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February 22, 2008

**[MEMORANDUM]{.underline}**

**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)

Number range CHAPTER

**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]{.underline} 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]{.underline} 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]{.underline} 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             ![](media/image2.png){width="1.5in"   NIH 2004
                        height="0.65625in"}                   

  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]{.underline}

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:

  ------------------------------------- ---------------------------------
  ^1^oral LD~50~ rat:                   1,487 to 2,102 mg/kg

  ^2^oral LD~50~ mice:                  1,520 mg/kg

  ^1^dermal LD~50~ rabbit~:~            \>2,000 mg/kg

  ^1^inhalation LC~50~ rat:             \>1.10 mg/L

  ^1^Eye Irritation:                    corrosive

  ^1^Dermal Irritation:                 corrosive

  ^1^Dermal Sensitization:              negative
  ------------------------------------- ---------------------------------

> ^1^Conducted with ferric (III) sulfate; ^2^Conducted 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]{.underline}

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]{.underline}

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]{.underline}

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 B6C3F~1~ 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]{.underline}

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]{.underline}

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]{.underline}

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]{.underline}

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.

EPA estimated dietary exposures for use of ferric citrate as an inert
ingredient using a dietary exposure screening model referred to as DEEM™
(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[^1]). 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         Estimated                         
  Subgroup^1^        Exposure                          
                     (mg/kg/day)^2^                    

                     Generic          Ferric Citrate   Ferric Citrate as
                                                       1% in Formulation

  U.S. Population    0.120            0.120            0.0012
  (total)                                              

  All infants (\<1   0.245            0.245            0.0025
  year)                                                

  Children (1-2      0.422            0.422            0.0042
  years)                                               

  Children (3-5      0.310            0.310            0.0031
  years)                                               

  Children (6-12     0.174            0.174            0.0017
  years)                                               

  Youth (13-19       0.100            0.100            0.0010
  years)                                               

  Adults (20-49      0.087            0.087            0.0009
  years)                                               

  Adults (50+ years) 0.086            0.086            0.0009

  Females (13-49     0.087            0.087            0.0009
  years)                                               
  ------------------ ---------------- ---------------- -------------------

^1^Only representative population subgroups are shown.

^2^Exposure 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
<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]{.underline} 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          |                 |                 |                 |
| Levels^1^ for   |                 |                 |                 |
| Iron in Terms   |                 |                 |                 |
| of mg/kg        |                 |                 |                 |
| bw/day**        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Age Group       | Iron Level      |                 |                 |
|                 | (mg/kg bw/day)  |                 |                 |
| (years)         |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 | Males and       | During          | During          |
|                 | Females         | Pregnancy       | Lactation       |
|                 |                 |                 |                 |
|                 |                 | (females only)  | (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              |                 |
+-----------------+-----------------+-----------------+-----------------+
| ^1^UL'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       | Iron   |        |                 |                 |
|                 | Level  |        |                 |                 |
| (years)         |        |        |                 |                 |
+-----------------+--------+--------+-----------------+-----------------+
|                 | Males  | F      | During          | During          |
|                 |        | emales | Pregnancy       | Lactation       |
|                 |        |        |                 |                 |
|                 |        |        | (females only)  | (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              |                 |
+-----------------+--------+--------+-----------------+-----------------+
| ^1^RDA'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      | Estimated     | UL's^3^  | Risk     |           |   |
| Subgroup        | Exposure to   |          | Metric   |           |   |
|                 | Ferric        | (mg      |          |           |   |
|                 | Citrate^2^    | /kg/day) | (% of    |           |   |
|                 |               |          | the      |           |   |
|                 | (mg/kg/day)   |          | UL)^3^   |           |   |
+-----------------+---------------+----------+----------+-----------+---+
|                 |               |          | For      | For       |   |
|                 |               |          | Ferric   | Ferric    |   |
|                 |               |          | Citrate  | Citrate   |   |
|                 |               |          |          | as 1% in  |   |
|                 |               |          |          | Fo        |   |
|                 |               |          |          | rmulation |   |
+-----------------+---------------+----------+----------+-----------+---+
| U.S. Population | 0.120         | 0.63     | 19.0     | 0.19      |   |
| (total)         |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| All infants     | 0.245         | 3.3      | 7.4      | 0.07      |   |
| (\<1 year)      |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| Children (1-2   | 0.422         | 3.3      | 12.8     | 0.13      |   |
| years)          |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| Children (3-5   | 0.310         | 1.8      | 17.2     | 0.17      |   |
| years)          |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| Children (6-12  | 0.174         | 1.8      | 9.7      | 0.10      |   |
| years)          |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| Youth (13-19    | 0.100         | 0.74     | 13.5     | 0.14      |   |
| years)          |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| Adults (20-49   | 0.087         | 0.63     | 13.8     | 0.14      |   |
| years)          |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| Adults (50+     | 0.086         | 0.63     | 13.7     | 0.14      |   |
| years)          |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| Females (13-49  | 0.087         | 0.63     | 13.8     | 0.14      |   |
| years)          |               |          |          |           |   |
+-----------------+---------------+----------+----------+-----------+---+
| ^1^See Table 2  |               |          |          |           |   |
| for             |               |          |          |           |   |
| calculations.   |               |          |          |           |   |
|                 |               |          |          |           |   |
| ^2^The UL's are |               |          |          |           |   |
| calculated in   |               |          |          |           |   |
| Table 3.        |               |          |          |           |   |
|                 |               |          |          |           |   |
| ^3^Calculated   |               |          |          |           |   |
| 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. 5^th^ 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.
<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,"
3^rd^ 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.
[http://chem.sis.nlm.nih.gov/chemidplus/](http://chem.sis.nlm.nih.gov/chemidplus/jsp/chemidheavy/ChemFull.jsp?MW=46.0684)

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.

<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.
<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.
<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.
<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.
<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.

U.S. EPA 2007. Memorandum from K. Leifer to K. Martin. Inert Ingredient
Dietary Exposure Screening Model Results for Iron Citrate. Inert
Ingredient Assessment Branch. Registration Division. Office of Pesticide
Programs. U.S. Environmental Protection Agency. April 25, 2007.

[^1]: The generic exposures 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.