TOXICOLOGICAL REVIEW

OF

TRIVALENT CHROMIUM

(CAS No. 16065-83-1) 

In Support of Summary Information on the 

Integrated Risk Information System (IRIS) 

August 1998 

U.S. Environmental Protection Agency 

Washington, DC 
DISCLAIMER 

This document has been reviewed in accordance with U.S. Environmental Protection 

Agency policy. Mention of trade names or commercial products does not constitute endorsement 

or recommendation for use. This document may undergo revisions in the future. The most upto-date version will be available electronically via the IRIS Home Page at 

http://www.epa.gov/iris. 

ii 
CONTENTS—TOXICOLOGICAL REVIEW FOR TRIVALENT CHROMIUM 

(CAS No. 16065-83-1) 

FOREWORD ................................................................v

AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................... . vi

LIST OF ABBREVIATIONS ................................................. . vii

1. INTRODUCTION ...........................................................1

2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS .....2

3. TOXICOKINETICS RELEVANT TO ASSESSMENTS ............................3

3.1. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . 3

3.1.1. Oral .......................................................3

3.1.2. Inhalation ..................................................4

3.1.3. Distribution .................................................5

3.1.4. Metabolism .................................................7

3.1.5. The Essentiality of Chromium ..................................7

4. HAZARD IDENTIFICATION .................................................8

4.1. STUDIES IN HUMANS ..............................................8

4.1.1. Oral .......................................................8

4.1.2. Inhalation ..................................................8

4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN

ANIMALS—ORAL AND INHALATION ............................. 12

4.2.1. Chronic Oral Studies ......................................... 12

4.2.2. Subchronic Oral Studies ...................................... 13

4.2.3. Chronic Inhalation Studies .................................... 14

4.2.4. Subchronic Inhalation Studies ................................. 15

4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION 

............................................................... 17

4.3.1. Oral Studies ...................................................... 17

4.3.2. Inhalation Studies ........................................... 18

4.4. OTHER STUDIES ................................................ 19

4.4.1. Contact Dermatitis .......................................... 19

4.4.2. Toxicant Interactions......................................... 19

4.4.3. Genotoxicity ...... ......................................... 19

4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS AND

MODE OF ACTION (IF KNOWN)—ORAL AND INHALATION ......... 20

4.5.1. Oral Studies ................................................ 20

4.5.1.1. Human Studies ...................................... 20

4.5.1.2. Animal Studies ...................................... 20

iii 
CONTENTS (continued) 

4.5.2. Inhalation Studies ...........................................21

4.5.2.1. Human Studies ......................................21

4.5.2.2. Animal Studies ......................................21

4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER

CHARACTERIZATION 

...............................................................22

4.7. OTHER HAZARD IDENTIFICATION ISSUES ..........................22

4.7.1. Possible Childhood Susceptibility ..............................22

4.7.2. Possible Sex Differences ......................................22

5. DOSE-RESPONSE ASSESSMENTS ..........................................23

5.1. ORAL REFERENCE DOSE (RfD) .....................................23

5.1.1. Choice of Principal Study and Critical Effect

.........................................................23

5.1.2. Methods of Analysis .........................................23

5.1.3. RfD Derivation .............................................24

5.2. INHALATION REFERENCE CONCENTRATION (RfC) ..................25

5.3. CANCER ASSESSMENT ............................................26

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION 

OF HAZARD AND DOSE RESPONSE .....................................26

6.1. HUMAN HAZARD POTENTIAL .....................................26

6.2. DOSE RESPONSE .................................................27

7. REFERENCES ............................................................28

APPENDIX A. EXTERNAL PEER REVIEW—

SUMMARY OF COMMENTS AND DISPOSITION ..........................39

iv 
FOREWORD 

The purpose of this Toxicological Review is to provide scientific support and 

rationale for the hazard and dose-response assessment in IRIS pertaining to chronic exposure to 

trivalent chromium. It is not intended to be a comprehensive treatise on the chemical or 

toxicological nature of trivalent chromium (III). 

In Section 6, EPA has characterized its overall confidence in the quantitative and 

qualitative aspects of hazard and dose response. Matters considered in this characterization 

include knowledge gaps, uncertainties, quality of data, and scientific controversies. This 

characterization is presented in an effort to make apparent the limitations of the assessment and 

to aid and guide the risk assessor in the ensuing steps of the risk assessment process. 

For other general information about this assessment or other questions relating to IRIS, 

the reader is referred to EPA’s Risk Information Hotline at 202-566-1676. 

v 
AUTHORS, CONTRIBUTORS, AND REVIEWERS 

Chemical Manager/Author 

Peter C. Grevatt, Ph.D., EPA Region 2 

Reviewers 

This document and summary information on IRIS have received peer review both by EPA 

scientists and by independent scientists external to EPA. Subsequent to external review and 

incorporation of comments, this assessment has undergone an Agencywide review process 

whereby the IRIS Program Manager has achieved a consensus approval among the Office of 

Research and Development; Office of Air and Radiation; Office of Prevention, Pesticides, and 

Toxic Substances; Office of Solid Waste and Emergency Response; Office of Water; Office of 

Policy, Planning, and Evaluation; and the Regional Offices. 

Internal EPA Reviewers 

Robert Benson, Ph.D., D.A.B.T., Region 8

Charles Hiremath, Ph.D., National Center for Environmental Assessment

Annie Jarabek, National Center for Environmental Assessment

Winona Victery, Ph.D., D.A.B.T., Region 9

External Peer Reviewers 

Richard Anderson, Ph.D., U.S. Department of Agriculture 

Robert Chapin, Ph.D., National Institute of Environmental Health Sciences 

Robert Drew, Ph.D., Consultant in Toxicology 

Gunter Obersorster, D.V.M., Ph.D., University of Rochester 

Elizabeth T. Snow, Ph.D., New York University Medical Center 

Summaries of the external peer reviewers’ comments and the disposition of their 

recommendations are in Appendix A. 

vi 
LIST OF ABBREVIATIONS

BAL bronchoalveolar lavage

BMD benchmark dose

BW body weight

CASRN Chemical Abstracts Service Registry Number

ESADDI estimated safe and adequate daily dietary intake

GTF glucose tolerance factor

IRIS Integrated Risk Information System

MTD maximum tolerated dose

NOAEL no-observed-adverse-effect level

NOEL no-observed-effect level

ppb parts per billion

ppm parts per million

RfC inhalation reference concentration

RfD oral reference dose

vii 
1. INTRODUCTION 

This document presents background and justification for the hazard and dose-response 

assessment summaries in EPA’s Integrated Risk Information System (IRIS). IRIS Summaries 

may include an oral reference dose (RfD), inhalation reference concentration (RfC) and a 

carcinogenicity assessment. 

The RfD and RfC provide quantitative information for noncancer dose-response 

assessments. The RfD is based on the assumption that thresholds exist for certain toxic effects 

such as cellular necrosis but may not exist for other toxic effects such as some carcinogenic 

responses. It is expressed in units of mg/kg-day. In general, the RfD is an estimate (with 

uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population 

(including sensitive subgroups) that is likely to be without an appreciable risk of deleterious 

effects during a lifetime. The inhalation RfC is analogous to the oral RfD. The inhalation RfC 

considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral 

to the respiratory system (extrarespiratory or systemic effects). It is generally expressed in units 

of mg/m3

. 

The carcinogenicity assessment provides information on the carcinogenic hazard potential 

of the substance in question and quantitative estimates of risk from oral exposure and inhalation 

exposure. The information includes a weight-of-evidence judgment of the likelihood that the 

agent is a human carcinogen and the conditions under which the carcinogenic effects may be 

expressed. Quantitative risk estimates are presented in three ways. The slope factor is the result 

of application of a low-dose extrapolation procedure and is presented as the risk per mg/kg-day. 

The unit risk is the quantitative estimate in terms of either risk per μg/L drinking water or risk 

per μg/m3

 air breathed. Another form in which risk is presented is a drinking water or air 

concentration providing cancer risks of 1 in 10,000; 1 in 100,000; or 1 in 1,000,000. 

Development of these hazard identifications and dose-response assessments for trivalent 

chromium has followed the general guidelines for risk assessment as set forth by the National 

Research Council (1983). EPA guidelines that were used in the development of this assessment 

may include the following: the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a), 

Guidelines for the Health Risk Assessment of Chemical Mixtures (U.S. EPA, 1986b), Guidelines 

for Mutagenicity Risk Assessment (U.S. EPA, 1986c), Guidelines for Developmental Toxicity 

Risk Assessment (U.S. EPA, 1991), Proposed Guidelines for Neurotoxicity Risk Assessment (U.S. 

EPA, 1995a), Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996a), 

Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996b), and Guidelines for 

Neurotoxicity Risk Assessment (U.S. EPA, 1998a); Recommendations for and Documentation of 

Biological Values for Use in Risk Assessment (U.S. EPA, 1988); (proposed) Interim Policy for 

Particle Size and Limit Concentration Issues in Inhalation Toxicity (U.S. EPA, 1994a); Methods 

for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry 

(U.S. EPA, 1994b); Peer Review and Peer Involvement at the U.S. Environmental Protection 

Agency (U.S. EPA, 1994c); Use of the Benchmark Dose Approach in Health Risk Assessment 

(U.S. EPA, 1995b); Science Policy Council Handbook: Peer Review (U.S. EPA, 1998b); and 

1
memorandum from EPA Administrator, Carol Browner, dated March 21, 1995, Subject: 

Guidance on Risk Characterization. 

Literature search strategies employed for this compound were based on the CASRN and 

at least one common name. At a minimum, the following databases were searched: RTECS, 

HSDB, TSCATS, CCRIS, GENETOX, EMIC, EMICBACK, DART, ETICBACK, TOXLINE, 

CANCERLINE, MEDLINE AND MEDLINE backfiles. Any pertinent scientific information 

submitted by the public to the IRIS Submission Desk was also considered in the development of 

this document. 

2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS 

Chromium (Cr) is a metallic element belonging to the first transitional series of the 

periodic table. Elemental chromium has a CAS Registry Number of 7440-47-3. The three most 

stable forms in which chromium occurs in the environment are the 0 (metal and alloys), +3 

(trivalent chromium), and +6 (hexavelent chromium) valence states. In the +3 valence state, the 

chemistry of chromium is dominated by the formation of stable complexes with both organic and 

inorganic ligands (Hartford, 1979). In the +6 valence state, chromium exists as oxo species such 

as CrO3 and CrO4

2- that are strongly oxidizing (Cotton and Wilkinson, 1980). 

Chromium in the ambient air occurs from natural sources, industrial and product uses, 

and burning of fossil fuels and wood. The most important industrial sources of chromium in the 

atmosphere originate from ferrochrome production. Ore refining, chemical and refractory 

processing, cement-producing plants, automobile brake lining and catalytic converters for 

automobiles, leather tanneries, and chrome pigments also contribute to the atmospheric burden of 

chromium (Fishbein, 1981). Chromate chemicals used as mist inhibitors in cooling towers and 

the mist formed during chrome plating are probably the primary sources of Cr(VI) emitted as 

mists in the atmosphere (Towill et al., 1978). 

Scarce information exists in the literature regarding the nature of the chemical species 

present in the atmosphere. Under normal conditions, Cr(III) and Cr(0) in the air do not undergo 

any reaction (Towill et al., 1978). Cr(VI) in the air eventually reacts with dust particles or other 

pollutants to form Cr(III) (NAS, 1974); however, the exact nature of such atmospheric reactions 

has not been studied extensively. Chromium is removed from air by atmospheric fallout and 

precipitation (Fishbein, 1981). The atmospheric half-life for the physical removal mechanism 

depends on the particle size and particle density of atmospheric chromium. Chromium particles 

of small aerodynamic diameter (< 10 μm) may remain airborne for long periods and may be 

transported great distances by wind currents and diffusion forces. 

Surface runoff, deposition from air, and release of municipal and industrial waste waters 

are the sources of chromium in surface waters. The most significant removal mechanism for 

Cr(III) from the aquatic environment is precipitation as Cr2O3· × H2O followed by sedimentation. 

Cr(VI), however, can exist in aquatic media as a water-soluble complex anion and may persist in 

water for long periods. Cr(VI) is a moderately strong oxidizing agent and will react with organic 

2
matter or other reducing agents to form Cr(III). Therefore, in surface water rich in organic 

content, Cr(VI) will exhibit a much shorter lifetime (Callahan et al., 1979). 

Chromium probably occurs as insoluble Cr2O3· × H2O in soil, given that organic matter in 

soil converts soluble chromate to insoluble Cr2O3 (U.S. EPA, 1983). There is no known 

chemical process that can cause chromium to be lost from soil. The primary processes by which 

chromium is lost from soil are physical. For example, chromium in soil can be transported to the 

atmosphere by way of dust or aerosol formation (U.S. EPA, 1983). Chromium is also 

transported from soil through runoff. Runoff can remove both chromium ions and bulk 

precipitates of chromium. In addition, flooding of soils and the subsequent anaerobic 

decomposition of plant matter may increase dissolution of Cr2O3 in soil through complexation 

(U.S. EPA, 1983). The water-soluble complexes may cause leaching of chromium from soil. 

Page (1981) reported the detection of a small concentration (l μg/L mean concentration) of 

chromium at a frequency of approximately 100% in ground water collected from New Jersey. 

The bioconcentration factor (BCF) for Cr(VI) in fish muscle appears to be < l.0, but 

values of 125 and 192 were obtained for oyster and blue mussel, respectively (U.S. EPA, 1980). 

For Cr(III), BCF values of 116, 153, and 86 were obtained with the American oyster, soft shell 

clam, and blue mussel, respectively (U.S. EPA, 1983). 

3. TOXICOKINETICS RELEVANT TO ASSESSMENTS 

3.1. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 

3.1.1. Oral 

Based on fecal excretion of 51Cr following oral administration of 51CrCl3 to human 

patients, Donaldson and Barreras (1966) estimated absorption to be approximately 0.4%. When 

51CrCl3 was administered intraduodenally, absorption was not appreciably changed. In rats, 

approximately 2% of the intragastric dose of CrCl3 appeared to be absorbed based on fecal 

excretion of chromium. Jejunal administration only slightly increased the apparent absorption of 

CrCl3. Anderson et al. (1983) confirmed the low absorption of trivalent chromium in humans 

following the administration of 200 μg of Cr(III) trichloride, and they suggested that the 

absorption efficiency of trivalent chromium is dependent on dietary intake. Anderson et al. 

(1986) reported that at low levels of dietary intake (10 μg) about 2% of trivalent chromium was 

absorbed. When intake increases to > 40 μg, the absorption efficiency dropped to approximately 

0.5%. Bunker et al. (1984) determined that elderly subjects absorbed less than 3% of trivalent 

chromium ingested in the diet. 

A number of animal studies confirm that trivalent chromium is poorly absorbed in the 

gastrointestinal tract. Visek et al. (1953) estimated that less than 0.5% of ingested CrCl3 was 

absorbed through the gastrointestinal tract of the rat. Mertz et al. (1965) estimated that rats 

absorbed less than 3% of a single dose of CrCl3 by gavage. MacKenzie et al. (1959) estimated 

that less than 3% of a single dose of CrCl3 by stomach tube was absorbed in rats. Ogawa (1976) 

3
found gastrointestinal absorption of CrCl3 to be less than 3% in rats. Henderson et al. (1979) 

determined that hamsters absorbed less than 1.5% of an administered oral dose of trivalent 

chromium. Furthermore, Mertz et al. (1965) reported that absorption in rats was independent of 

the administered dose and dietary chromium status (deficient or supplemented in chromium) of 

the animals. Cr(III) was found to be better absorbed in fasted than in fed rats (MacKenzie et al., 

1959). 

3.1.2. Inhalation 

A number of factors can influence the absorption of chromium following inhalation, 

including the size, oxidation state and solubility of the chromium particles, the activity of 

alveolar macrophages, and the interaction of chromium with biomolecules following deposition 

in the lung (ATSDR, 1993). Absorption of inhaled chromium compounds following 

occupational exposure has been demonstrated by the measurement of chromium in the serum and 

urine and hair of workers in the chromium industry (Minoia and Cavalleri, 1988; Randall and 

Gibson, 1987; Tossavainen et al., 1980). Cr(III) is less well absorbed than Cr(VI) due to the 

relative inability of Cr(III) to cross cell membranes. However, workers exposed to Cr(III) 

lignosulfonate dust at 0.005-0.23 mg Cr(III)/m3

 had detectable concentrations of chromium in the 

urine at the end of the workday (Kiilunen et al., 1983). 

Animal studies have shown that trivalent chromium is absorbed very slowly by 

inhalation. Baetjer et al. (1959a) administered CrCl3 to guinea pigs intratracheally. Ten minutes 

post-treatment, 69% of the administered dose remained in the lungs, while 4% was found in the 

blood and tissues. Percentages of administered chromium found in the lungs 24 hours, 30 days, 

and 60 days post-treatment were 45%, 30%, and 12%, respectively. These investigators 

hypothesized that the slow absorption of trivalent chromium is due to the fact that it forms 

insoluble complexes with macromolecules. Furthermore, clearance from the respiratory tract to 

the gastrointestinal tract may be a factor when chromium compounds are administered by 

inhalation. Visek et al. (1953) found similar results when 51CrCl3 was instilled intratracheally in 

guinea pigs. In this study, absorption from the lungs was estimated to be approximately 5%. The 

authors suggested that the majority of the CrCl3 was cleared from the lungs by mucociliary action 

and passed through the gastrointestinal tract because 55% and 7% of the administered 51Cr had 

been recovered from the feces and urine, respectively, within 7 days. 

Wada et al. (1983) exposed male Sprague-Dawley strain rats to CrCl3 at an atmospheric 

concentration of 14.1 mg/m3

 (Cr) and observed that the chromium was associated with both highand low-molecular-weight proteins. The chromium that remained in the lungs was associated 

with the high-molecular-weight fraction, and this fraction slowly decreased with time following 

exposure. The level of chromium associated with the low-molecular-weight fraction remained 

constant for the 5 days of observation following treatment; however, chromium associated with 

this fraction accumulated with time in the liver. The authors suggested that the low-molecularweight protein may be involved in the absorption and transport of chromium following 

inhalation. 

4
Suzuki et al. (1984) exposed rats to potassium dichromate(VI) or Cr(III) trichloride by 

inhalation and determined that while lung clearance of both valence states was dependent on 

particle size, Cr(VI) was absorbed with threefold greater efficiency than Cr(III). 

3.1.3. Distribution 

Much work has been performed on in vivo reduction of Cr(VI) to Cr(III), and some 

characterizations can be made. Ingested hexavalent chromium is efficiently reduced to the 

trivalent form in the gastrointestinal tract (DeFlora et al., 1987). In the lungs, hexavalent 

chromium can be reduced to the trivalent form by ascorbate and glutathione. The reduction by 

ascorbate is more rapid than that by glutathione and results in a shorter residence time in the 

lungs (Suzuki and Fukuda, 1990). There is no evidence that trivalent chromium is converted to 

hexavalent chromium in biological systems (Amdur et al., 1993). 

Once absorbed, Cr(III) compounds are cleared rapidly from the blood and more slowly 

from the tissues. Hopkins (1965) injected 0.1 μg 51Cr (as chromium chloride)/100g 

intravenously in male rats. The blood chromium content as a percentage of the blood 

concentration decreased from 94% at 30 minutes to 17% in 24 hours and to 5% at 96 hours. Lim 

et al. (1983) followed distribution of 51CrCl3 after intravenous administration in six adults. 

Within several hours of dosing, > 50% of the chromium in plasma was distributed to the liver, 

spleen, and other organs. After 3 months, the liver contained > 50% of the total body burden of 

51Cr. 

Visek et al. (1953) reported organ distribution of several chromium salts following 

intravenous injection in rats. CrCl3 concentrated in the liver, spleen, and bone marrow; once 

deposited, it cleared slowly. The liver in the CrCl3-exposed rats was the only organ to clear 

significant amounts of chromium over the study period (45 days). In rats receiving 

intraperitoneal administration of Cr(III) nitrate for 30 or 60 days, the highest levels of chromium 

were observed in the liver, followed by the kidneys, testes, and brain. Tissue concentration 

increased nonlinearly with dose, and concentrations in the kidney increased significantly with 

duration (Tandon et al., 1979). Trivalent chromium was detected only in the livers of mice 

following administration of 4.8, 6.1, or 12.3 mg Cr(III)/kg-day as chromium (III) trichloride in 

drinking water for 1 year (Maruyama, 1982). Tissue concentrations were 40-90 times below 

those reported following administration of hexavalent chromium in this study. MacKenzie et al. 

(1958) reported that tissue concentrations of rats given Cr(III) trichloride were ninefold lower 

than those given potassium dichromate in drinking water. Sullivan et al. (1984) treated adult and 

neonatal rats with an acute oral dose of radiolabeled Cr(III) trichloride. Seven days following the 

dose, neonates and adults retained approximately 35% and 0.2% of the dose in the gut, 

respectively. Neonates accumulated 0.12%, 0.05%, and 0.0088% in the kidney, liver, and lung, 

while adults accumulated 0.003%, 0.002% and 0.0003% in the kidney, liver and lung, 

respectively. Red blood cells were found to accumulate significantly more chromium than white 

blood cells following intravenous administration of CrCl3 in the rat (Coogan et al., 1991). 

Mice given a single intraperitoneal injection of Cr(III) trichloride were found to have 

retained 87%, 73%, and 45% of the dose on day 3, 7, and 21 post-treatment. The retention of 

5
chromium was attributed to the formation of trivalent chromium complexes with proteins and 

amino acids (Bryson and Goodall, 1983). 

Mertz (1969) studied placental transfer of a variety of chemical forms of trivalent 

chromium in rats. Male and female rats fed commercial or chromium-depleted yeast diets and 

drinking water with or without 2 ppb chromium were mated. Neonates whose dams were fed the 

commercial diet contained nearly twice the chromium as neonates of dams fed the chromiumdeficient diet. Exposure of dams to trivalent chromium in drinking water did not increase the 

chromium content of the neonates. Neonatal concentrations of chromium were not increased 

following administration of CrCl3 intravenously or by gavage before, during, or after mating. 

However, administration of chromium in the form of glucose tolerance factor (GTF) by gavage 

during gestation resulted in levels in neonates that were 20%-50% of those in the dams. 

Danielsson et al. (1982) studied placental transfer of trivalent chromium in mice following 

intravenous injection of CrCl3. The highest maternal chromium concentrations were found in the 

renal cortex, skeleton, liver, and ovaries. The fetal concentration of chromium was 0.4% and 

0.8% of the maternal serum concentration when dams were injected in mid- and late-gestation, 

respectively. Chromium accumulated in the fetal skeleton and yolk sac placenta. Iijima et al. 

(1983) also reported that trivalent chromium crossed the placenta of mice injected 

intraperitoneally with CrCl3. Visek et al. (1953) reported that an insignificant amount of 51Cr 

crossed the placenta of rats in the 24 hours following intravenous injection regardless of the 

chemical form injected, the valence state, the gestational stage, or the size of the litter. In no 

instance was the radioactivity measured in the fetuses greater than 0.13% of the dose. Casey and 

Hembridge (1984) demonstrated that chromium can be transferred to infants through breast milk. 

The breast milk of 45 lactating women was found to have a chromium content averaging 0.3 

μg/L. These concentrations were taken to represent background levels in women whose 

chromium exposure occurs primarily through the diet. 

Hexavalent chromium readily enters cells through the phosphate and sulfate anionexchange carrier pathway, although a portion may remain in plasma for an extended period 

(Wiegand et al., 1985). While Cr(III) compounds are unable to cross the cell membrane by this 

pathway (Gray and Sterling, 1950), they may enter cells, but only with very low efficiency 

(Lewalter et al., 1985; O’Flaherty, 1996). Hexavalent chromium is reduced to the trivalent form 

intracellularly by the action of glutathione (Debetto and Luciani, 1988; Petrilli and De Flora, 

1978b). Following reduction to the trivalent form, chromium may interact with cellular 

macromolecules, including DNA (Wiegand et al., 1985), or may be slowly released from the cell 

(Bishop and Surgenor, 1964). 

A physiologically based model for chromium has recently been developed, which 

incorporates absorption and disposition schemes for Cr(VI) and Cr(III) throughout the body 

(O’Flaherty, 1996). The model was calibrated on the basis of published oral and intratracheal 

kinetic studies using soluble Cr(III) and Cr(VI) in the rat, and it accounts for most of the major 

features of chromium kinetics in the rat, including reduction of Cr(VI) to Cr(III). The model 

suggests the following in vivo disposition for chromium. Both Cr(III) and Cr(VI) are poorly 

absorbed from the lung and the gastrointestinal tract. Following inhalation exposure, chromium 

may be absorbed into the systemic circulation, transferred to the gastrointestinal tract by 

6
mucociliary action, or remain in the lung. Cr(VI) is reduced to Cr(III) in all tissues, including the 

lung and the gastrointestinal tract. Both Cr(III) and Cr(VI) are better absorbed from the 

gastrointestinal tract in the fasted than in the fed state, and the absorption efficiency of Cr(III) 

salts is largely dependent on the nutritional status of the animal as well as the nature of the anion 

making up the Cr(III) salt. The model assumes that reduction of Cr(VI) does not occur in the 

plasma. Cr(VI) enters cells by the phosphate and sulfate anion-exchange carrier pathway. Cr(III) 

travels in the bloodstream largely bound to amino acids, other organic acids, and plasma proteins 

such as globulins. The complexes of Cr(III) which are bound to lower molecular weight ligands 

are most likely to be able to traverse cell membranes (Mertz, 1969). A significant amount of 

absorbed chromium is taken up in the bone (Witmer and Harris, 1991; Weber, 1983). Chromium 

is also concentrated in tissues of the liver, kidney, and spleen. Once in the cell, Cr(VI) may be 

reduced to Cr(III), which may subsequently interact with cellular macromolecules, including 

DNA (Wiegand et al., 1985), or may be slowly released from the cell (Bishop and Surgenor, 

1964). 

The model suggests that the bioaccessibility of chromium to absorption processes may be 

the single most important factor determining the toxicity of a specific chromium source 

(O’Flaherty, 1996). 

Given the rapid reduction of Cr(VI) to Cr(III) in vivo, it is relevant to consider whether 

environmental exposures to Cr(VI) or administration of Cr(VI) in controlled animal experiments 

is essentially identical to environmental exposures to Cr(III) or administration of Cr(III) in 

controlled experiments. While considerably more data are available for Cr(VI) than for Cr(III), it 

appears at present that exposures to Cr(VI) have considerably different outcomes than exposures 

to Cr(III). Cr(VI) has been shown to be more toxicologically active than Cr(III) as it more readily 

crosses cell membranes. The Agency has prepared the Toxicological Reviews and IRIS 

Summaries for Cr(VI) and Cr(III) from this perspective. 

3.1.4. Metabolism 

Trivalent chromium potentiates the activity of insulin in vitro and in vitro. In the 

biologically active form, chromium occurs in a complex referred to as GTF, tentatively identified 

as a chromium-nicotinic acid complex. GTF has been suggested to operate through activation of 

membrane phosphotyrosine phosphatase in mammals, although the complete structure of the 

complex has not been identified (Mertz, 1993; Davis et al., 1996). 

3.1.5. The Essentiality of Chromium 

Cr(III) potentiates insulin action in peripheral tissue and is essential for lipid, protein, and 

fat metabolism in animals and humans. Chromium deficiency causes changes in the metabolism 

of glucose and lipids and may be associated with maturity-onset diabetes, cardiovascular 

diseases, and nervous system disorders (Anderson, 1993, 1995). The National Research Council 

(NRC) has identified an estimated safe and adequate daily dietary intake (ESADDI) for 

chromium of 50-200 μg/day (NRC, 1989), corresponding to 0.71-2.9 μg/kg-day for a 70 kg adult. 

7
The Food and Drug Administration (FDA) has selected a Reference Daily Intake for chromium 

of 120 μg/d (U.S. DHHS, 1995). 

4. HAZARD IDENTIFICATION 

Hexavalent chromium is widely considered to have significantly greater toxicity than the 

trivalent form. This results in part from the recognition of hexavalent chromium as a known 

human carcinogen by the inhalation route of exposure, from the caustic properties of many of the 

hexavalent compounds, the greater absorption of the hexavalent species following exposure by 

ingestion and inhalation, and the ability of hexavalent chromium to efficiently traverse cell 

membranes. However, relatively few studies are available in the literature that directly address 

the toxicity of trivalent chromium, particularly by the inhalation route of exposure. This lack of 

data results in considerable uncertainty regarding the hazard associated with exposures to 

trivalent chromium. 

4.1. STUDIES IN HUMANS 

4.1.1. Oral 

The essential role of trivalent chromium in glucose and lipid metabolism has been widely 

studied; however, only one study was located that addressed the oral toxicity of trivalent 

chromium in humans. Kusiak et al. (1993) reported increased mortality due to stomach cancer in 

gold miners in Ontario, Canada. Exposures to arsenic, chromium, mineral fiber, diesel 

emissions, and aluminum powder were considered as possible explanations for the excess 

stomach cancer. The authors found that the excess incidence of stomach cancer was best 

associated with the time-weighted index of exposure to chromium in miners under the age of 60. 

However, a similar association between the index of exposure to chromium and excess stomach 

cancer was not seen in older gold miners in this study. Although diet is an important risk factor 

in the onset of stomach cancer, the study was unable to consider the role of dietary habits in the 

onset of stomach cancer in the study population. While the authors suggest that chromium or a 

substance closely associated with chromium may be the causative agent for stomach cancer, the 

inability to consider important confounding factors and the absence of a clear pattern of disease 

incidence with increasing exposure make this association highly uncertain. The substantial 

uncertainties related to the association between chromium exposure and disease incidence and 

the significant confounding factors make this study unusable for risk assessment purposes. 

4.1.2. Inhalation 

Occupational exposure to chromium by inhalation has been studied in the chromate 

manufacturing and ferrochromium industries; however, exposures all include mixed exposures to 

both Cr(III) and Cr(VI). The Cr(VI) species is widely considered to be the etiologic agent in 

reports of excess cancer risk in chromium workers. However, studies are inadequate to rule out a 

8
contribution by Cr(III), and Cr(VI) cannot be unequivocally demonstrated to be the etiologic 

agent for noncarcinogenic effects following inhalation. 

Studies addressing exposures to Cr(III) alone are not available, and the role of Cr(III) in 

disease following exposures to mixtures of Cr(III) and Cr(VI) cannot be determined. Significant 

reduction of Cr(VI) to Cr(III) occurs in the lungs, and absorption of Cr(III) from lung tissue is 

known to occur (O’Flaherty, 1996). In order to be comprehensive, a summary of the results of 

studies involving mixed exposures to Cr(III) and Cr(VI) is presented below. 

A number of epidemiologic studies have considered the association between inhalation of 

chromium and noncarcinogenic endpoints, including upper respiratory irritation and atrophy, 

lower respiratory effects, and systemic effects. 

Bloomfield and Blum (l928) examined 23 men from six chromium plating plants in the 

United States. Fourteen of these workers typically spent 2-7 hours/day over vats of chromic acid, 

which generated airborne hexavalent chromium ranging from 0.12-5.6 mg/m3

. These men 

experienced nasal tissue damage, including perforated septum (2), ulcerated septum (3), chrome 

holes (6), nosebleed (9), and inflamed mucosa (9). In general, the nine remaining workers 

examined, who were not directly exposed to chromium vapors, had only inflamed mucosae. The 

authors concluded that chromic acid at concentrations greater than 0.1 mg/m3

 is likely to cause 

nasal tissue injury. However, while no concentrations lower than 0.12 mg/m3 were observed, 

injury to nasal tissue caused by lower concentrations could not be ruled out. 

Machle and Gregorius (1948) reported an incidence of nasal septal perforation of 43.5% 

in 354 employees who worked in a chromate-producing plant that manufactured sodium 

chromate and bichromate. At the time of the study, airborne chromate concentrations ranged 

from 0.1 to 2.8 mg/m3

. The plant had been in operation for at least 17 years, and some 

employees probably worked in the plant when reverberatory furnaces, a prominent source of high 

chromate exposure, were used. 

Mancuso (1951) reported on physical examinations of a random sample of 97 workers 

from a chromate-chemical plant. The results indicated that 61 of the 97 workers (63%) had 

septal perforation. The data suggested to the author that Cr(III) may be partly responsible for the 

perforations; however, there were insufficient data to make an unequivocal conclusion. 

The U.S. Public Health Service conducted a study of workers in seven 

chromate-producing plants in the early 1950s. Of 897 chromate industry workers in the study, 

57% were found to have a nasal septum perforation. Perforated septum was observed even in 

workers employed fewer than 6 months. The study indicated that exposure to chromate results in 

severe nasal tissue destruction, but exposure levels were not measured; hence, the data are of 

limited usefulness for risk assessment purposes (Federal Security Agency, 1953). 

Vigliani and Zurlo (1955) reported nasal septal perforation in workers exposed to 

chromic acid and chromates in concentrations of 0.11-0.15 mg/m3

. The lengths of exposure were 

not known. Hanslian et al. (1967) reported on otolaryngologic examinations of 77 persons 

9
exposed to chromic acid aerosol during chrome plating. Of those, 19% were observed to have 

septal perforation and 48% to have nasal mucosal irritation. The workers averaged 6.6 years of 

exposure to an airborne chromium concentration of 0.4 mg/m3

. In 14 persons, papillomas of the 

oral cavity and larynx were found. The diagnosis of papilloma was confirmed by histologic 

examination. There were no signs of atypical growth or malignant degeneration. 

Kleinfeld and Russo (1965) reported some degree of nasal septal ulceration in seven of 

nine workers in a chrome-plating plant, with four of seven demonstrating frank perforations. 

Analyses of air samples showed chromium concentrations of 0.18-1.4 mg/m3

. Data regarding the 

length of exposure and exposure concentration for individual workers were not available. 

Gomes (1972) examined 303 employees who worked in 81 electroplating operations in 

Sao Paulo, Brazil. Over two-thirds of the workers had mucous membrane or cutaneous lesions, 

with many of them having ulcerated or perforated nasal septa. The duration of exposure was not 

stated, but the author mentioned that the harmful effects were noted in under 1 year. A direct 

correlation between workers exposed to a given airborne concentration of Cr(VI) and the 

development of harmful effects could not be made. 

Cohen and Kramkowski (1973) and Cohen et al. (1974) examined 37 workers (7 male 

and 30 female) employed in the nickel-chrome department of an electroplating plant in 

comparison with 21 workers (15 male and 6 female) in other areas of the plant not significantly 

exposed to chromic acid. Smoking demographic data was not provided. Environmental air 

samples were collected from breathing zones of several workers in the exposed and control 

groups to determine concentrations of total chrome and Cr(VI). Brief medical histories were 

confined to the ear, nose, throat, and cutaneous structures. Within 1 year of employment, 12 

workers experienced nasal ulceration or perforation. Nasal ulcers and perforations were 

associated with total chromium concentrations of 1.4 to 49.3 μg/m3

, averaging 7.1 μg/m3, and 

Cr(VI) concentrations of 0.09 to 9.1 μg/m3, averaging 2.9 μg/m3. Ninety-five percent of the 37 

workers studied exhibited pathologic changes in nasal mucosa in a concentration-duration 

response. More than half of the workers employed less than 1 year had nasal pathology that was 

more severe than simple redness of the nasal mucosa. Almost all the workers (35 of 37) 

employed longer than 1 year had nasal tissue damage. The authors noted the lack of good 

industrial hygiene practices, implicating direct contact, such as touching of the nose with 

chromium-contaminated hands, as a potentially important route of exposure. 

Lucas and Kramkowski (1975) conducted a health hazard evaluation of 11 employees in 

the “hard” chrome area of an industrial plating facility. The average age of the employees was 39 

years, and the average duration of employment in the hard chrome area was 7.5 years. Medical 

examinations were conducted to evaluate the presence of dermatitis, chrome holes, old chrome 

hole scars, ulcerated nasal septum, infection of the mucosa, nasal redness, perforated nasal 

septum, reddened throat, conjunctivitis, and wheezing. Environmental air samples were 

collected from the breathing zone on all workers in the hard chrome area to determine the 

concentrations of hexavalent chromium. Cr(VI) concentrations ranged from 1 to 20 μg/m3

, 

averaging 4 μg/m3

. However, the authors attributed the nasal pathology primarily to direct 

contact. Clinical observations included injection of the nasal mucosa in five workers, ulcerated 

10
nasal septum in two workers, atrophic scarring indicative of the presence of past ulceration in 

two workers, and complete perforation of the nasal septum in four workers. Poor hygiene 

practices, including touching the nose with the hand, were noted at the plant and represented a 

confounding factor in the etiology of the nasal lesions. 

Markel and Lucas (1973) conducted a health hazard evaluation of 32 workers at a “cold 

dip” chrome plating plant who were employed in the chrome department or who regularly spent a 

portion of their workday in that area. Twenty of the employees worked in the chrome area of the 

plant for more than 5 years. A total of 16 personal and 7 general air samples were taken to 

determine the concentrations of Cr(VI). Maximum airborne Cr(VI) concentration was 3 μg/m3

. 

No workers were found to have ulcerated nasal mucosa or perforated nasal septa. Half of the 32 

employees had varying degrees of mucosal irritation. The authors did not consider this to be 

significant, because the survey was carried out at the peak of the 1972-1973 influenza epidemic. 

Lindberg and Hedenstierna (1983) compared lung function, the condition of the nasal 

septum, and subjective symptoms related to respiratory health (data obtained by questionnaire) in 

unexposed controls (119) and workers (43) exposed to chromic acid in chrome plating 

operations. Workers were further divided into low (< 2 μg Cr[VI]/m3

) and high (> 2 μg 

Cr[VI]/m3) exposure groups. Complaints of diffuse nasal symptoms (“constantly running nose,” 

“stuffy nose,” or “a lot to blow out”) were registered by 4/19 workers in the low group and half 

of the 24 workers in the high group. The authors reported reddening of the nasal mucosa at 1 to 

2 μg/m3 and nasal irritation (chronic and nasal septal ulceration and perforation) in two-thirds of 

the subjects at concentrations from 2 to 20 μg/m3. All workers with nasal ulceration had been 

exposed to chrome acid mist, which contained Cr(VI) at 20 μg/m3

, or greater near the baths. For 

pulmonary function measurements, changes in vital capacity and forced expiratory volume at 1 

second (FEVl

) were seen from Cr(VI) exposures greater than 2 μg/m3. Examination of the nasal 

septum revealed that damage was significantly greater in exposed workers than in unexposed 

controls and appeared to be somewhat more severe in the high group than in the low group. 

There was a tendency for lung function parameters to return to normal over a 2-day weekend. 

In the United States, 97 workers in chromate-producing plants had a higher incidence of 

severely red throats and pneumonia, but they did not show any increase in the incidence of other 

respiratory diseases when compared with control groups. Although bilateral hilar enlargement 

was observed, there was no evidence of excessive pulmonary fibrosis in these workers (Federal 

Security Agency, 1953). The various lung changes described in these workers may represent a 

nonspecific reaction to irritating material or a specific reaction to chromium compounds. Many 

of the conditions mentioned occur widely in the general population (NAS, 1974). 

Lindberg and Vesterberg (1983b) studied urinary excretion of proteins in 24 currently 

employed chrome platers and 27 former chrome platers. Results were compared with those for a 

group of 37 referents. Exposures for current workers were determined using personal samplers 

and were found to range from 2 to 20 μg/m3

, with an average level of 6 μg/m3. Exposures of 

former platers were thought to be higher than those for the current workers. The duration of 

exposure ranged from < 1 to 26 years. Cr(VI) exposure was found to result in renal effects in a 

dose-dependent fashion (based on elevated excretion of �-2-microglobulin as an indicator of 

11
nephrotoxicity) in current workers exposed to 4 to 20 μg/m3

 Cr(VI) over 8-hour shifts. The 

effect may be reversible since former chrome platers did not have an elevated concentration of 

either B-2-microglobulin or albumin in their urine. Most of the currently exposed workers were 

also observed to have irritation symptoms of the airways, including ulcerated nasal septum and 

complete perforations. Severe objective and subjective levels for the airway effects occurred at 

no-observed-adverse-effect levels (NOAELs) for renal toxicity. 

In another study, Saner et al. (1984) did not find increased urinary �-2-microglobulin 

levels in tannery workers in comparison with referent control workers. However, comparison of 

urinary chromium concentrations of the tannery workers in this study versus the chrome platers 

in the Lindberg and Vesterberg (1983a,b) study suggests that the latter had distinctly higher 

chromium exposures. 

Exposure to vapors of chromium salts has been suspected as a cause of asthma, coughing, 

wheezing, and other respiratory distress in ferrochromium workers (Langard, 1980). Novey et al. 

(1983) identified chromium-specific antibodies in a 32-year-old white male worker who 

experienced a productive cough, wheezing, and dyspnea within 2 weeks of beginning a new job 

electroplating with chromium. Laboratory testing of this individual was performed with placebo 

and nickel and chromium solutions vaporized by heat. The nickel and chromium solutions 

precipitated asthmatic symptoms identical to those experienced on the job. The authors 

concluded that the affected individual developed an acquired sensitivity to chromium and nickel 

vapors. 

Actual Cr(III) and Cr(VI) exposure levels in many of the studies attributing respiratory 

effects to chromium were unknown. In addition, data on other confounding factors such as 

smoking were frequently unavailable. These caveats significantly complicate determination of 

the potential health effects associated with exposure to chromium. 

Various other disease states have been attributed to chromium, but in most cases, the 

etiologic relation to chromium is doubtful because of the presence of other chemicals (NAS, 

1974). These studies, reviewed by the U.S. EPA (1984), will not be reviewed here. 

4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN 

ANIMALS—ORAL AND INHALATION 

4.2.1. Chronic Oral Studies 

Two oral chronic rodent bioassays of Cr(III) were located in the literature. Ivankovic and 

Preussman (1975) fed 60 male and female rats (per dose group) 0%, l%, 2%, or 5% Cr2O3, baked 

in bread, 5 days/week for 600 feeding days (120 weeks). The primary purpose of this study was 

to assess the carcinogenic potential of Cr2O3. The authors estimated, based on measures of food 

consumption and body weight (bw), that rats consumed 360 g/kg bw, 720 g/kg bw, and 1,800 

g/kg bw of total Cr2O3 over the duration of the study in the l%, 2%, and 5% Cr2O3 feeding 

groups, respectively. The animals were maintained on control diets following termination of the 

12
exposure until they became moribund or died. No adverse effects were noted at any feeding 

level. The highest dose level (5%), which represented a total Cr2O3 consumption for 600 days of 

feeding of 1,800 g/kg bw, corresponds to a total Cr(III) intake of 1,232 g/kg or 1,467 mg/kg-day, 

expanding exposure over 840 days (600 days at 5 days/week = 120 weeks or 840 days). The lack 

of toxicity given the high concentrations of trivalent chromium used in the dose groups may 

reflect the poor absorption of trivalent chromium by the oral route of exposure (Visek et al., 

1953; Mertz et al., 1965; MacKenzie et al., 1959; Ogawa, 1976; Henderson et al., 1979). Cr(III) 

has been found to be better absorbed in fasted than in fed rats (MacKenzie et al., 1959). The use 

of baked bread as a vehicle for dosing may have further reduced the absorption of chromium in 

the Ivankovic and Preussman (1975) study. 

Schroeder et al. (1965) exposed 54 male and 54 female Swiss mice to drinking water that 

contained 5 ppm chromium (as chromium acetate) for life (0.46 mg Cr(III)/kg/day). No increase 

in the incidence of tumors was seen in the treated animals with respect to controls. Similar 

results were obtained by Schroeder et al. (1965) for Long-Evans rats. The dose of trivalent 

chromium used in this study was 2,000- to 10,000-fold lower than the dose in the Ivankovic and 

Preussman (1975) study, and most likely did not approach the maximum tolerated dose (MTD). 

The Schroeder et al. (1965) study is considered to be an inadequate test of carcinogenicity. 

4.2.2. Subchronic Oral Studies 

Several subchronic studies regarding oral exposure to trivalent chromium were located in 

the literature. Akatsuka and Fairhall (1934) fed cats 50-100 mg of Cr(III)/day for 1-3 months. 

No effects on weights or gross or microscopic pathology of major organs were noted. This study 

cannot be used for quantitative risk assessment since the dose and duration of exposure were not 

defined precisely. 

MacKenzie et al. (1958) provided rats with 25 ppm Cr(III) in drinking water for 12 

months and noted no change in body weight, macroscopic or microscopic pathology, or clinical 

chemistry variables. The MacKenzie et al. (1958) study suggests a no-observed-effect level 

(NOEL) at 25 ppm CrCl3, equivalent to 8.2 ppm trivalent chromium. Assuming that an average 

rat weighs 0.35 kg and consumes 0.035 L water/day, 8.2 ppm is adjusted to 0.82 mg trivalent 

chromium/kg bw/day. 

Ivankovic and Preussman (1975) fed rats baked bread containing up to 5% chromic oxide 

(Cr2O3) for 90 days. The only effects observed were reductions in the absolute weights of the 

livers and spleens of animals in the high-dose group, which does not necessarily represent an 

adverse effect. This study suggests a NOAEL of 5% Cr2O3 (50,000 ppm), although no clear 

adverse effects were observed at any dose used in the study. The authors calculated, based on 

measured food consumption and body weight, that male rats in the 5% feeding group consumed 

180 g/kg Cr2O3 total over the 88-day experimental period. This corresponds to 1,399 mg/kg-day 

Cr(III). 

Anderson et al. (1997) fed Sprague-Dawley rats 0-100 mg/kg Cr(III) chloride or Cr(III) 

tripicolinate (trivalent chromium coordinated with 2-carboxypyridine) in the diet for 24 weeks. 

13
No statistical differences in body weight or blood variables were noted among the groups 

examined at 11, 17, or 24 weeks. Histological examination of the animals in the high-dose 

groups did not reveal any detectable differences. Animals fed chromium picolinate were found 

to have liver and kidney chromium concentrations two- to threefold greater than those fed 

chromium chloride, demonstrating the higher absorption of chromium tripicolinate. No toxicity 

was observed in any of the dose groups in this study. 

4.2.3. Chronic Inhalation Studies 

Several animal studies have been performed to assess the carcinogenic potential of Cr(III) 

in the respiratory tract. Only one study was located that utilized an exposure route similar to that 

expected for humans (inhalation of chromium dusts) (Baetjer et al., 1959b). 

Three strains of mice (strain A, Swiss, and C57BL) were exposed to chromiumcontaining dust (Baetjer et al., 1959b). These strains have, respectively, high, medium, and low 

spontaneous lung tumor incidences. The dust was similar to that found in the chromium 

chemical manufacturing industry, containing 13.7% Cr(VI) oxide (CrO3) and 6.9% Cr(III) oxide 

(Cr2O3), along with other metal oxides. In addition, potassium dichromate (K2Cr2O7) was added 

at a level of 1%. The animals were exposed to the dust-laden atmosphere containing between 0.5 

and 1 mg total chromium 4 hours/day, 5 days/week for an average of 39.7 weeks (range of 16 to 

58 weeks). At death or termination of exposure, the lungs were examined by means of a lowpower microscope, and abnormal tissues were submitted for histologic confirmation of tumors. 

The incidence of lung tumors was not different in exposed mice of any strain as compared 

with approximately equal numbers of the appropriate controls of unexposed mice of the same 

age. There was also no difference in those strains having high spontaneous tumor incidence with 

regard to the average number of tumors per mouse or the percent of mice with multiple tumors. 

The lung tumors present in both control and treated animals were adenomas, which appeared to 

be histologically similar; however, in exposed animals, the adenomas developed slightly earlier 

in the strain A mice. Three additional small groups of mice (two groups of 10 Swiss female mice 

and one group of 9 female strain A mice) were exposed to high concentrations of chromium dust 

(7.8 to 13 mg Cr/m3

) in a nose-only chamber 0.5 hours/day, 5 days/week for 43, 52, and 20 

weeks, respectively. No increase in the incidence of lung tumors was observed. It is unclear 

from the report whether the MTD was achieved by the dosing regimen used in these studies. 

Data on lung chromium content presented in the report indicated levels that were considerably 

lower than those observed in humans exposed occupationally. Ambiguity regarding the MTD 

and the variation in exposure periods used complicates the interpretation of the results. 

Several studies assessed the carcinogenic potential of Cr(III) in the respiratory tract 

following exposure by intratracheal introduction, intrapleural injection, or intrabronchial 

implantation (Baetjer et al., 1959b; Hueper and Payne, 1962; Levy and Venitt, 1975; Levy and 

Martin, 1983). These studies did not report an increased incidence of tumors following exposure 

to trivalent chromium. 

14
Baetjer et al. (1959b) suspended a chromium dust, similar in composition to that used in 

the inhalation studies, in olive oil, and zinc chromate and barium chromate in saline prior to 

intratracheal introduction into strain A, Swiss, and C57BL mice and mixed-breed rats (Wistar 

and McCollum stocks). The mice each received five to six installations of 0.01 to 0.05 mg 

chromium at 4- to 6-week intervals, while the rats received 15 introductions at the same dose at 

2-week intervals. The total duration of the studies was between 32 and 52 weeks. The mice 

treated with chromium had a tumor incidence similar to age-matched controls, and the rats in 

both the treated and control groups had no benign or malignant tumors. 

Hueper and Payne (1962) noted that no implantation site tumors were observed in 42 rats 

during a 24-month period following eight intrapleural implantations of 25 mg trivalent chromium 

acetate in gelatin over a 13-month period. 

The National Institute for Occupational Safety and Health (NIOSH, 1975) criteria 

document on hexavalent chromium described a written communication (Levy and Venitt, 1975) 

reporting the results of a study performed at the Chester Beatty Research Institute in London. 

Random-bred Parton Wistar rats of both sexes received a pellet in the left inferior bronchiolus 

via tracheotomy under anesthesia. The rats were kept for 2 years. One hundred rats were used in 

the test group. The pellets that were implanted contained 2 mg ground chromite ore suspended 

50/50 (weight/weight) in cholesterol. Negative control groups received either blank metal pellets 

or pellets and vehicle. Positive control groups received 3-methylcholanthrene. The lungs of all 

rats either dying during the study or killed at its termination were examined both macroscopically 

and microscopically. No bronchial carcinomas of the left lung were observed in the chromite ore 

test group. 

Levy and Martin (1983) conducted an extensive investigation of 21 chromium-containing 

test materials in Wistar rats by intrabronchial implantation of a stainless steel wire mesh pellet 

containing 2 mg test material suspended in 2 mg cholesterol. The rats were allowed to live for 2 

years, after which the study was terminated. No bronchial carcinomas were observed in the 

group receiving high silica chrome ore (III). 

4.2.4. Subchronic Inhalation Studies 

Data from subchronic animal studies identify the respiratory tract as the primary target of 

chromium toxicity following inhalation. Johansson et al. (1986) exposed rabbits to aerosols of 

hexavalent (0.9 mg/m3

 Na2CrO4) or trivalent (0.6 mg/m3 Cr(NO3)3) chromium for 5 days/week, 6 

hours/day for 4 to 6 weeks. The number of macrophages obtained from the lungs of the rabbits 

exposed to Cr(VI) was significantly increased. While the numbers of macrophages from rabbits 

exposed to Cr(III) were not increased, striking morphologic changes were observed, including 

round dark chromium-rich inclusions in the cytoplasm, an increased number of cells with a 

smooth inactive cell surface, enlarged Golgi apparatus, and a tendency toward elongated cell 

shape. The macrophages from rabbits exposed to Cr(VI) showed less marked morphologic 

changes than those exposed to Cr(III). 

15
Johansson et al. (1980) exposed groups of four rabbits to chromium dust at 

concentrations of 3.1 mg/m3

 and 0.6 mg/m3 for 5 days/week, 6 hours/day for 4 weeks. 

Macrophages collected from rabbits exposed to the higher concentration of chromium 

phagocytized significantly more chromium particles than the controls, although the number of 

nonviable macrophages was less than 3%. 

Akatsuka and Fairhall (1934) exposed two cats to chromium carbonate dust at a level that 

varied from 3.3-83 mg/m3

 (average = 58.3 mg/m3) for 86 sessions. Each session varied from 

10-60 minutes, averaging 28 minutes for one cat and 57 minutes for the other. No effects in 

terms of gross or microscopic pathology were observed upon termination of the experiment. 

Examination of control animals, if there were any, was not reported. 

Glaser et al. (1985) exposed 5-week-old male Wistar rats to aerosols of sodium 

dichromate at concentrations ranging from 0.025 to 0.2 mg Cr(VI)/m3

 22 hour/day in subacute 

(28 days) or subchronic (90 days) protocols. Subacute and subchronic exposures to Cr(VI) 

aerosol concentrations resulted in a positive correlation between exposure dose and significant 

effects on alveolar macrophages and immunologic function. Inhaled chromium was found to 

preferentially accumulate in the lung following exposure to chromate aerosols. Lung and spleen 

weights were significantly increased after both subacute and subchronic inhalation of chromate 

aerosols at concentrations greater than 0.025 mg/m3. Serum contents of triglycerides and 

phospholipids differed significantly from controls (p < 0.05) in rats exposed subchronically to 0.2 

mg/m3

 chromate. Inhalation of Cr(VI) aerosols stimulated the humoral immune system. 

Differences in the mean total serum immunoglobulin were significant at exposures above 0.025 

mg/m3

, while exposures to aerosol concentrations greater than 0.1 mg/m3 resulted in depression 

of the immune system stimulation. The primary antibody response to the B-cell-dependent 

antigen sheep red blood cell was elevated in a chromium-time and dose-dependent manner. The 

immune-stimulating effect of subchronic exposure to an aerosol with 0.05 mg/m3 chromium was 

not reversed after 2 months of fresh air regeneration. The spleen T-lymphocyte subpopulation 

was also stimulated by subchronic exposure to 0.2 mg/m3 chromium. Bronchoalveolar lavage 

(BAL) cell counts were significantly decreased following subchronic exposure to levels above 

0.025 mg/m3 chromium. The number of lymphocytes and granulocytes showed a slight but 

significant increase in the lavage fluids of the subacute and subchronically exposed groups. At 

subacute exposure concentrations up to 0.05 mg/m3

, the phagocytic activity of the alveolar 

macrophages increased; however, subchronic exposure at 0.2 mg/m3

 decreased this function 

significantly. Following subacute exposure to 0.2 mg/m3

 chromium, reductions in macrophage 

cell counts and phagocytic activities correlate with an observed lower clearance of inhaled iron 

oxide. 

Glaser et al. (1990) exposed 8-week-old male Wistar rats to sodium dichromate at 0.05, 

0.1, 0.2, and 0.4 mg Cr(VI)/m3

 22 hours/day, 7 days/week for 30-90 days. Chromium-induced 

effects were observed to occur in a strong dose-dependent manner. The authors observed 

obstructive respiratory dyspnea and reduced body weight following subacute exposure at the 

higher dose levels. The mean white blood cell count was increased at all doses (p < 0.05) and 

was related to significant dose-dependent leukocytosis following subacute exposures. Mean lung 

weights were significantly increased at exposure levels of 0.1 mg/m3

 following both the subacute 

16
and subchronic exposures. Accumulation of macrophages was seen in all of the exposure groups 

and was postulated to be a chromium-specific irritation effect that accounted for the observed 

increases in lung weights. 

Focal inflammation was observed in the upper airways following the subchronic 

exposure. BAL analyses provided more detailed information on the nature of the dichromateinduced irritation effect. BAL albumin was increased following the subacute exposure and was 

taken to indicate exudation into the alveolar region as an early irritation effect. The mean protein 

content of the cell-free lavage fluid was significantly increased in a dose-dependent fashion after 

the subacute and subchronic exposures. However, protein levels returned to control levels 

following a recovery period. Cytosolic lactate dehydrogenase and the number of mononuclear 

macrophages were also elevated following the subacute and subchronic exposures, particularly at 

the highest dose levels. The enzyme activity and number of macrophages returned to the control 

level following the recovery period. The authors concluded that chromium inhalation induced 

pneumocyte toxicity and suggested that inflammation is essential for the induction of most 

chromium inhalation effects and may influence the carcinogenicity of Cr(VI) compounds (Glaser 

et al., 1990). 

Lee et al. (1988) exposed groups of 30 male and 30 female rats to 0.5 mg/m3

 or 25 mg/m3 

CrO2 (IV) for 6 hours/day, 5 days/week for 2 years. Dust-laden alveolar macrophages with slight 

type II pneumocyte hyperplasia were noted following exposure at 0.5 mg/m3. Inhaled particles 

were deposited mainly in the alveoli adjacent to the alveolar ducts, and the dust particles 

appeared as dense particles and were phagocytized by intra-alveolar macrophages. Exposure at 

25 mg/m3

 overwhelmed the lung clearance mechanisms and resulted in significant increases in 

dust-laden macrophages, bronchioloalveolar cell hyperplasia with foamy macrophage response, 

and cholesterol granuloma in females in comparison with males. Two female rats developed 

well-differentiated cystic keratinizing squamous cell carcinomas with no tumor metastasis. The 

tumors were not characterized as neoplastic lesions. 

4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION 

4.3.1. Oral Studies 

No studies were located on reproductive or developmental effects in humans following 

exposure to Cr(III) compounds. Male and female rats treated with 1,806 mg Cr(III) kg/day as 

Cr(III) oxide 5 days/week for 60 days before gestation and throughout the gestation period had 

normal fertility, gestational length, and litter size (Ivankovic and Preussman, 1975). 

Zahid et al. (1990) fed BALB/c albino Swiss mice trivalent (chromium sulfate) and 

hexavalent (potassium dichromate) chromium at concentrations of 100, 200, and 400 ppm for 35 

days in the diet. The authors stated that the exposure groups included seven animals per group, 

and an additional seven animals were used as controls, although the report presents conflicting 

summaries of the actual group sizes throughout the report. Following the treatment, the authors 

examined the testes and epididymis of the animals. The epididymis was weighed and minced 

17
suspended in buffered formalin. Sperm counts were then subsequently determined and sperm 

were examined for morphological abnormalities. Testes were fixed with Bouin’s fluid for 1 

week and were subsequently sectioned to 0.6 micron thickness and stained with haematoxylin 

and eosin for histologic examination. Ten sections were chosen randomly from the anterior, 

middle, and posterior parts of each testis and studied. One seminiferous tubule was chosen and 

examined to determine the cellular stages of spermatogenesis and the number of degenerated 

tubules. Statistical analyses of the data were conducted using the t-test between means and the 

2 × 2 contingency Chi-square test between percentages. The authors reported deleterious effects 

on the male mouse testes, including ambiguous levels of degeneration in the outermost cellular 

layers of the seminiferous tubules, reduced (or absence of) spermatogonia per tubule, 

accumulation of germ cells in the resting spermatocytes stage, reduced sperm count in the 

epididymis, and increased percentage of morphologically abnormal sperm at all chromium 

sulfate dose levels. The authors concluded that the small but significant increase of hexavalent 

chromium in the testes of fed animals induced significant degeneration. 

Serious questions have been raised regarding the design and conduct of this study (Finley 

et al., 1993; NTP, 1996a,b, 1997). The methods utilized by Zahid et al. (1990) are considered to 

be insufficient to identify spermatogonia, likely generated nonreproducible counts of epididymal 

sperm, and resulted in the biologically implausible conclusion of reduction in spermatogonia 

numbers concurrent with unchanged spermatocyte and spermatid numbers. Additional questions 

have been raised with regard to uncertainties regarding the actual groupings of animals used and 

the statistical analysis of the data (Finley et al., 1993). 

Elbetieha and Al-Hamood (1997) examined fertility following chromium chloride 

exposures in mice. Sexually mature male and female mice were exposed to 1,000, 2,000, or 

5,000 mg/L chromium chloride in drinking water for 12 weeks. The effects of the exposures on 

fertility were examined at 140 days. No mortality or clinical signs of toxicity were reported in 

any group of male or female mice exposed at any concentration in the experiment. The authors 

reported a number of effects, although in many cases the results were not strongly dosedependent. The authors reported exposure of male mice to 5,000 ppm trivalent chromium 

compounds for 12 weeks had adverse impacts on male fertility. Testes weights were increased in 

the males exposed in the 2,000 and 5,000 mg/L dose groups, while seminal vesicle and preputial 

gland weights were reduced in the 5,000 mg/L exposed males. The number of implantation sites 

and viable fetuses were significantly reduced in females exposed to 2,000 and 5,000 mg/L 

chromium chloride. The authors did not report the amount of water ingested by the animals, 

other than to note that water ingestion was reduced in animals exposed to chromium. While the 

results of this study suggest the potential presence of reproductive effects, the lack of dose 

dependence in reported effects and the absence of data indicating actual exposures to the animals 

preclude the use of these data in risk assessment. 

4.3.2. Inhalation Studies 

No studies were located on reproductive or developmental effects in humans following 

exposure to Cr(III) compounds. No histopathologic abnormalities were observed in the testes of 

rats exposed to 0.1 mg total chromium (as a 3:2 mixture of Cr(VI) trioxide and Cr(III) oxide) for 

18
18 months (Glaser et al., 1986, 1988). No additional data regarding the teratogenicity of inhaled 

trivalent chromium could not be located in the available literature. 

4.4. OTHER STUDIES 

4.4.1. Contact Dermatitis 

Dermal exposure to chromium has been demonstrated to produce irritant and allergic 

contact dermatitis (Bruynzeel et al., 1988; Polak, 1983; Cronin, 1980; Hunter, 1974). Primary 

irritant dermatitis is related to the direct cytotoxic properties of chromium, while allergic contact 

dermatitis is an inflammatory response mediated by the immune system. Allergic contact 

dermatitis is a cell-mediated immune response that occurs in a two-step process. In the first step 

(induction), chromium is absorbed into the skin and triggers an immune response (sensitization). 

Sensitized individuals will illicit an allergic dermatitis response when exposed to chromium 

above a threshold level (Polak, 1983). Induction is generally considered to be irreversible. 

Chromium allergic dermatitis is characterized by symptoms of erythema, swelling, papules, small 

vesicles, dryness, scaling, and fissuring (Adams, 1990; MacKie, 1981). 

Chromium is one of the most common contact sensitizers in males in industrialized 

countries (Fowler, 1990; Cronin, 1980) and is associated with occupational exposures to 

numerous materials and processes, including chrome plating baths, chrome colors and dyes, 

cement, tanning agents, wood preservatives, anticorrosive agents, welding fumes, lubricating oils 

and greases, cleaning materials, and textiles and furs (Burrows and Adams, 1990; Polak et al., 

1973). Solubility and pH appear to be the primary determinants of the capacity of individual 

chromium compounds to elicit an allergic response (Fregert, 1981; Polak et al., 1973). The low 

solubility Cr(III) compounds are much less efficient contact allergens than Cr(VI) (Spruit and van 

Neer, 1966). While chromium compounds have been found to elicit an allergic response in 

occupational settings, this endpoint is not considered suitable for the development of a noncancer 

dose-response assessment. 

4.4.2. Toxicant Interactions 

Ascorbic, picolinic, and nicotinic acids have all been demonstrated to facilitate the 

absorption of Cr(III) through the intestinal wall (Anderson, 1997; ATSDR, 1993). 

4.4.3. Genotoxicity 

Trivalent chromium has been demonstrated to decrease the fidelity of DNA synthesis 

(Snow and Xu, 1991; Snow, 1994). Trivalent chromium chloride has been shown to produce 

genotoxic DNA adducts that inhibit DNA replication and are mutagenic (Snow, 1994). In 

general, trivalent chromium was not mutagenic in bacterial assays when tested with or without a 

mammalian activation system (Venitt and Levy, 1974; Petrilli and DeFlora, 1977, 1978a,b). In 

one study, trivalent chromium was mutagenic in Baccillus subtilis, but this activity was low 

compared with compounds of hexavalent chromium (Nakamuro et al., 1978). 

19
There is conflicting information with regard to the ability of trivalent chromium to 

interact with DNA. Compounds of trivalent chromium were found to be clastogenic in BALB/c 

cells as CrCl3 (Raffetto, 1977); CHO cells as CrCl3, Cr(NO3)3, KCr(SO4)2, or Cr(CH3COO)3 

(Levis and Majone, 1979); Don Chinese hamster cells as hydrated CrCl3 (Ohno et al., 1982); and 

cultured human leukocytes as Cr(CH3COO)3 (Nakamuro et al., 1978). However, compounds of 

Cr(III) were not clastogenic in mouse FM3A cells as Cr2(SO4)3 (Umeda and Nishimura, 1979), 

cultured human leukocytes as CrCl3 or Cr(NO3)3 (Nakamuro et al., 1978), or Don Chinese 

hamster cells as Cr2(SO4)3 (Ohno et al., 1982). 

Cr(III) picolinate was shown to produce chromosome damage 3- to 18-fold above the 

control levels following soluble doses of 0.05, 0.1, 0.5, and 1.0 mM over a 24-hour treatment. 

The chromosome damage was inferred to result from the picolinate ligand following the 

demonstration of clastogenicity in the absence of Cr(III) (Stearns et al., 1995). 

4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS AND 

MODE OF ACTION (IF KNOWN)—ORAL AND INHALATION 

4.5.1. Oral Studies 

4.5.1.1. Human Studies 

No human studies addressing noncarcinogenic effects of trivalent chromium were located 

in the available literature. 

4.5.1.2. Animal Studies 

Two oral chronic rodent bioassays of Cr(III) were located in the literature. Ivankovic and 

Preussman (1975) fed male and female rats up to 5% Cr2O3 baked in bread 5 days/week for 120 

weeks. No adverse effects were noted at any feeding level. Schroeder et al. (1965) exposed mice 

and rats to drinking water containing 5 ppm Cr(III) for life. No increase in the incidence of 

tumors was seen in the treated animals with respect to controls. 

Anderson et al. (1997) evaluated the subchronic toxicity of Sprague-Dawley rats fed 0-

100 mg/kg Cr(III) chloride or Cr(III) tripicolinate in the diet for 24 weeks. No statistical 

differences in body weight or blood variables were noted among the groups examined at 11, 17, 

or 24 weeks. Histologic examination of the animals in the high-dose groups did not reveal any 

detectable differences. No toxicity was observed in any of the dose groups in this study. 

20
4.5.2. Inhalation Studies 

4.5.2.1. Human Studies 

All of the available studies of occupational exposures include mixed exposures to both 

Cr(III) and Cr(VI). The Cr(VI) species has been suggested as the likely etiologic agent in reports 

of excess cancer risk in chromium workers; however, Cr(VI) cannot be unequivocally 

demonstrated to be the etiologic agent for noncarcinogenic effects following inhalation. While 

data addressing exposures to Cr(III) alone are not available, significant reduction of Cr(VI) to 

Cr(III) occurs in the lungs, and absorption of Cr(III) from lung tissue is known to occur (ATSDR, 

1993; O’Flaherty, 1996). The following discussion presents results of studies involving mixed 

exposures to Cr(III) and Cr(VI). 

4.5.2.1.1. Respiratory tract effects. Three studies on chrome platers seem to provide some 

quantitative information on upper respiratory irritation after exposure to Cr(VI) as chromic acid. 

Cohen et al. (1974) reported that nasal ulcers and perforations were associated with total 

chromium concentrations of 1.4 to 43.9 μg/m3

, averaging 7.1 μg/m3, and Cr(VI) concentrations 

of 0.09 to 9.1 μg/m3, averaging 2.9 μg/m3. The authors implicated direct contact, such as 

touching of the nose with chromium-contaminated hands, as a potentially important route of 

exposure. Lucas and Kramkowski (1975) reported similar results following worker exposure to 

Cr(VI) concentrations ranging from 1 to 20 μg/m3

, averaging 4 μg/m3. Lindberg and 

Hedenstierna (1983) also found similar effects on nasal pathology and subjective symptoms. 

They reported reddening of the nasal mucosa at 1 to 2 μg/m3, and nasal irritation (chronic and 

nasal septal ulceration and perforation) in two-thirds of the subjects at concentrations from 2 to 

20 μg/m3

. Changes in vital capacity and forced expiratory volume were reported following 

Cr(VI) exposures greater than 2 μg/m3. 

4.5.2.1.2. Renal effects. Cr(VI) exposure as low as 4 to 6 μg/m3

 has been reported to result in 

elevated excretion of �-2-microglobulin (Lindberg and Vesterberg, 1983b). The effect may be 

reversible since former chrome platers did not have an elevated concentration of either 

�-2-microglobulin or albumin in their urine. 

In conclusion, effects on the airways and kidney have been observed in chrome platers 

exposed subchronically to chromic acid mist containing chromium in air at concentrations 

greater than 1 μg/m3

. Such effects include reddening of nasal mucosa, nasal irritation 

(ulceration, perforation), changes in pulmonary function, and renal proteinuria. Few of the 

available studies, however, provide quantitative concentration-response data on chromium health 

effects. 

4.5.2.2. Animal Studies 

In the only study specifically addressing noncarcinogenic effects by inhalation of Cr(III), 

Johansson et al. (1986) exposed rabbits to aerosols of trivalent chromium (Cr(NO3)3) at 

concentrations of 0.6 and 0.9 mg/m3 for 6 hours/day, 5 days/week for 4-6 weeks. Striking 

morphologic changes were observed, including round dark chromium-rich inclusions in the 

21
cytoplasm, an increased number of cells with a smooth inactive cell surface, enlarged Golgi 

apparatus, and a tendency toward elongated cell shape. 

Johansson et al. (1980) exposed rabbits to chromium dust at 3.1 mg/m3

 and 0.6 mg/m3 for 

5 days/week, 6 hours/day for 4 weeks. Alveolar macrophages harvested from the exposed 

animals phagocytized significantly more chromium particles than those harvested from controls, 

although the number of nonviable macrophages was within the normal range (less than 3%) 

(Johansson et al., 1980). 

4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION 

Applying the criteria for evaluating the overall weight of evidence for carcinogenicity to 

humans outlined in EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a), 

trivalent chromium is most appropriately designated a Group D–Not classified as to its human 

cartinogenicity. Using the Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 

1996a), there are inadequate data to determine the potential carcinogenicity of trivalent 

chromium. The classification of hexavalent chromium as a known human carcinogen raises a 

concern for the carcinogenic potential of trivalent chromium. The inability to elucidate the 

contribution of trivalent chromium to cancer incidence following exposures to total chromium 

mixtures in these studies precludes a separate determination of whether trivalent chromium 

alone has carcinogenic potential. Data from oral and inhalation exposures of animals to trivalent 

chromium are inadequate to determine the carcinogenicity of trivalent chromium. The 

International Agency for Research on Cancer (IARC, 1990) concluded that animal data are 

inadequate for the evaluation of the carcinogenicity of Cr(III) compounds. Furthermore, 

although there is sufficient evidence of respiratory carcinogenicity associated with exposure to 

chromium, the relative contributions of Cr(III), Cr(VI), metallic chromium, or soluble versus 

insoluble chromium to carcinogenicity cannot be elucidated. 

4.7. OTHER HAZARD IDENTIFICATION ISSUES 

4.7.1. Possible Childhood Susceptibility 

A number of factors may differentially affect the response of children to toxicants such as 

Cr(III). These factors include diet, physical environment, as well as maturation of physiological 

and biochemical processes. At present, there is too little information to make any statements 

about how these factors may specifically affect the toxicological responses of Cr(III) in children, 

be they cancer or noncancer. 

4.7.2. Possible Sex Differences 

At present, there is too little information to make any statements about the extent to 

which men differ from women in susceptibility to Cr(III) toxicity. 

22
5. DOSE-RESPONSE ASSESSMENTS 

5.1. ORAL REFERENCE DOSE (RfD) 

The RfD is based on the assumption that thresholds exist for certain toxic effects such as 

cellular necrosis, but may not exist for other toxic effects such as carcinogenicity. In general, the 

RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure 

to the human population (including sensitive subgroups) that is likely to be without an 

appreciable risk of deleterious effects during a lifetime. Please refer to the Oral RfD Background 

Document (on IRIS) for an elaboration of these concepts. 

5.1.1. Choice of Principal Study and Critical Effect 

Relatively few studies were located in the literature that addressed the oral toxicity of 

Cr(III). Ivankovic and Preussman (1975) fed rats baked bread containing up to 5% chromic 

oxide (Cr2O3) for 840 days. No effects due to Cr2O3 treatment were observed at any dose level. 

Ivankovic and Preussman (1975) also fed rats baked bread containing up to 5% Cr2O3 for 90 

days. The only effects observed were reductions in the absolute weights of the livers and spleens 

of animals in the high-dose group. The absence of toxicity of trivalent chromium following these 

extraordinarily high doses likely reflect the low oral bioavailability of dietary Cr2O3. 

In a subchronic study, Anderson et al. (1997) evaluated the toxicity of 0-100 mg/kg 

Cr(III) chloride and Cr(III) tripicolinate fed to Sprague-Dawley rats in the diet. Both of these 

forms of chromium have considerably higher bioavailability than that of Cr2O3. Histologic 

examination of the animals in the high-dose groups did not reveal any detectable differences with 

controls, and no toxicity was observed in any of the dose groups in this study. Dose levels in this 

study were considerably lower than those used by Ivankovic and Preussman (1975). 

Elbetieha and Al-Hamood (1997) examined fertility following chromium chloride 

exposures in sexually mature mice at concentrations of 1,000, 2,000, or 5,000 mg/L chromium 

chloride in drinking water for 12 weeks. No mortality or clinical signs of toxicity were reported 

in any group of male or female mice exposed at any concentration in the experiment. The 

authors reported a number of effects on male fertility, although in many cases the results were not 

strongly dose dependent. The authors also reported a reduced number of implantation sites and 

viable fetuses in exposed females. The authors did not report the amount of water ingested by 

the animals, other than to note that water ingestion was reduced in animals exposed to chromium. 

While this study suggests the potential presence of reproductive effects, the lack of dose 

dependence in reported effects and the absence of data indicating actual exposures to the animals 

preclude the use of these data in risk assessment. 

The Ivankovic and Preussman (1975) studies are considered to be most appropriate for 

development of the RfD. 

5.1.2. Methods of Analysis 

23
Ivankovic and Preussman (1975) fed groups of 60 male and 60 female rats chromic oxide 

(Cr2O3) baked in bread at dietary levels of 0%, 1%, 2%, or 5%, 5 days/week for 600 feedings 

(840 total days). Body weight and food consumption were monitored. The average total 

amounts of ingested Cr2O3 were given as 360, 720, and 1,800 g/kg bw for the 1%, 2%, and 5% 

treatment groups, respectively. The animals were maintained on control diets following 

termination of exposure until they became moribund or died. All major organs were examined 

histologically. Other toxicologic parameters were not mentioned explicitly but may have 

included some or all of those described for the accompanying subchronic study (see below). No 

effects due to Cr2O3 treatment were observed at any dose level. 

Ivankovic and Preussman (1975) also treated rats (both sexes, 12-19 rats/group) at dietary 

levels of 0%, 2%, or 5% Cr2O3 in bread, 5 days/week for 90 days. Food consumption and body 

weight were monitored. Toxicologic parameters included serum protein, bilirubin, hematology, 

urinalysis, organ weights, and histopathology. With the exception of reductions (12%-37%) in 

the absolute weights of the livers and spleens of animals in the high-dose group, no effects could 

be detected that could be attributed to the Cr2O3 treatment. 

5.1.3. RfD Derivation 

No effects were reported at any dose level in Ivankovic and Preussman (1975) chronic 

study. The highest dose group (receiving 5% Cr2O3 in the diet for 600 feedings) can be 

considered a NOAEL for the study and was selected for derivation of the reference dose. The 5% 

dose group received an equivalent of 1,800 g/kg body weight. Adjustment of this dose level 

based on the amount of ingested Cr(III) (0.6849 Cr/g Cr2O3) and the feeding schedule (600 

feeding days × 5 days/7 days) yields an adjusted NOAEL of 1,468 mg/kg-d. The lack of toxicity 

given the high concentrations of trivalent chromium used in the dose groups may reflect the poor 

absorption of trivalent chromium by the oral route of exposure (Visek et al., 1953; Mertz et 

al.,1965; MacKenzie et al., 1959; Ogawa, 1976; Henderson et al., 1979). Cr(III) has been found 

to be better absorbed in fasted than in fed rats (MacKenzie et al., 1959). The use of baked bread 

as a vehicle for dosing may have further reduced the absorption of chromium in the Ivankovic 

and Preussman (1975) study. 

The adjusted NOAEL is further modified by two 10-fold uncertainty factors to account 

for the expected interspecies and interhuman variability in lieu of specific data. An additional 

10-fold modifying factor is applied to reflect database deficiencies, including the lack of a study 

in a nonrodent mammal, lack of unequivocal data evaluating reproductive impacts, and the 

concern regarding potential reproductive effects raised by the study of Elbetieha and Al-Hamood 

(1997). The following additional uncertainties relate to the NOAEL derived from the Ivankovic 

and Preussman (1975) study: (1) the effects observed in the 90-day study were not explicitly 

addressed in the 2-year study; (2) the effect of the vehicle (baked bread) on absorption of 

chromium is uncertain, and the relevance of this dosing regimen to exposures in the environment 

is unclear; and (3) animals were allowed to die naturally after exposure stopped (2 years) and 

only then was histology performed. Application of the 100-fold uncertainty factor and 10-fold 

modifying factor to the adjusted NOAEL of 1,468 mg/kg-d gives the reference dose of 1.5 

mg/kg-d. 

24
5.2. INHALATION REFERENCE CONCENTRATION (RfC) 

The inhalation RfC is based on the assumption that thresholds exist for certain toxic 

effects such as cellular necrosis but may not exist for other toxic effects such as carcinogenicity. 

In general, the RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a 

daily exposure to the human population (including sensitive subgroups) that is likely to be 

without an appreciable risk of deleterious effects during a lifetime. 

Studies of occupational exposure to chromium by inhalation all involve mixed exposures 

to both Cr(III) and Cr(VI). While data addressing exposures to Cr(III) alone are not available, 

significant reduction of Cr(VI) to Cr(III) occurs in the lungs, and absorption of Cr(III) from lung 

tissue is known to occur (O’Flaherty, 1996). Cr(VI) cannot be unequivocally demonstrated to be 

the sole etiologic agent for noncarcinogenic effects following inhalation. 

Three studies on chrome platers reported upper respiratory irritation after exposure to 

Cr(VI) as chromic acid. In the study of Cohen et al. (1974), nasal ulcers and perforations were 

associated with total chromium concentrations of 1.4 to 43.9 μg/m3

, averaging 7.1 μg/m3. 

Ninety-five percent of the 37 workers studied exhibited pathologic changes in nasal mucosa in a 

concentration-duration response. More than half of the workers employed less than 1 year had 

nasal pathology that was more severe than simple redness of the nasal mucosa. Almost all 

workers (35 of 37) employed longer than 1 year had nasal tissue damage. The authors implicated 

direct contact, such as touching of the nose with chromium-contaminated hands, as a potentially 

important route of exposure. Lucas and Kramkowski (1975) revealed similar results. Lindberg 

and Hedenstierna (1983) also found similar effects on nasal pathology and subjective symptoms. 

All workers with nasal ulceration had been exposed to chrome acid mist, which contained Cr(VI) 

at 20 μg/m3

, or greater near the baths. Changes in vital capacity and forced expiratory volume 

were seen following Cr(VI) exposures greater than 2 μg/m3

. 

Only one animal study addressed exposure to Cr(III) by inhalation. Johansson et al. 

(1986) reported the results of a subchronic study in which rabbits were exposed to aerosols of 

trivalent chromium (Cr(NO3)3) at concentrations of 0.6 and 0.9 mg/m3 for 6 hours/day, 5 

days/week for 4-6 weeks. Striking morphologic changes were observed, including round dark 

chromium-rich inclusions in the cytoplasm, an increased number of cells with a smooth inactive 

cell surface, enlarged Golgi apparatus, and a tendency toward elongated cell shape. This study 

utilized small groups and focused on endpoints that are not considered to be appropriate for 

development of an RfC for Cr(III). 

Data are considered to be inadequate for development of an RfC due to the lack of a 

relevant toxicity study addressing respiratory effects of Cr(III). The currently available data are 

inadequate to elucidate the contribution of trivalent chromium to respiratory effects observed 

following occupational exposures to mixtures of trivalent and hexavalent chromium. The one 

animal study that evaluated the toxicity of trivalent chromium by the inhalation route of exposure 

(Johansson et al., 1986) utilized only one exposure concentration and did not identify a lowestobserved-adverse-effect level. As a result, this study is considered inadequate to support the 

25
development of an RfC for trivalent chromium, and an RfC for trivalent chromium cannot be 

developed at this time. 

5.3. CANCER ASSESSMENT 

Occupational exposure to airborne chromium has been studied in the chromate 

manufacturing and ferrochromium industries; in all cases exposures all include mixed exposures 

to both Cr(III) and Cr(VI). Data addressing exposures to Cr(III) alone are not available. Cr(VI) 

has been classified as a known human carcinogen, and the contribution of Cr(III) to the observed 

lung cancer in these populations cannot be elucidated from these studies. Animal data are 

inadequate for the evaluation of the carcinogenicity of Cr(III) compounds. The two oral studies 

located in the available literature (Schroeder et al., 1965; Ivankovic and Preussman, 1975) 

reported negative results for rats and mice. Several animal studies have been performed to assess 

the carcinogenic potential of Cr(III) by inhalation. These studies have not found an increased 

incidence of lung tumors following exposure either by natural routes, intrapleural injection or 

intrabronchial implantation (Baetjer et al., 1959b; Hueper and Payne, 1962; Levy and Venitt, 

1975; Levy and Martin, 1983). For the reasons stated above, a quantitative dose-response 

assessment has not been generated for Cr(III). 

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION 

OF HAZARD AND DOSE RESPONSE 

6.1. HUMAN HAZARD POTENTIAL 

Chromium is a naturally occurring element that may exist in several chemical forms and 

valence states in the environment. The most commonly occurring valence states are chromium 

metal (0), trivalent chromium (III), and hexavalent chromium (VI). Cr(III) potentiates the action 

of insulin in peripheral tissue and is essential for animals and humans. Adults in the United 

States are estimated to ingest approximately 60 μg/day of chromium from food (ATSDR, 1993). 

NRC has identified an ESADDI for chromium of 50-200 μg/d (NRC, 1989), 

corresponding to 0.71-2.9 μg/kg/day for a 70 kg adult. FDA has selected a Reference Daily 

Intake for chromium of 120 μg/d (U.S. DHHS, 1995). 

The bioavailability of chromium may be the single most important factor determining the 

toxicity of a specific chromium source (O’Flaherty, 1996). Ingested hexavalent chromium is 

efficiently reduced to the trivalent form in the gastrointestinal tract. Gastrointestinal absorption 

of Cr(VI) occurs with greater efficiency than absorption of Cr(III), and absorption of ingested 

trivalent chromium is estimated to be less than 3%. Trivalent chromium is absorbed very slowly 

by inhalation. Following inhalation exposure, chromium may be absorbed into the systemic 

circulation, transferred to the gastrointestinal tract by mucociliary action, or remain in the lung. 

26
A significant amount of absorbed chromium is taken up in the bone, liver, kidney, and 

spleen. Hexavalent chromium readily crosses cell membranes through the phosphate and sulfate 

anion-exchange carrier pathway. Cr(III) compounds may cross cell membranes, but only with 

very low efficiency. There is conflicting information regarding the ability of trivalent chromium 

to interact with DNA. In general, trivalent chromium was not mutagenic in bacterial assays when 

tested with or without a mammalian activation system. 

Occupational exposure to trivalent chromium and other chromium compounds by 

inhalation has been studied in the chromate manufacturing and ferrochromium industries; 

however, all studies include mixed exposures to both Cr(III) and Cr(VI). While the Cr(VI) 

species is the likely etiologic agent in reports of excess cancer risk in chromium workers, studies 

are inadequate to rule out a contribution of Cr(III) to chromium carcinogenicity, and data 

addressing exposures to Cr(III) alone are not available. 

Relatively few studies were located in the literature that addressed the oral or inhalation 

toxicity of Cr(III). No effects other than reductions of the absolute weights of livers and spleens 

of rats have been observed following oral exposure to Cr(III). While striking morphologic 

changes occurred in the macrophages of rabbits exposed to Cr(III) aerosols in the one inhalation 

study of Cr(III) in animals, the database is inadequate to support development of an RfC for 

Cr(III). 

Chromium is one of the most common contact sensitizers in industrialized countries, and 

allergic contact dermatitis is associated with occupational exposures to numerous materials and 

processes, including chrome plating baths, chrome colors and dyes, cement, leather tanning 

agents, and wood preservatives. 

6.2. DOSE RESPONSE 

Studies of inhalation of mixtures of trivalent and hexavalent chromium in occupational 

populations support the classification of Cr(VI) as a known human carcinogen but provide 

inadequate data for evaluation of carcinogenicity of Cr(III) compounds. 

The database on noncarcinogenic effects of Cr(III) is also lacking. Relatively few studies 

were located in the literature that addressed the oral toxicity of Cr(III). Of these, the Ivankovic 

and Preussman (1975) study was judged to be the only study suitable for development of an RfD 

for Cr(III). The confidence in the RfD developed using the Ivankovic and Preussman (1975) 

study is low. The primary purpose of the Ivankovic and Preussman (1975) study was to assess 

the carcinogenic potential of Cr2O3. The confidence in the principal study is considered low 

because of the lack of explicit detail on study protocol and results. No effects due to Cr2O3 

treatment were observed at any dose level in this study. No macroscopic or histologic signs of 

toxicity were noted in the 2-year study, although the effects observed in the 90-day study were 

not explicitly addressed. Animals in this study were allowed to die naturally after exposure 

stopped (2 years) and only then was histology performed. Data on potential reproductive and 

developmental effects of Cr(III) are lacking. A modifying factor of 10 was applied to the 

27
adjusted NOAEL to account for the potential reproductive toxicity identified by the study of 

Elbetieha and Al-Hamood (1997) and the absence of a credible study addressing reproductive 

endpoints. The adjusted NOAEL is further modified by two 10-fold uncertainty factors to 

account for the expected interspecies and interhuman variability in lieu of specific data. Only 

one study was located that specifically addressed noncarcinogenic effects of Cr(III) by the 

inhalation route of exposure (Johansson, 1986). While this study reported striking morphologic 

changes in the macrophages of rabbits exposed to Cr(III) aerosols, the database is inadequate to 

support development of an RfC for Cr(III). Nasal septum irritation, atrophy, and perforations 

have been widely reported following mixed exposures to hexavalent and trivalent chromium in 

the occupational setting. The available studies are inadequate to determine whether trivalent 

chromium contributed to the observed effects. 

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Baetjer, AM; Lowney, JF; Steffee, H; et al. (1959b) Effect of chromium on incidence of lung 

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Bishop, C; Surgenor, M, eds. (1964) The red blood cell: a comprehensive treatise. New York: 

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38
APPENDIX A. EXTERNAL PEER REVIEW— 

SUMMARY OF COMMENTS AND DISPOSITION 

The support document and IRIS summary for trivalent chromium have undergone both 

internal peer review performed by scientists within EPA and a more formal external peer review 

performed by scientists in accordance with EPA guidance on peer review. Comments made by 

the internal reviewers were addressed prior to submitting the documents for external peer review 

and are not part of this appendix. The external peer reviewers were tasked with providing written 

answers to general questions on the overall assessment and on chemical-specific questions in 

areas of scientific controversy or uncertainty. A summary of significant comments made by the 

external reviewers and EPA’s response to these comments follows. 

Comments on General Questions 

1. Are you aware of any other data/studies that are relevant (i.e., useful for the hazard 

identification or dose-response assessment) for the assessment of the adverse health effects, 

both cancer and noncancer, of this chemical? 

A. Comment: A new report has been found showing significant embryotoxic and fetotoxic 

damage due to exposure of rats and mice to high doses of Cr(VI) or Cr(III) in drinking water. I 

don’t feel confident rederiving an RfD based on these data, and the doses are clearly very high. 

However, derivation of an RfD based on an observed toxicological effect appears to be 

preferable to an RfD based on a NOAEL. 

Response to Comment: The report has been added to the reproductive/developmental 

studies section of the toxicological review document. The study reports on a variety of 

embryotoxic and fetotoxic endpoints; however, many of the observed effects did not occur in a 

clear dose-dependent fashion. Further, the authors did not indicate the amount of water ingested 

by the animals and only stated that water ingestion was reduced in the treatment groups relative 

to the controls. This omission precludes determination of the actual doses experienced by the 

treated animals. This study is not considered to be sufficient for development of the RfD for 

Cr(III). 

B. Comment: The study by Baetjer et al. (1959b) needs some more discussion regarding the 

question as to whether the MTD has been achieved in this particular study. From the published 

paper there is no indication that, indeed, the animals had been sufficiently dosed, and it is 

therefore questionable whether this study should be labeled an adequate carcinogenicity study. 

Response to Comment: The discussion has been added to the text. 

C. Comment: The documents correctly state that Cr(VI) gets transformed to Cr(III) in vivo, but 

they skirt the issue of whether or not a Cr(VI) study is really a study of in vivo exposure to 

Cr(III). 

39
Response to Comment: Given the rapid reduction of Cr(VI) to Cr(III) in vitro, it is 

relevant to consider whether environmental exposures to Cr(VI) or administration of Cr(VI) in 

controlled animal experiments is essentially identical to environmental exposures to Cr(III) or 

administration of Cr(III) in controlled experiments. While considerably more data are available 

for Cr(VI) than for Cr(III), it appears at present that exposures to Cr(VI) have considerably 

different outcomes than exposures to Cr(III). The Agency has prepared the Toxicological 

Reviews and IRIS files for Cr(VI) and Cr(III) from this perspective. 

2. For the RfD and RfC, has the most appropriate critical effect been chosen (i.e., that adverse 

effect appearing first in a dose-response continuum)? For the cancer assessment, are the 

tumors observed biologically significant? Relevant to human health? Points relevant to this 

determination include whether or not the choice follows from the dose-response assessment, 

whether the effect is considered adverse, and if the effect (including tumors observed in the 

cancer assessment) and the species in which it is observed is a valid model for humans. 

A. Comment: I believe the Agency is a bit conservative regarding the confidence of the RfD. 

The Ivankovic and Preussman (1975) study appears to be done according to acceptable practices 

at the time. I also take issue with the modifying factors. The Agency used a modifying factor of 

10 to reflect uncertainty in the database. I disagree with the speculation that the NOAEL could 

be a LOAEL. The fact that uptake is low and variable does not justify such a high uncertainty 

factor, and the fact that the animals died naturally if anything would tend to increase disease 

incidence rates. I believe a threefold modifying factor is sufficient. I would also note that the 

authors arbitrarily dropped the RfD by an additional 1/3 by rounding down from 1.468 to 1. A 

more realistic estimate might be 1,468/300 = 5 mg/kg-day. 

Response to Comment: In order to be conservative regarding the limited database on 

Cr(III), the Agency supports the use of a 10-fold modifying factor to reflect uncertainty in the 

database, including uncertainty resulting from the deficiencies in the database addressing 

potential reproductive and developmental effects. The speculation that the NOAEL could be a 

LOAEL has been removed from the document. The RfD has been rounded to 1.5. 

B. Comment: In consideration of uncertainties surrounding the critical study for the RfD, such 

as the appropriateness of the method of administration (in baked bread, which might be expected 

to have a lesser bioavailability than if administered in feed or water), the use/application of a 

modifying factor of 3 (reducing the RfD to about 0.3 mg/kg-day) seems appropriate. 

Response to Comment: The derivation of the RfD using the data of Ivankovic and 

Preussman (1975) incorporated a 10-fold uncertainty factor to account for uncertainties in the 

study, including the likely low absorption of chromium from the baked bread. The Agency 

considers the current uncertainty factors to be sufficient for development of the RfD. 

3. Have the noncancer and cancer assessments been based on the most appropriate studies? 

These studies should present the critical effect/cancer (tumors or appropriate precursor) in 

40
the clearest dose-response relationship. If not, what other study (or studies) should be 

chosen and why? 

A. Comment: The RfC should be for total chromium since it is not clear that soluble chromium 

species make up all of the hexavalent chromium species in the mixture, nor that insoluble 

chromium species consist solely of trivalent species. Furthermore, the data suggest that there 

might be a positive interaction between the two forms of chromium and that the risk for exposure 

to a mixture is not the sum (or average) of the risks from either species. However, the available 

data do not provide any evidence that trivalent chromium alone is toxic by inhalation. The data 

are inconclusive with regard to inhalation exposure to trivalent chromium. 

Response to Comment: Considerable data are available regarding the effects of 

inhalation of hexavalent chromium in the form of chromic acid mists and hexavalent chromium 

particulates. The limited data available for trivalent chromium suggest that this compound may 

behave essentially as a nuisance dust upon inhalation. The Agency considers the data to be 

insufficient to support the application of the RfCs derived for hexavalent chromium to the 

trivalent species. 

4. Studies included in the RfD and RfC under the heading “Supporting/Additional Studies” are 

meant to lend scientific justification for the designation of critical effect by including any 

relevant pathogenesis in humans, any applicable mechanistic information, any evidence 

corroborative of the critical effect, or to establish the comprehensiveness of the database 

with respect to various endpoints (such as reproductive/developmental toxicity studies). 

Should other studies be included under the “Supporting/Additional” category? Should some 

studies be removed? 

A. Comment: Some of the statements related to the genotoxic effects of trivalent chromium are 

either inaccurate or misleading. 

Response to Comment: The recommended modifications to this section have been made. 

B. Comment: The new data on reproductive toxicity of chromium in the drinking water needs 

to be carefully compared to the NTP study in which rats and mice were fed potassium chromate 

in the diet. The form of chromium and route of exposure are clearly of paramount importance. 

Response to Comment: A discussion comparing and contrasting the results of the NTP 

studies and the new report has been added to the reproductive/developmental studies section of 

the Toxicological Review document. The report of Elbetieha and Al-Hamood (1997) raises the 

possibility of reproductive effects at very high doses, but the observed endpoints do not show a 

clear dose response, and the authors did not provide the data on drinking water ingestion required 

to determine the doses experienced by the treatment groups. This study is not considered 

sufficient for development of the RfD. 

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5. For the noncancer assessments, are there other data that should be considered in developing 

the uncertainty factors or the modifying factor? Do you consider that the data support the 

use of different (default) values than those proposed? 

A. Comment: The appropriate data have been considered in developing the uncertainty factors 

and the modifying factor. 

6. Do the confidence statements and weight-of-evidence statements present a clear rationale 

and accurately reflect the utility of the studies chosen, the relevancy of the effects (cancer 

and noncancer) to humans, and the comprehensiveness of the database? Do these statements 

make sufficiently apparent all the underlying assumptions and limitations of these 

assessments? If not, what needs to be added? 

A. Comment: The evidence for the role or lack of role of trivalent chromium in human cancer 

is not convincingly presented. In particular the lack of effect of feeding rats chromium-laden 

bread is not balanced by any demonstration of chromium uptake in the animals. 

Response to Comment: The Toxicological Review document concludes that there are 

inadequate data to determine the potential carcinogenicity of trivalent chromium. This should 

not be construed as a conclusion that trivalent chromium is not carcinogenic. 

Comments on Chemical-Specific Questions 

1. Are the conclusions of Zahid et al. (1990) regarding potential reproductive toxicity of Cr(III) 

in any way countered by the results of the NTP study? 

A. Comment: If NTP was not able to reproduce Zahid’s results, I do not believe Zahid’s results 

should be considered. 

B. Comment: The Zahid et al. studies are supported, but in a more realistic fashion by the 

studies of Juniad and Kanojia. 

Response to Comments: The studies of Zahid et al. (1990) and Juniad et al. and Kanojia 

et al. (1996) did not involve common endpoints. The NTP study was unable to repeat the 

findings of Zahid et al. The results of Juniad and Kanojia provide evidence of reproductive and 

fetotoxic effects of Cr(VI) at high doses but do not support the findings of Zahid et al. regarding 

toxicity of Cr(III). 

C. Comment: Additional description should be provided regarding the report of Zahid et al. in 

relation to the NTP study. 

Response to Comment: Additional description has been added. 

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2. Are there any studies available which could be used to develop an RfC for trivalent 

chromium? 

A. Comment: I agree with the document that there are no adequate data for Cr(III). 

B. Comment: I agree with EPA’s assessment that there are no suitable data sets to use in 

calculating an RfC for airborne Cr(III). 

Response to Comments: An RfC for airborne Cr(III) has not been developed. 

3. The principal study (Mancuso, 1975) and the follow-up study (Mancuso, 1997) show the best 

dose-response relationship for total chromium, but animal data only support a conclusion of 

carcinogenicity of hexavalent chromium. Should the potency estimate address total 

chromium or hexavalent chromium? 

A. Comment: Mancuso alleges that his data support a conclusion that both Cr(III) and Cr(VI) 

are carcinogens. His data set is very small, and in my view, it lacks the power to distinguish 

between Cr(VI) and total chromium. The animal data present a convincing story that Cr(III) is 

not carcinogenic. Hence, I believe the potency estimates should address only hexavalent 

chromium. EPA should be more explicit as to why they discount Mancuso’s allegation. 

Response to Comment: Additional commentary has been added to the section addressing 

the conclusion that only Cr(VI) is known to be carcinogenic by the inhalation route of exposure. 

B. Comment: The potency estimate should be based on total chromium but should note that the 

exposure is mixed (and give the relative proportions of Cr(III) and Cr(VI) to which the workers 

were exposed). Although it is probably true that the carcinogenicity is due to the hexavalent 

chromium, the finding that trivalent chromium can be taken up by the aveolar macrophages could 

imply that the carcinogenic process may be modulated by the presence of trivalent chromium. 

Response to Comment: The Agency acknowledges that the cohort was occupationally 

exposed to mixtures of trivalent and hexavalent chromium, and agrees that it is probably true that 

the carcinogenicity is due to the hexavalent chromium. The ratio of trivalent and hexavalent 

chromium in the mixture have been provided. However, the Agency considers the data on 

carcinogenicity of trivalent chromium to be insufficient to support a conclusion that trivalent 

chromium contributed to the cancer observed in the cohort. The Agency concluded that Cr(VI) is 

known to be carcinogenic in humans and that data are insufficient to form a conclusion regarding 

the potential carcinogenicity of trivalent chromium. 

C. Comment: It is obvious that based on the human data hexavalent chromium is a Group A 

carcinogen. However, because of the insufficient data, a contribution of the trivalent chromium 

cannot be ruled out since the workers are always exposed to a mixture of both chromium types. 

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Response to Comment: The Toxicological Review document concludes that there are 

insufficient data to determine whether trivalent chromium is a carcinogen. This conclusion 

should not be misconstrued as ruling out a role for trivalent chromium in carcinogenicity. 

4. There is a Canadian study that relates stomach cancer to gold mining following exposures to 

chromium. Does this study justify/support determination of an oral factor for chromium? 

A. Comment: No. 

Response to Comment: The Canadian study has not been used to develop an oral slope 

factor for chromium. 

REFERENCES 

Junaid, M; Murthy, RC; Saxena, DK. (1996) Embryotoxicity of orally administered chromium in 

mice: Exposure during the period of organogenesis. Toxicol Lett 84:143-148. 

Kanojia, RK; Junaid, M; Murthy, RC. (1996) Chromium induced teratogenicity in female rat. 

Toxicol Lett 89:207-213. 

Mancuso, TF. (1975) International Conference on Heavy Metals in the Environment, Toronto, CN, 

Oct. 27-31. 

Mancuso, TF. (1997) Chromium as an industrial carcinogen: Part 1. Am J Ind Med 31:129-139. 

Zahid, ZR; Al-Hakkak, ZS; Kadhim, AHH; et al. (1990) Comparative effects of trivalent and 

hexavalent chromium on spermatogenesis of the mouse. Toxicol Environ Chem 25:131-136. 

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