citrate be
exempt from the requirement of tolerance in or on raw agricultural
commodities when used as an inert ingredient stabilizing agent in
pesticide formulations under 40 CFR 180.910.  In considering the
potential risk posed by the use of ferric as an inert ingredient in a
pesticide formulation, the Agency considered available toxicity and
exposure information.  

	Ferric citrate is not acutely toxic via the oral route.  In subchronic
toxicity using mice, no effects were noted at the maximum tolerated
dose, which is 0.12% ferric citrate in distilled water (this is
approximately equivalent to 0.17 mg/kg/day).  In chronic toxicity
testing, no effects were seen at 0.22 mg/kg/day.  Ferric citrate has not
been shown to be mutagenic or carcinogenic.  Finally, no developmental
and reproductive effects have been shown.  Based on this information
there is no concern, at this time, for increased sensitivity to infants
and children to ferric citrate when used as an inert ingredient in
pesticide formulations.  For the same reason, a safety factor analysis
has not been used to assess risk and, therefore, the additional tenfold
safety factor for the protection of infants and children is also
unnecessary.

	To characterize the chronic dietary risk resulting from the use of
ferric citrate as an inert ingredient, EPA estimated dietary exposure
(see Table 2) and compared it to a toxicity endpoint.  In the Pesticide
Program the “population adjusted dose (PAD)” is commonly used as the
toxicity endpoint for dietary risk assessment.  A “population adjusted
dose” or “PAD” is a reference dose (RfD) that has been adjusted to
take into account the FQPA (Food Quality Protection Act of 1996) Safety
Factor.  For ferric citrate, EPA is using the “Tolerable Upper Intake
Level” (UL) as the toxicity endpoint for risk characterization. 
Because the NAS DRIs, which include UL, have been so extensively
peer-reviewed, are so widely accepted, and were developed for dietary
assessment purposes EPA believes that using these for its dietary risk
assessment is appropriate.  

	The National Academy of Sciences IOM establishes DRIs which are
“reference values that are estimates of nutrient intakes to be used
for planning and assessing diets for apparently healthy people” (IOM
2001).  DRI’s include:  RDA’s and UL’s.  An RDA is “the dietary
intake level that is sufficient to meet the nutrient requirement of
nearly all (97 to 98 percent) of healthy individuals in a particular
life stage and gender group.”  A UL is “the highest level of
nutrient intake that is likely to pose no risk of adverse health effects
for almost all individuals in the general population.  As intake
increases above the UL, the risk of adverse effects increases.”  IOM
(2001) has established UL’s and RDA’s for iron; they are provided in
Tables 3 and 4, respectively.  The critical adverse effect for the UL is
GI distress with a LOAEL of 70 mg/day (IOM 2001).



Table 3.  Tolerable Upper Intake Levels1 for Iron in Terms of mg/kg
bw/day

Age Group 

(years)	Iron Level (mg/kg bw/day)

	Males and Females	During Pregnancy 

(females only)	During Lactation 

(females only)

0 to 3	3.3	NA

4 to 8	1.8

	9 to 13	0.98

	14 to 18	0.74	0.79	0.79

19 to 50	0.63	0.69	0.69

51+	0.63	NA

1UL’s, as provided by IOM (2001) are reported in units of mg/day (for
iron, the UL’s range from 40 to 45 mg/day).  EPA assumed that a child
under 3 years of age weighs 12.2 kg; a 4 to 8 year-old weighs 22.8 kg; a
9 to 13 year-old weighs 41.0 kg; a 14 to 18 year-old weighs 60.6 kg; and
an average adult weighs 71.8 kg.  In addition, EPA assumes that a 14 to
18 year-old female weighs 56.9 kg and a 19 to 50 year-old female weighs
65.4 kg. (USEPA 1997)

Table 4.	Recommended Dietary Allowances1 for Iron (mg/kg/day) in Terms
of 	mg/kg bw/day

Age Group

 (years)	Iron Level

	Males 	Females	During Pregnancy 

(females only)	During Lactation 

(females only)

<1	1.21	NA

1 to 3	0.53

	4 to 8	.44

	9 to13	0.20

	14 to18	0.18	0.26

0.18

19 to 50	0.11	0.28	0.41	0.14

51+	0.11	NA

1RDA’s, as provided by IOM (2001) are reported in units of mg/day (for
iron, the UL’s

range from 7 to 27 mg/day.  EPA assumed that a child less than one year
weighs 9.1 kg; a 1 to 3 year-old weighs 13.3 kg; a 4 to 8 year-old
weighs 22.8 kg; a 9 to 13 year-old weighs 41.0 kg; a 14 to 18 year-old
weighs 60.6 kg; and an average adult weighs 71.8 kg.  In addition, EPA
assumes that a 14 to 18 year-old female weighs 56.9 kg and a 19 to 50
year-old female weighs 65.4 kg. (USEPA 1997)

	Comparing estimated dietary exposure (see Table 2 for details of
calculations) to the appropriate UL’s (see Table 3), a metric of
dietary risk is calculated; it is expressed as % of the UL.  Provided in
Table 5 is a summary of the estimated % of the UL. 



Table 5.	Estimated Chronic Dietary Risk for Ferric Citrate Use in
Glyphosate 	(USEPA 2007)

Population Subgroup	Estimated Exposure to Ferric Citrate2

(mg/kg/day)	UL’s3

(mg/kg/day)	Risk Metric

(% of the UL)3

	For Ferric Citrate	For Ferric Citrate as 1% in Formulation

U.S. Population (total)	0.120	0.63	19.0	0.19

All infants (<1 year)	0.245	3.3	7.4	0.07

Children (1-2 years)	0.422	3.3	12.8	0.13

Children (3-5 years)	0.310	1.8	17.2	0.17

Children (6-12 years)	0.174	1.8	9.7	0.10

Youth (13-19 years)	0.100	0.74	13.5	0.14

Adults (20-49 years)	0.087	0.63	13.8	0.14

Adults (50+ years)	0.086	0.63	13.7	0.14

Females (13-49 years)	0.087	0.63	13.8	0.14

1See Table 2 for calculations.

2The UL’s are calculated in Table 3.

3Calculated by dividing the Adjusted Estimated Exposure by the UL and
multiplying by 100.

As shown in Table 5, the ‘% of the UL’ for the overall U.S.
population is about 19%; the ‘% of the UL’ for young children is
about 7%.  Please note that these estimates of dietary risk, which
represent the contribution for food only, are very conservative.  If 1%
ferric citrate were used in the formulation, the ‘% of the UL’ for
the U.S. population would be less than 1% and the ‘% of the UL’ for
young children also less than 1%.  

	Looking at the other potential sources of iron exposure:  on a daily
basis average adults should consume 0.11 mg/kg/day (this is the RDA) of
iron to maintain health (IOM 2001).  Contrasting the amount that EPA
expects an average adult to be exposed to through use of ferric citrate
as an inert ingredient (0.0012 mg/kg/day), the pesticidal exposure is
quite small.  Regarding drinking water, iron is a naturally-occurring
element ground and surface waters.  Some exposure is expected but is not
expected to be of concern to human health.  EPA’s Office of Ground
Water and Drinking Water regulates iron as a secondary contaminant. 
Secondary contaminants are those that are considered to be
“nuisance” chemicals (e.g., affect taste or color) rather than
health concerns (USEPA 1992).  EPA expects EPA expects that when used as
an inert ingredient in pesticide products, ferric citrate would either
remain on the plant or be washed off with rain or irrigation where it
would be adsorbed to the soil.  The Agency does not expect that it would
deposit in ground or surface water.  As a pharmaceutical, about a
quarter of the U.S. population is estimated to ingest about 0.014
mg/kg/day of iron; again, compared to the RDA, this exposure is low. 
Therefore, dietary (food and drinking water) exposures of concern are
not anticipated from use of ferric citrate in pesticides.  Exposures
from residential uses of pesticides containing ferric citrate, and from
consumer products containing the chemical, are not expected to be of
concern considering its low dermal and inhalation toxicity.

Taking into consideration all available information on ferric citrate,
it has been determined that there is a reasonable certainty that no harm
to any population subgroup will result from aggregate exposure to ferric
citrate when used as an inert ingredient in pesticide formulations when
considering dietary exposure and all other nonoccupational sources of
pesticide exposure for which there is reliable information.  Therefore,
the exemption from the requirement of a tolerance requested by the
petitioner, The Shepherd Chemical Company, for residues of ferric
citrate, can be considered assessed as safe under section 408(q) of the
FFDCA.

	B.	Ecological 

	Based on a previous Agency environment and ecological risk assessment
for iron salts (USEPA 1993), EPA concludes that ferric citrate as an
inert ingredient in pesticide formulations does not pose ecological
risks of concern.  

REFERENCES

Committee on Food Chemicals Codex.  2003.  Food Chemicals Codex.  5th
ed.  

National Academies Press.

Curry SC, et al.  1990.  An ovine model of maternal iron poisoning in
pregnancy.  Ann Emerg Med.  1990 Jun;19(6):632-8.

Inai K; Fujihara M, Yonehara S, Kobuke T.  1994.  Tumorigenicity study
of ferric citrate administered orally to mice.  Food Chem Toxicol.  1994
Jun;32(6):493-8

IOM.  2001.  Dietary Reference Intakes for Vitamin A, Vitamin K,
Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum,
Nickel, Silicon, Vanadium, and Zinc.  Panel on Micronutrients,
Subcommittees on Upper Reference Levels of Nutrients and of
Interpretation and Use of Dietary Reference Intakes, and the Standing
Committee on the Scientific Evaluation of Dietary Reference Intakes. 
Food and Nutrition Board, Institute of Medicine.  National Academy of
Sciences.  National Academy Press.  Washington DC.    HYPERLINK
"http://books.nap.edu/openbook.php?record_id=10026&page=1" 
http://books.nap.edu/openbook.php?record_id=10026&page=1 

Ishidate M, et al.  1984.  Primary mutagenicity screening of food
additives currently used in Japan.  Food Chem Toxicol. 1984
Aug;22(8):623-36.

Klaasen, CD, et al, editors.  1986.  “Casarett and Doull’s
Toxicology,” 3rd edition.  Macmillan Publishing Company, New York. 
p.613.

NIH.  2004.  ChemID Plus.  U.S. Department of Health and Human Services.
 National Institutes of Health, Department of Health & Human Services. 
U.S. National Library of Medicine.  Website last modified on September
9, 2004.    HYPERLINK
"http://chem.sis.nlm.nih.gov/chemidplus/jsp/chemidheavy/ChemFull.jsp?MW=
46.0684"  http://chem.sis.nlm.nih.gov/chemidplus/ 

NIH.  2005a.  Dietary Supplement Fact Sheet:  Iron.  Office of Dietary
Supplements. NIH Clinical Center.  National Institutes of Health.  U.S.
Department of Health and Human Services.  Updated:  July 26, 2005. 
Information retrieved on July 17, 2007.  

  HYPERLINK "http://ods.od.nih.gov/factsheets/iron.asp#h2" 
http://ods.od.nih.gov/factsheets/iron.asp#h2 

NIH.  2005b.  Hazardous Substances Data Bank.  U.S. Department of Health
and Human Services.  National Institutes of Health, Department of Health
& Human Services.  U.S. National Library of Medicine.  Website last
modified:  February 5, 2005.  Information retrieved on July 17, 2007.   
HYPERLINK "http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB" 
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB 

NRC.  1989.  Diet and Health:  Implications for Reducing Chronic Disease
Risk.  National Research Council.  Committee on Diet and Health. 
National Academy of Sciences.  The National Academy Press.  Washington
DC.  

Piperno, A.  1998.  Classification and Diagnosis of Iron Overload. 
Haematologica. May;83(5):447-55. 

U.S. EPA.  1992.  Secondary Drinking Water Regulations:  Guidance for
Nuisance Chemicals.  U.S. Environmental Protection Agency.  Office of
Water.  July 1992.  EPA 810/K-92-001.    HYPERLINK
"http://www.epa.gov/safewater/consumer/2ndstandards.html" 
http://www.epa.gov/safewater/consumer/2ndstandards.html 

U.S. EPA.  1993.  Reregistration Eligibility Decision (RED):  Iron
Salts.  U.S. Environmental Protection Agency.  Prevention, Pesticide and
Toxic Substances.  February 1993.  EPA 738-F-93-002.    HYPERLINK
"http://www.epa.gov/oppsrrd1/REDs/old_reds/iron_salt.pdf" 
http://www.epa.gov/oppsrrd1/REDs/old_reds/iron_salt.pdf 

U.S. EPA.  1997.  Exposure Factors Handbook.  U.S. Environmental
Protection Agency.  Office of Research and Development.  National Center
for Environmental Assessment.  PB98-124217.    HYPERLINK
"http://www.epa.gov/ncea/pdfs/efh/front.pdf" 
http://www.epa.gov/ncea/pdfs/efh/front.pdf .  Retrieved on April 16,
2007.

U.S. EPA.  2002.  Memorandum from K. Boyle and K. Leifer to R. Forrest. 
“IIFG Decision Documents on Reassessing Exemptions from the
Requirement of a Tolerance for the Mineral Acids (Hydrochloric,
Carbonic, Phosphoric, and Sulfuric) and their Ammonium, Calcium,
Ferrous, Ferric, Magnesium, Potassium, Sodium, and/or Zinc Salts.” 
Registration Division.  Office of Pesticide Programs.  U.S.
Environmental Protection Agency.  July 24, 2002.  

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.and ferric citrate exposures are the same because it was assumed that
ferric citrate would be used at a concentration of 100%.  If a lower
concentration of ferric citrate were assumed, the generic exposures
would be adjusted accordingly.  

 PAGE   1 

 PAGE   2 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF PREVENTION, 

PESTICIDES, AND TOXIC SUBSTANCES