Superfund Technical Support Center

National Center for Environmental Assessment

U.S. Environmental Protection Agency

26 West Martin Luther King Drive, MS-AG41

Cincinnati, Ohio 45268

Jon Reid/Director, Teresa Shannon/Administrator

Hotline 513-569-7300, FAX 513-569-7159, E-Mail: Superfund_STSC@epa.gov

March 19, 2009

Robert Truesdale

RTI International

Accepted Requestor

ASSISTANCE REQUESTED: PPRTV for iron (RfD and sRfD only).

Attachment 1: PROVISIONAL PEER REVIEWED TOXICITY 

INFORMATION FOR IRON (CASRN 7439-89-6)

AND COMPOUNDS Derivation of Subchronic and

Chronic Oral RfDs 

BE ADVISED: Unless specifically indicated to have been peer reviewed, it is to be noted that the

attached Provisional Toxicity Value Paper(s) have not been through the U.S. EPA’s

formal review process; therefore, they do not represent a U.S. EPA verified assessment.

If you have any questions regarding this transmission, please contact the STSC at (513) 569-7300.

Attachments (1)

cc: STSC files

Supported by ECFlex, Incorporated, under

U.S. Environmental Protection Agency Contract No. EP-C-06-088.
9-11-2006 

Provisional Peer Reviewed Toxicity Values for 

Iron and Compounds 

(CASRN 7439-89-6) 

Derivation of Subchronic and Chronic Oral RfDs 

Superfund Health Risk Technical Support Center 

National Center for Environmental Assessment 

Office of Research and Development 

U.S. Environmental Protection Agency 

Cincinnati, OH 45268
Acronyms and Abbreviations 

bw body weight 

cc cubic centimeters 

CD Caesarean Delivered 

CERCLA Comprehensive Environmental Response, Compensation and 

Liability Act of 1980 

CNS central nervous system

cu.m cubic meter 

DWEL Drinking Water Equivalent Level 

FEL frank-effect level 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

g grams 

GI gastrointestinal 

HEC human equivalent concentration 

Hgb hemoglobin 

i.m. intramuscular 

i.p. intraperitoneal 

i.v. intravenous 

IRIS Integrated Risk Information System

IUR inhalation unit risk 

kg kilogram

L liter 

LEL lowest-effect level 

LOAEL lowest-observed-adverse-effect level 

LOAEL(ADJ) LOAEL adjusted to continuous exposure duration 

LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human 

m meter 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

mg milligram

mg/kg milligrams per kilogram

mg/L milligrams per liter 

MRL minimal risk level 

MTD maximum tolerated dose 

MTL median threshold limit 

NAAQS National Ambient Air Quality Standards 

NOAEL no-observed-adverse-effect level 

NOAEL(ADJ) NOAEL adjusted to continuous exposure duration 

NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human 

NOEL no-observed-effect level 

OSF oral slope factor 

p-IUR provisional inhalation unit risk 

p-OSF provisional oral slope factor 

p-RfC provisional inhalation reference concentration 

i
p-RfD provisional oral reference dose 

PBPK physiologically based pharmacokinetic 

ppb parts per billion 

ppm parts per million 

PPRTV Provisional Peer Reviewed Toxicity Value 

RBC red blood cell(s) 

RCRA Resource Conservation and Recovery Act 

RDDR Regional deposited dose ratio (for the indicated lung region) 

REL relative exposure level 

RfC inhalation reference concentration 

RfD oral reference dose 

RGDR Regional gas dose ratio (for the indicated lung region) 

s.c. subcutaneous

SCE sister chromatid exchange

SDWA Safe Drinking Water Act 

sq.cm. square centimeters 

TSCA Toxic Substances Control Act 

UF uncertainty factor 

μg microgram

μmol micromoles 

VOC volatile organic compound 

ii
9-11-2006 

PROVISONAL PEER REVIEWED TOXICITY INFORMATION FOR 

IRON (CASRN 7439-89-6) AND COMPOUNDS 

Derivation of Subchronic and Chronic Oral RfDs

Background

On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of 

Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human 

health toxicity values for Superfund risk assessments, establishing the following three tiers as the 

new hierarchy: 

1. EPA's Integrated Risk Information System (IRIS). 

2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund 

Program. 

3. Other (peer-reviewed) toxicity values, including: 

< Minimal Risk Levels produced by the Agency for Toxic Substances and Disease 

Registry (ATSDR), 

< California Environmental Protection Agency (CalEPA) values, and 

< EPA Health Effects Assessment Summary Table (HEAST) values. 

A PPRTV is defined as a toxicity value derived for use in the Superfund Program when 

such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are 

developed according to a Standard Operating Procedure (SOP) and are derived after a review of 

the relevant scientific literature using the same methods, sources of data, and Agency guidance 

for value derivation generally used by the EPA IRIS Program. All provisional toxicity values 

receive internal review by two EPA scientists and external peer review by three independently 

selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the 

multi-program consensus review provided for IRIS values. This is because IRIS values are 

generally intended to be used in all EPA programs, while PPRTVs are developed specifically for 

the Superfund Program. 

Because science and available information evolve, PPRTVs are initially derived with a 

three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program

sometimes request that a frequently used PPRTV be reassessed. Once an IRIS value for a 

specific chemical becomes available for Agency review, the analogous PPRTV for that same

chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a 

PPRTV cannot be derived based on inadequate data. 

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Disclaimers

Users of this document should first check to see if any IRIS values exist for the chemical 

of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional 

Superfund and RCRA program offices are advised to carefully review the information provided 

in this document to ensure that the PPRTVs used are appropriate for the types of exposures and 

circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically 

updated; therefore, users should ensure that the values contained in the PPRTV are current at the 

time of use. 

It is important to remember that a provisional value alone tells very little about the 

adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, 

users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths 

and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of 

Research and Development’s National Center for Environmental Assessment, Superfund Health 

Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may 

choose of their own initiative to use these PPRTVs are advised that Superfund resources will not 

generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund 

Program. 

Questions Regarding PPRTVs

Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on 

chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed 

to the EPA Office of Research and Development’s National Center for Environmental 

Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI 

INTRODUCTION 

A reference dose (RfD) for iron is not available on the Integrated Risk Information 

System (IRIS) (U.S. EPA, 2006) or the Drinking Water Standards and Health Advisories list 

(U.S. EPA, 2005). The Health Effects Assessment Summary Tables (HEAST) (U.S. EPA, 1997) 

reported that data regarding iron were inadequate for quantitative risk assessment. The Chemical 

Assessment and Related Activities (CARA) list (1991, 1994) includes a Health Effects 

Assessment (HEA) for Iron and Compounds (U.S. EPA, 1984) that found no reliable quantitative 

oral toxicity data. Iron has not been the subject of a toxicological review by the Agency for 

Toxic Substances Disease Registry (ATSDR) (2005) or the World Health Organization (WHO) 

(2005). Monographs by the International Agency for Research on Cancer (IARC) (1972, 1987), 

toxicity reviews by Jacobs (1977), Bothwell et al. (1979), Lauffer (1991) and Grimsley (2001), a 

review on dietary iron by the National Academy of Sciences (NAS) (2001), and the National 

Toxicology Program (NTP) (2001, 2005) management status report and chemical repository 

summary were consulted for relevant information. The NAS (2001) derived a Tolerable Upper 

Intake (TUI) level of 45 mg iron/day. The TUI is based on a minimal LOAEL of 70 mg/day (60 

mg iron as ferrous fumerate plus 11 mg/day of dietary iron) identified by Frykman et al. (1994) 

for gastrointestinal effects and an uncertainty factor of 1.5 for use of a minimal LOAEL; a higher 

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uncertainty factor was not used since the nature of the observed gastrointestinal effects was 

considered to be self-limiting. The U.S. Food and Drug Administration (FDA) promulgated a 

Rule in 1997 for labeling of iron-containing dietary supplements for the prevention of accidental 

poisoning in children (U.S. FDA, 1997). The Rule, as modified in 2003, does not contain 

specific exposure limits (U.S. FDA, 2003). In general, the FDA follows the NAS guidance on 

exposure limits for toxicity of essential elements, such as iron. Previous literature searches were 

conducted through September, 2001 as follows: TOXLINE (oral and inhalation toxicity and 

cancer from 1983 - September, 2001); CANCERLIT (1990 - September, 2001); MEDLINE 

(1991 - September, 2001); TSCATS, RTECS, DART/ETICBACK, EMIC/EMICBACK, HSDB, 

GENETOX, and CCRIS. Update literature searches were performed in October, 2005 in 

MEDLINE, TOXLINE (NTIS subfile), TOXCENTER, TSCATS, CCRIS, DART/ETIC, 

GENETOX, HSDB, RTECS and Current Contents. 

REVIEW OF PERTINENT LITERATURE 

Iron is an essential element and deriving a risk assessment value for such chemicals poses 

a special problem in that the dose-adversity curve is "U-shaped". Thus, the risk value must be 

protective against deficiency as well as toxicity. The NAS (2001) has established guidelines for 

iron intake that take into account physiological differences during different life stages. For nonbreast-fed infants aged 0-6 months, the NAS (2001) established a daily adequate intake (AI) for 

iron of 0.27 mg/day (0.04 mg/kg-day for infants 2-6 months old) based on the daily amount of 

iron secreted in human milk; breast-fed infants typically receive only 0.15 to 0.3 mg Fe/day. The 

NAS (2001) Dietary Reference Intakes (DRIs) for children are as follows: 11 mg/day (1.2 

mg/kg-day) for infants between the ages of 7 and 12 months, 7 mg/day (0.54 mg/kg-day) for 

children aged 1-3 years, 10 mg/day (0.45 mg/kg-day) for ages 4-8 years, 8 mg/day (0.2 mg/kgday) for ages 9-13 years and 11 mg/day (0.17 mg/kg-day) for boys and 15 mg/day (0.26 mg/kgday) for girls aged 14-18 years. The DRI for men aged 19 years and above is 8 mg/day (0.11 

mg/kg-day). The DRI for non-pregnant women is 18 mg/day (0.29 mg/kg-day) for ages between 

19 and 50 years and 8 mg/day (0.13 mg/kg-day) for ages 51 years and older. The DRI for 

pregnant women is 27 mg/day (0.37 mg/kg-day for those aged 14-18 years and 0.35 mg/kg-day 

for those aged 19-50 years). The DRI during lactation is 10 mg/day (0.18 mg/kg-day) for 

women aged 14-18 years and 9 mg/day (0.15 mg/kg-day) for women aged 19-50 years. 

According to the Centers for Disease Control and Prevention (CDC, 1998; CDC, 2005), 

iron deficiency is one of the most common known forms of nutritional deficiency. Its prevalence 

is highest among young children and women of childbearing age, particularly pregnant women. 

In children, iron deficiency causes developmental delays and behavioral disturbances, and in 

pregnant women, it increases the risk for a preterm delivery and delivering a low-birthweight 

baby. Young children are at great risk of iron deficiency because of rapid growth and increased 

iron requirements. Iron deficiency can occur due to lack of iron in the diet. If this continues, 

anemia results. Anemia is a manifestation of iron deficiency when it is relatively severe. Iron 

deficiency anemia significantly impairs mental and psychomotor development in infants and 

children. Although iron deficiency can be reversed with treatment, the reversibility of the mental 

and psychomotor impairment is not yet clearly understood. Thus, prevention and treatment need 

to be emphasized more than detection. In addition, iron deficiency increases a child’s 

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susceptibility to lead toxicity. Lead replaces iron in the absorptive pathway when iron is 

unavailable. 

In humans and other animals, levels in the body are regulated primarily through changes 

in the amount of iron absorbed by the gastrointestinal mucosa. The absorption of dietary iron is 

influenced by body stores, by the amount and chemical nature of iron in ingested food and by a 

variety of dietary factors that increase or decrease the availability of iron for absorption 

(Hillman, 2001; Santi and Masters, 2001). Iron contained in meat protein (hemoglobin and 

myoglobin) is absorbed intact without first being broken down to elemental iron. Non-heme iron 

must first be reduced to ferrous iron (Fe2+) before it can be absorbed. Ferrous iron is transported 

across intestinal mucosal cells by active transport with the rate of transport inversely related to 

body iron stores. Depending upon the iron status of the body, iron is stored bound to ferritin 

within mucosal cells and macrophages in the liver, spleen and bone, or is transported in the 

plasma bound to transferrin. Serum levels of ferritin and transferrin, along with several red 

blood cell parameters, can be used clinically to evaluate iron balance. Although iron absorption 

is regulated, excessive accumulation of iron in the body resulting from chronic ingestion of high 

levels of iron cannot be prevented by intestinal regulation and humans do not have a mechanism

to increase excretion of absorbed iron in response to elevated body levels (NAS, 1989, 2001). 

Human Studies 

Acute Exposure

Information on acute oral toxic doses of iron in humans is available from numerous case 

reports of ingestion by children, but values vary because it is difficult to obtain accurate 

estimates of the amount taken in most overdose situations. Reviews of these case reports 

indicate that doses in the range of 200-300 mg iron/kg are generally considered lethal (Arena, 

1970; Krenzelok and Hoff, 1979; NRC, 1979; Engle et al., 1987; Mann et al., 1989; KleinSchwartz et al., 1990). 

Therapeutic Studies

Ferrous salts are administered orally for the therapeutic treatment of iron deficiency. The 

oral absorption of ferrous iron supplements is considered to be essentially the same for all 

ferrous salts (e.g., sulfate, fumarate, succinate and gluconate) and is approximately three times 

greater than that of ferric (Fe3+) salts (Hillman, 2001); thus, ferric iron is not used 

therapeutically. Constipation and other gastrointestinal effects, including nausea, vomiting, 

diarrhea and gastrointestinal pain are commonly associated with administration of oral ferrous 

salt supplements (Hillman, 2001; Santi and Masters, 2001). Severity of effects is variable, 

ranging from mild to severe, and depends upon dose and individual susceptibility. The onset of 

symptoms typically occurs at the initiation of treatment and continues throughout the duration of 

treatment. Although there is no indication that the severity of gastrointestinal effects varies over 

the course of treatment, severity is decreased in some patients when iron supplements are 

administered with food (Hillman, 2001; Santi and Masters, 2001). For most patients, iron 

deficiency is reversed within six months of treatment, thus limiting the duration of exposure. 

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The mechanism of iron-induced gastrointestinal toxicity is not established, although it is 

postulated that adverse effects are due to irritant effects of the free iron ion on the gastric 

muscosa (Liguori, 1993). The role of absorbed iron in the development of gastrointestinal 

adverse effects is unknown. The adverse effects of exposure to oral iron supplements has been 

investigated in several studies (Blot et al., 1981; Brock et al., 1985; Coplin et al., 1991; Fryklman 

et al., 1994; Hallberg et al., 1966; Liguori, 1993). 

Frykman et al. (1994) evaluated the adverse effects of daily oral therapy with iron 

fumarate in a double-blind, crossover, placebo-controlled study in Swedish male [n=25; mean 

age 45 years (range 40-52)] and female [n=23; mean age 41 years (range 34-45)] adult blood 

donors. Study subjects were administered 60 mg elemental iron as a daily dose of iron fumarate 

for one month, with each study subject serving as their own placebo control. Compared to the 

placebo treatment period, the percentage of subjects reporting constipation (placebo 20%, ferrous 

fumarate 35%, p<0.05) and total gastrointestinal symptoms (nausea, obstipation, gastric pain and 

diarrhea (placebo 14%, ferrous fumarate 25%, p<0.01) was significantly increased during ferrous 

fumarate treatment. Although the severity of gastrointestinal effects was graded as minor in 

most study subjects, four subjects withdrew from the study due to severe gastrointestinal 

symptoms associated with iron fumarate. In a matched group of 49 adults taking a daily 

combination supplement of porcine-derived heme-iron and iron fumarate containing a total daily 

supplement of 18 mg iron/per day, the frequency of gastrointestinal symptoms was not increased 

compared to placebo. No differences in therapeutic efficacy, as measured by serum ferritin and 

hemoglobin levels, were observed between the non-heme iron and heme-iron treatment groups. 

Adverse effects of four oral iron preparations were evaluated in 1496 male and female

adult blood donors in a series of double-blind, placebo controlled trials (Hallberg et al., 1966). 

The following treatment groups were compared: (1) placebo (195 subjects) and ferrous sulfate 

(198 subjects; 222 mg elemental iron/day); (2) placebo (199 subjects), ferrous sulfate (120 

subjects; 222 mg elemental iron/day), ferrous fumarate (118 subjects, 222 mg elemental 

iron/day), and ferrous gluconate (120 subjects; 222 mg elemental iron/day); and (3) placebo (200 

subjects), ferrous sulfate (195 subjects; 180 mg elemental iron/day), ferrous glycine sulfate (200 

subjects; 180 mg elemental iron/day), and ferrous gluconate (196 subjects; 180 mg elemental 

iron/day). Treatments were administered for two weeks. For all iron treatments, the frequency 

of adverse gastrointestinal effects was significantly increased compared to the matched placebo 

group (p<0.05). Adverse effects reported include constipation, diarrhea, heartburn, nausea and 

epigastric pain. No statistically significant differences in the frequency of adverse effects were 

observed between iron treatments for subjects receiving 222 mg elemental iron/day or between 

iron treatments for subjects receiving 180 mg elemental iron/day. In the seven iron treatment 

groups, the percentage of subjects reporting gastrointestinal effects ranged from 22.9% in the 

222 mg ferrous sulfate group to 31.5% in the 222 mg ferrous gluconate group. In the three 

placebo treatment groups, the percentage of subjects reporting gastrointestinal effects ranged 

from 12.4 to 13.6%. Although statistical comparisons were not made between the 180 and 222 

mg iron/day treatments, the frequency of adverse effects was similar for all iron treatment 

groups. 

Gastrointestinal symptoms were reported in pregnant women treated daily with oral iron 

supplements containing 105 mg elemental iron and 500 mg ascorbic acid (55 women) or 105 mg 

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elemental iron, 500 mg ascorbic acid and 350 mg folic acid (54 women) during the third 

trimester of pregnancy (Blot et al., 1981). The form of iron was not reported. No placebo 

control group was included. Gastrointestinal adverse effects reported include nausea, diarrhea, 

constipation and epigastric pain. Approximately 16% of all patients reported minor 

gastrointestinal symptoms, 14% reported severe effects and 6% stopped treatment due to adverse 

effects. Adverse effects occurred with approximately the same frequency in the two treatment 

group, although data were not reported. 

The tolerability of iron protein succinylate and ferrous sulfate were compared in a 

double-blind clinical trial in 1095 patients with iron deficiency (Liguori, 1993). Patients 

received daily treatment with a controlled-release formulation of ferrous sulfate containing 105 

mg elemental iron (64 males and 485 females) or iron protein succinylate containing 120 mg

elemental iron (55 males and 491 females) for 60 days. No placebo control group was included. 

In the ferrous sulfate group, 26.3% of patients reported adverse gastrointestinal effects 

(heartburn, epigastric pain, constipation and abdominal pain), compared to 11.5% of patients 

treated with iron protein succinylate (p<0.05). 

The adverse effects of oral treatment with a conventional ferrous sulfate tablet were 

compared to a ferrous sulfate wax-matrix tablet in a single-blind, parallel group study in 543 

subjects (Brock et al., 1985). No placebo control group was included. Subjects were 

administered a conventional ferrous sulfate table containing 50 mg elemental iron/day (272 

subjects) or a sulfate wax-matrix tablet containing 50 mg elemental iron/day (271 subjects) for 

56 days. Approximately 45% of subjects treated with conventional ferrous sulfate reported 

moderate-to-severe gastrointestinal effects, including abdominal discomfort, nausea, vomiting, 

constipation and diarrhea, compared to approximately 17% of subjects treated with the ferrous 

sulfate wax-matrix preparation, a statistically significant difference (p<0.001). 

The tolerability of ferrous sulfate (50 mg elemental iron/day) and bis-glycino iron II (50 

mg elemental iron/day) was compared in a double-blind, crossover trial in 42 women (Coplin et 

al., 1991). The treatment period for each iron supplement was two weeks. No placebo treatment 

period was included. The frequency of adverse gastrointestinal effects (abdominal pain, 

bloating, constipation, diarrhea and nausea) was similar for the two treatments, with 54% and 

59% of subjects reporting gastrointestinal symptoms during treatment with bis-glycino iron II 

and ferrous sulfate, respectively. The difference between treatments was not statistically 

significant. 

Effects of iron therapy on the upper gastrointestinal tract were evaluated in 14 healthy 

volunteers [13 women, 1 man; mean age 29 years (range: 24-48 years)] who were instructed to 

ingest 325 mg tablets of ferrous sulfate (119.5 mg elemental iron) three times/day before meals 

(358.5 mg elemental iron/day) for 2 weeks (Laine et al., 1988). Evaluation consisted of a 

gastrointestinal symptom survey, qualitative (Hemoccult) and quantitative (HemoQuant; mg

mercury/g stool) testing for fecal blood loss, endoscopy of the upper gastrointestinal tract and 

histological examination of pinch biopsies of the gastric body, antrum and duodenum. Based on 

actual average ingestion of 2.5 tablets/day (2-week study) and 2.6 tablets/day (1-week study) and 

a reference human body weight of 70 kg (U.S. EPA, 1987), the estimated doses consumed by the 

subjects were 4.3 and 4.4 mg iron/kg-day, respectively, in addition to dietary iron. Compared to 

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baseline measurements in the two weeks prior to treatment, all subjects had significantly 

increased (p<0.05) dark brown-black stools and symptoms of nausea and vomiting during the 

treatment period, but not abdominal pain. Hemoglobin levels in stool did not change 

significantly after iron treatment. Endoscopic examination showed a significant (p=0.003) 

increase in abnormalities in the stomach, but not duodenum, after therapy. These changes 

consisted of erythema, small areas of subepithelial hemorrhage and solitary antral erosions in 

nine, six and two subjects, respectively, and were considered only minimally abnormal. No 

treatment-related histological changes were observed. Although it was speculated that the 

changes in the stomach could represent a mild form of iron poisoning, the investigators 

concluded that the treatment caused mild endoscopic abnormalities of uncertain clinical 

significance in the stomach. Evidence for iron overload (tissue biopsies or hematologic iron 

status indices) was not examined. Considering additional dietary exposure, an exposure level of 

about 4.3 mg/kg-day represents, at worst, a minimal LOAEL. 

Adverse developmental effects in humans have not been associated with the ingestion of 

supplemental iron during pregnancy. As indicated above, NAS (2001) recommended that 

pregnant women supplement their diets with 27 mg iron/day (0.35 mg/kg-day). McElhatton et 

al. (1991) reported on 49 women who took an overdose of a simple iron preparation (53%) or 

iron with folate preparation (47%). In 48 of the women, the amount of iron ingested was known; 

28 took > 1.2 g and the remainder took  1.2 g. There were 25 women who received chelation 

treatment with desferrioxamine (DFO) and 12 who received an emetic. Maternal toxicity, 

consisting of nausea, vomiting, hematoemesis, abdominal pain and diarrhea, was observed in 35 

of the women. Two spontaneous abortions occurred and there were three premature deliveries. 

One of the spontaneous abortions and the premature deliveries were not related to the iron 

overdose. It is not known if the other spontaneous abortion occurring at 22 weeks (3 weeks after 

the overdose) was caused by the iron overdose. No conclusions on the developmental toxicity of 

iron can be made. 

Chronic Exposure

While chronic iron toxicity occurs in people with genetic metabolic disorders resulting in 

excessive iron absorption or abnormal hemoglobin synthesis, or who receive frequent blood 

transfusions (Jacobs, 1977; Bothwell et al., 1979), there is a long-standing controversy as to 

whether a chronic overload due to oral intake is possible in individuals with a normal ability to 

control iron absorption (Hillman and Finch, 1985). Nevertheless, "the cumulative experience in 

human subjects suffering from iron overload of various etiologies strongly suggests that iron is 

noxious to tissues [when]...present in parenchymal cells...for a sufficiently long period of time" 

(Bothwell et al., 1979). 

Looker et al. (1988) made comparisons of dietary iron intake and biochemical indices of 

iron status based on values taken from the second National Health and Nutrition Examination 

Survey (NHANES II) data base1

. NHANES II was a probability sample of the 

noninstitutionalized U.S. population aged 6 months to 74 years, conducted between 1976 and 

 1

 The latest version of this data base, NHANES III (1984-1988) evaluated 30,000 subjects aged 2 months and above

(NAS, 2001). Despite minor differences in the data sets, the conclusions drawn by Looker et al. (1988) based on

NHANES II appear to be valid for the NHANES III data. 

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1980 by the National Center for Health Statistics. These data suggest that normal intake of iron 

by men 16-74 years old exceeds the DRI, and that iron intake is somewhat lower than the DRI 

for women younger than 51 years. Concomitant with the study of dietary intake, the NHANES 

II measured the iron status of these populations. The percent serum transferrin saturation, a 

measure of the residual capacity of the iron transport system to process potential variations in 

iron from dietary intake or catabolized body stores, ranged from 24% saturation for pre- and 

post-menopausal women not using iron supplements to 29% saturation for adult male 

supplement users. These values are within the normal range (20-40%). The Looker et al. (1988) 

evaluation of the NHANES II iron status data concerned iron deficiencies, only, and did not 

address iron overload directly. However, iron overload conditions would likely be evidenced by 

increased saturation of serum transferrin and increased serum ferritin concentrations, which were 

also within the normal range. Therefore, the corresponding dietary intakes are presumed to 

represent chronic NOAELs. Looker et al. (1988) estimated daily iron intakes ranging from 10.0 

for elderly women to 18.7 mg/day for young adult men in the study population. These daily 

intakes correspond to a range of about 0.15 to 0.27 mg/kg-day, depending on assumptions of 

average body weight. Taking the highest intake level of 18.7 mg/day and a body weight of 70 

kg, a NOAEL of 0.27 is established for chronic iron toxicity. 

Hemosiderosis (or siderosis) and iron overload are increases in tissue iron or a general 

increase in iron stores without associated tissue damage (Bothwell et al., 1979; Jacobs, 1977). 

Hemochromatosis describes massive iron overload (15 g of body iron stores or greater) together 

with cirrhosis and/or other tissue damage attributable to iron. Although focal deposits of iron 

may occur in any part of the body where red cells are extravasated, the clinical syndrome of 

hemochromatosis typically involves damage to the hepatic parenchyma (particularly fibrosis), 

heart (cardiac dysfunction including failure) and endocrine glands (particularly hypogonadism). 

Pancreatic iron deposition is common and massive deposits may be associated with fibrosis and 

diabetes. A number of studies involving chronic oral administration of iron to animals have been 

designed in an attempt to identify an animal model for hemochromatosis. Most of these studies 

have been negative (Bothwell et al., 1979; NRC, 1979). Animal studies involving parenteral 

administration of iron have been generally negative as well, even though parenteral routes bypass 

the mechanisms that regulate absorption of iron from the gastrointestinal tract. 

Chronic iron toxicity has been observed in people with idiopathic hemochromatosis (a

genetic metabolic disorder resulting in excessive iron absorption), abnormalities of hemoglobin 

synthesis (e.g., thalassemia) or various anemic states (e.g., sideroblastic anemia), frequent blood 

transfusions or a combination of these conditions (Jacobs, 1977; Bothwell et al., 1979). Chronic 

hemochromatosis has also occurred among the South African Bantu population from an 

excessive intake of absorbable iron in an alcoholic beverage. 

Habitual excessive intake of iron by the Bantus is attributed to consumption of homebrewed Kaffir beer, which was contaminated by iron vessels during brewing (Bothwell and 

Bradlow, 1960; Bothwell et al., 1964). The beer's high acidity (pH 3-3.5) enhanced iron 

leaching from the vessels. The iron in the beer is readily assimilable (i.e., ionizable) due to the 

acidity and presence of iron-complexing ligands such as fructose, and is absorbed to approximately the same degree as ferric chloride. The alcohol content of the beer is also believed to 

contribute to the bioavailability of the iron (Jacobs, 1977; Finch and Monsen, 1972). Based 

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primarily on drinking habits and analyses of beer samples, the estimated average dietary iron 

intake of the Bantu men ranged from 50-100 mg/day from beer alone (Bothwell et al., 1964). 

Using a reference body weight of 70 kg (U.S. EPA, 1987), this range corresponds to 0.7-1.4 

mg/kg-day. Histological examinations of the liver of 147 Bantus (129 male, 18 female) ranging 

in age from 11-70 years (most were between 20 and 50 years old) that died from acute traumatic 

causes were performed (Bothwell and Bradlow, 1960). Varying degrees of hepatic siderosis 

were observed in 89% of the cases; the degree tended to increase with age 40-50 years or less. 

The siderosis was mild in 59% and severe in 19% of the cases, respectively. There was a close 

correlation between hepatic iron concentration and portal fibrosis and cirrhosis. Although the 

overall prevalence was low (15.6% fibrosis and 1.4% cirrhosis), all 11 subjects with the highest 

iron concentrations (>2.0% dry weight of liver) showed either fibrosis or cirrhosis. Histological 

examination of the spleen (50 subjects) also showed siderosis and unspecified histological 

changes. Malnutrition and alcoholism could have played a role in the etiology of the hepatic and 

splenic siderosis in the Bantus. A NOAEL in the range of 0.7 - 1.4 mg/kg-day is indicated but 

may be low given the likely higher bioavailability of iron in the beer than for normal dietary 

exposure. Given the generally poor nutritional health status of this population, the relevance of 

this study for application to the U.S. population is questionable. 

Ethiopia reportedly has the highest per capita iron intake in the world, with an average 

daily intake of 471 mg iron/day (range 98-1418 mg/day; 1.4-20.3 mg iron/kg-day assuming 70 

kg body weight) (Roe, 1966; Hofvander, 1968). Increased stored iron in the liver and adverse 

health effects have not been observed due to low bioavailability of the iron in Ethiopian food. 

A few studies have suggested that high iron intake may be a risk factor for myocardial 

infarction (Salonen et al., 1992; Lauffer, 1991; Sullivan, 1992). Five other large studies found 

no association between serum ferritin levels and coronary heart disease (NAS, 2001). Various 

other measures of iron status (serum transferrin saturation, serum iron concentration and total 

iron-binding capacity) have been examined for a possible link to cardiovascular disease in 

prospective cohort studies, but results overall have been characterized as contradictory (Meyers, 

1996; NAS, 2001). The NAS (2001) concluded that the available evidence “does not provide 

convincing support for a causal relationship” between the level of dietary iron intake and the risk 

for coronary heart disease, although iron cannot be definitively excluded as a risk factor. 

Animal Studies

Repeated-dose oral studies in experimental animals found no significant effect of 

treatment with inorganic iron compounds. No treatment-related adverse changes in clinical 

signs, body or organ weights, food consumption or histopathology were observed in male 

Sprague-Dawley rats that had daily dietary intakes of 35, 70 or 140 mg of iron (as FeSO4 or 

FeEDTA) per kg for up to 61 days (Appel et al., 2001). In male and female F344 rats that were 

exposed to drinking water containing 0.25 or 0.5% ferric chloride (FeCl3 • 6H2O) for 104 weeks, 

there were no dose-related effects other than reduced water intake (possibly affected by 

palatability) and body weight gain (Sato et al., 1992). In the latter study, the iron intakes were 58 

or 110 mg/kg-day in males and 65 or 116 mg/kg-day in females. 

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No treatment-related teratogenic or embryotoxic effects were observed in rats given 2.7 

mg iron/kg-day as ferric chloride on gestational days 6-15 (Nolen et al., 1972), or in rats and 

mice given 24-76 mg iron/kg-day as ferrous sulfate for 6 days during gestation (days 

unspecified) (Tadokoro et al., 1979). Some embryonic mortality (numbers and species not 

reported) occurred in the latter study at 240 mg iron/kg-day. 

DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC RfDs FOR IRON

Iron is an essential element, as such, the RfD must be protective against both toxicity and 

deficiency. Using the values for dietary intake and iron status indices taken from the second 

National Health and Nutrition Examination Survey (NHANES II) data base, it is possible to 

establish a NOAEL for chronic toxicity. Looker et al. (1988) made comparisons of dietary iron 

intake and biochemical indices of iron status using data from NHANES II. The average intakes 

of iron ranged from 0.15 to 0.27 mg/kg-day. The serum ferritin levels and percent serum

transferrin saturation were within the normal range. Thus, intake levels of 0.15-0.27 mg/kg-day 

are sufficient to protect against iron deficiency. However, the NHANES II data do not provide 

information to identify daily dietary iron intakes associated with toxicity. Therefore, daily 

dietary iron intakes were not considered as the basis for the p-RfD. 

Most of the quantitative chronic oral toxicity data for iron have been obtained from

studies of the Bantu population of South Africa. These data indicate that intakes in the range of

0.7-1.4 mg iron/kg-day in home-brewed beer are associated with hemosiderosis and liver 

cirrhosis (Bothwell and Bradlow, 1960; Bothwell et al., 1964). However, confounding factors 

such as malnutrition and unusually high iron bioavailability due to the high acidity and ethanol in 

the beer preclude use of these data for risk assessment. Much higher dietary intakes (average 6.7 

mg/kg-day) of less soluble forms of iron are tolerated in non-western diets as indicated by 

studies of populations in Ethiopia. Thus, although toxicity associated with iron overload due to 

chronic oral intake can be demonstrated qualitatively or even semiquantitatively, assignment of a 

precise LOAEL for normal individuals consuming western diets is compromised by studies 

containing confounding factors. 

Gastrointestinal toxicity, which is commonly associated with the therapeutic use of iron 

supplements, was identified as the critical effect for the basis of the provisional subchronic and 

chronic RfDs. The most frequently reported symptoms include epigastric pain, nausea, 

vomiting, constipation and diarrhea. Several prospective clinical trials in healthy subjects and 

iron-deficient patients identify a LOAEL for gastrointestinal toxicity of 50 to 180 mg elemental 

iron/day; NOAELs were not established (Blot et al., 1981; Brock et al., 1985; Coplin et al., 1991; 

Frykman et al., 1994; Hallberg et al., 1966; Liguori, 1993). The treatment durations in these 

studies range from 2 weeks to approximately 3 months. Although no chronic exposure studies 

reporting gastrointestinal toxicity were identified, clinical experience with iron supplements 

indicates that gastrointestinal effects are associated with oral iron therapy, regardless of the 

duration of treatment and that symptom intensity does not change over the course of treatment 

(Hillman, 2001; Santi and Masters, 2001). This observation suggests that the response is related 

to the concentration of iron in the intestinal tract and not to the time-integrated dose. Therefore, 

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gastrointestinal toxicity is considered as the critical effect for both the subchronic and chronic pRfDs. 

The lowest LOAEL of 50 mg elemental iron/day for gastrointestinal toxicity associated 

with iron supplements was reported in two studies that did not use a placebo-controlled design 

(Brock et al., 1985; Coplin et al., 1991); therefore, data were not considered suitable for 

derivation of the p-RfD. The placebo-controlled, cross-over design study by Frykman et al. 

(1994) reporting a LOAEL of 60 mg/day in Swedish men and women was identified as the 

critical study. Results of this study show that daily treatment with ferrous fumarate (60 mg

elemental iron/day) for one month produced a statistically significant increase in gastrointestinal 

effects compared to placebo. To determine the LOAEL for total daily iron intake, the LOAEL 

for daily supplementation with ferrous fumarate of 60 mg elemental iron/day was added to the 

estimated mean dietary intake for six European countries of 11 mg elemental iron/day (NAS, 

2001) for a total daily iron intake of 71 mg elemental iron/day. Based on a reference body 

weight of 70 kg (U.S. EPA, 1987), the LOAEL for gastrointestinal effects for total daily iron 

intake is 1 mg elemental iron/kg-day. This LOAEL is considered to be a minimal LOAEL 

because gastrointestinal effects were characterized by most study participants as minor in 

severity. 

The provisional subchronic and chronic RfD for iron was derived from the LOAEL of 1 

mg/kg-day for total daily iron intake for adverse gastrointestinal effects as follows: 

 p-RfD (subchronic and chronic) = LOAEL ÷ UF 

 = 1 mg/kg-day ÷ 1.5 

 = 0.7 mg/kg-day 

Dividing the LOAEL of 1 mg/kg-day by an uncertainty factor of 1.5 yields a subchronic and 

chronic p-RfD of 0.7 mg/mg-day. The uncertainty factor of 1.5 includes the individual 

uncertainty factors of 1.5 for use of a minimal LOAEL, 1 for sensitive individuals, 1 for less than 

lifetime exposure, and 1 for an adequate data base. An uncertainty factor of 1.5 was applied to 

account for extrapolation from a minimal LOAEL to a NOAEL for a non-serious effect. A 

higher uncertainty factor for use of a minimal LOAEL was not used since the observed 

gastrointestinal effects are not considered serious and are reversible when exposure is 

discontinued. Furthermore, gastrointestinal symptoms are not associated with dietary intake of 

similar levels of iron (NAS, 2001). Because individuals sensitive to gastrointestinal symptoms

are considered to be included in the studies investigating effects of therapeutic iron; an 

uncertainty factor of 1 for sensitive individuals results. An uncertainty factor of 1 was used to 

account for less than lifetime exposure. Although exposure duration in the Frykman et al. (1994) 

study was only one month, there is no evidence to suggest that symptoms increase with longer 

exposure periods. An uncertainty factor of 1 was used to reflect an adequate database in humans, 

due to the extensive use of therapeutic iron. 

Except for individuals with disorders of iron metabolism, little information is available 

on the long-term systemic toxicity of orally ingested iron. This assessment, therefore, focuses 

more on what is known to be a safe oral intake of iron for the general human population (i.e., 

apparently healthy normal individuals). The provisional reference dose is estimated to be an 

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intake for the general population that is adequately protective from adverse health effects. 

Further, it is also important to note that individual requirements for, as well as adverse reactions 

to, iron may be highly variable. Some individuals may, in fact, consume a diet that contributes 

more than the provisional reference dose, without any cause for concern. In addition, specific 

population subgroups may have higher nutritional requirements than the provisional RfD would 

provide. The p-RfD may not be protective of individuals with inherited disorders of iron 

metabolism or other conditions which affect iron homeostasis. 

This assessment is essentially the same as that proposed by Stifelman et al. (2005). 

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