List of IRIS Substances Search IRIS by Keyword

IRIS Summaries/Toxicological Reviews Entire IRIS Website

Category (section) Status Last Revised You are here: EPA Home Research Environmental Assessment IRIS IRIS Summaries

view QuickView

Reference Dose for Chronic Oral Exposure( RfD ) 

##  You will need Adobe Reader to view some of the files on this page. See EPA's PDF page to learn more.

Note:A TOXICOLOGICAL REVIEW is available for this chemical in Adobe PDF Format (70 Pages,189 Kbytes). Similar documents can be found in the List of Available IRIS Toxicological Reviews. Links to specific pages in the toxicological review are available throughout this summary . To utilize this feature, your Web browser and Adobe progra m must be configured properly so the PDF displays within the browser window. If your browser and Adob e program need configuratio n, please go to EPA's PDF page for instructions. [UPDATE] This assessment is currently under development and the latest draft can be found at, IRIS Toxicological Review of HexavalentChromium (External Review Draft)

0144 Chromium (VI) ; CASRN 18540-29-9; 09/03/1998 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supp orting information and explanations of the methods used to derive the values given in IRISare provided in the guidance documents located on the IRIS website. STATUS OF DATA FOR Chromium (VI) File First On-Line 03/31/1987

Oral RfD Assessment (I.A.) on-line 09/03/1998 Inhalation RfC Assessme nt (I.B.) on-line 09/03/1998 Carcinogenicity Assessm ent (II.) on-line 09/03/1998 

## Integrated Risk Information System http://www.epa.gov/iris/subst/0144.htm Last updated on Thursday, August 09, 2012 

### http://www.epa.gov/iris/subst/0144.htmCritical Effect Experimental Doses* 

### _I. Chronic Health Hazard Assessments for Noncarcino g enic Effects _I.A. Reference Dose for Chronic Oral Exposure (RfD) Substance Name — Chromium (VI) CASRN — 18540-29-9 Last Revised — 09/03/1998 The oral Reference Dose (RfD) is based on the a ssumption that thresholdsexist for certain toxic effects such as cellular necrosis. 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. Plea se refer to the Background Document for an elaboration of these concepts. RfDs can also be derived for the noncarcino genic health effects of substances that are also carcinogens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a summary of that evaluation will be contained in Section II of this file. __I.A.1. Oral RfD Summary UF MF RfD

None Reported Rat, 1-year drinking water study MacKenzie et al., 1958 NOAEL: 25 mg/L of chromium as K 2 CrO 4 2.5 mg/kg-day (adj.) LOAEL: None 300 3 3E-3 mg/kg-day

*Conversion Factors and Assumpti ons — Drinking water consumption = 0.1 L/kg-day (reported). __I.A.2. Principal and Supporting Studies (Oral RfD) MacKenzie, RD; Byerrum, RU; Decker, CF, et al. (1958) Chronic toxicity st udies. II. Hexavalent and trivalent chromium administered in drinking water to rats. Am Med Assoc Arch Ind Health 18:232-234. Groups of eight male and eight female Sprague-Dawley rats weresupplied with drinking water containing 0.45-11.2 ppm (0.45-11.2 mg/L) hexavalent chromium (as K 2 CrO 4 ) for 1 year. The control group (10/sex) received di stilled water. A second experime nt involved three groups of 12 male and 9 female rats. One group was given 25 ppm (25 mg/L) chromium (as K 2 CrO 4 ), a second received 25 ppm chromium in the form of chro mic chloride, and the controls again received distilled water. No significant adverse effects were seen in appearance, weight gain, or food consumption, and there were no pathologic ch anges in the blood or other tissues in any treatment group. The rats rece iving 25 ppm of chromium (as K 2 CrO 4 ) showed an approximate 20% reduction in water consumption. Based on the body weight of th e rat (0.35 kg) and the average daily drinking water consumption for the ra t (0.035 l/day), this dosecan be converted to give an adjusted NOAEL of 2.5 mg/kg-day chromium(VI). For rats treated with 0-11 ppm (in drinking wa ter), blood was examined monthly, and tissues (livers, kidneys, and femurs) were examined at 6 mo and 1 year. Spleens were also examined at 1 year. The 25 ppm groups (and corresponding contro ls) were examined similarly, except that no 

### http://www.epa.gov/iris/subst/0144.htmanimals were killed at 6 mo. An abrupt rise in tissue chromium concentrat ions was noted in rats treated with more than 5 ppm. The authors stat ed that "apparently, ti ssues can accumulate considerable quantities of ch romium before pathological ch anges result." In the 25 ppm treatment groups, tissue concentrations of ch romium were approximately 9 times higher for those treated with hexavalent chromium than fo r the trivalent group. Similar no-effect levels have been observed in dogs. Anwa r et al. (1961) observed no sign ificant effects in female dogs (2/dose group) given up to 11.2 ppm chromium(VI) (as K 2 CrO 4 ) in drinking water for 4 years. The calculated doses were 0.012 -0.30 mg/kg of chromium(VI). __I.A.3. Uncertainty and Mo difying Factors (Oral RfD) UF = 300. The uncertainty factor of 300 represents two 10-fold decreases in dose to account for both the expected interhuman and interspecies variability in the toxicity of the chemical in lieu of specific data, and an additional factor of 3 to compensatefor the less-than-lifetime exposure duration of the principal study.

MF = 3. The modifying factor of 3 is to account for concerns raised by the study of Zhang and Li (1987). __I.A.4. Additional Stud ies/Comments (Oral RfD) This RfD is limited to soluble salts of hexavale nt chromium. Examples of soluble salts include potassium dichromate (K 2 Cr 2 O 7 ), sodium dichromate (Na 2 Cr 2 O 7 ), potassium chromate (K 2 Cr 2 O 4 ), and sodium chromate (Na 2 CrO 4 ). Trivalent chromium is an essential nutrient. There is evidence to indicate that hexavalent chromium is reduced in part to trivalent chromium in vivo (Petrilli and DeFlora, 1977, 1978; Grub er and Jennette, 1978). In 1965, a study of 155 subjects ex posed to drinking water at conc entrations of ap proximately 20 mg/L was conducted outside Jinzhou, China. Subjects were observed to ha ve sores in the mouth, diarrhea, stomachache, indigestion, vomiting, el evated white blood cell co unts with respect to controls, and a higher pe r capita rate of cancers, including lung cancer and stomach cancer. Precise exposure concentrations, exposure du rations, and confounding factors were not discussed, and this study does not provide a NOAE L for the observed effect s. However, the study suggests that gastrointestinal effects may occu r in humans following exposures to hexavalent chromium at levels of 20 ppm in drinking water (Zhang and Li, 1987). Zahid et al. (1990) fed BALB/C al bino Swiss mice trivalent (chrom ium disulfate) and hexavalent (potassium dichromate) ch romium at concentrations of 100, 200, and 400 ppm for 35 days in the diet. The author concluded that a small but significant increase of hexavalent chromium in the testes of fed animals induced significant degeneration. The National Toxicology Program (1996a,b, 1997) recently conducted a three-part study to investig ate the potential reproductive toxicity of hexavalent chromium in rats and mi ce. The study included oral administration of potassium dichromate in Sprague- Dawley rats, a repeat of the study of Zahid et al. (1990) using BALB/C mice, and a reproductive assessment by continuous breeding study in BALB/C mice. The reproductive assessment indicate d that potassium dichromate ad ministered at 15-400 ppm in the diet is not a reproductive toxicant in either sex of BALB/C mice or Sprague-Dawley rats. Several reports of possible fetal damage caused by chromium compounds were located in the 

### http://www.epa.gov/iris/subst/0144.htmliterature. High doses (250-1,000 ppm) of orally administered chromium (VI) compounds have been reported to cause developmental toxicity in mice (Trivedi et al., 1989). The authors observed significant increases in preimplantation and postimplantation losses and dosedependent reductions in total weight and crown-rump length in the lower dose groups. Additional effects included treatment-related increases in abnormalities in th e tail and wrist forelimbs, and subdermal hemorrhagic patches in the offspring. Junaid et al. (1996) and Kanojia et al. (1996) exposed female Swiss albino mice and female Swiss albino rats, respectively, to 250, 500, or 750 ppm potassium dichromate in drinking water to determine the potential embryotoxicity of hexa valent chromium during days 6-14 of gestation. The authors reported retarded fetal development and embryo- an d fetotoxic effects including reduced fetal weight , reduced number of fetuse s (live and dead) per dam, and higher incidences of stillbirths and post-implant ation loss in the 500 and 750 ppm dosed mothers. Significantly reduced ossificati on in bones was also observed in the medium- and high-dose groups. Based on the body weight and the drinking water ingested by the animals in the 250 ppm dose group, the exposure levels in the 250 ppm groups can be identified as 67 mg/kg-day and 37 mg/kg-day in mice and rats, respectively. The Junaid et al. (1996) and Kanojia et al. (1996) studies utilized dose s approximately 10-fold higher than those used in Mackenzie et al (1 958), but neither of the reproductive studies identified a clear NOAEL for the embryotoxic effect s of hexavalent chromium . On the basis of the body weight and the drinking wa ter ingested by the animals in the low-dose groups (250 ppm), the LOAELs of 67 mg/kg-day and 37 mg/kg-day can be identified from Ju naid et al. (1996) and Kanojia et al. (1996) in mice and rats, respectively. Application of 10-fold uncertainty factor to extrapolate from LOAELs to NOAELs in these st udies would generate NOAELs of 6.7 mg/kg-day and 3.7 mg/kg-day, respectively. These extrapolated NOAEL values are similar to, and support the use of, the NOAEL of 2.5 mg/k g-day identified from the study of MacKenzie et al. (1958) for development of the reference dose. Elbetieha and Al-Hamood (1997) re ported impacts on fertility fo llowing potassium dichromate exposures in mice; however, many of the obse rved effects did not occur in a clear dosedependent fashion. The authors di d not indicate the amount of wa ter ingested bythe animals, and stated only that water ingestion was reduced in the treatment groups relative to the controls. Chromium is one of the most common contact sens itizers in males in indu strialized countries and is associated with occupational exposures to numerous materials and processes, including chrome plating baths, chrome colors an d dyes, cement, tanning agents, wood preservatives, anticorrosive agents, welding fumes, lubricatin g oils and greases, cleaning ma terials, 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 chromi um compounds to elicit an allergic response (Fregert, 1981; Polak et al., 197 3). The low solubilitychromium (III) compounds are much less efficient contact allergens than chro mium (VI) (Spruit and van Neer, 1966). Dermal exposure to chro mium has been demonstrated to prod uce 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 medi ated by the immune system. Allergic contact dermatitis is a cell-mediated immune response that occurs in a two-step proc ess. In the first step (induction), chromium is absorbed into the skin and triggers an immune response (sensitization). Sensitized individuals will exhibit an allergic dermatitis response when exposed to chromium above a threshold level (Polak, 1983). Induction isgenerally considered to be irreversible. Concentrations of hexavalent chromium in environmental media that are protective of 

### http://www.epa.gov/iris/subst/0144.htmcarcinogenic and noncarcinogenic effects are likely to be lower than the concentrations required to cause induction of allergic contact dermatitis. However, these concentrations may not be lower than concentrations required to elicit an allergic response in individuals who have been induced. The RfD was updated in 1998. The RfD is simila r to the previous value on IRIS but now incorporates a threefold uncertai nty factor to account for the le ss-than-lifetime ex posure in the principal study and a threefold modifying factor toaccount for uncertaintie s related to reports of gastrointestinal effects following drinking water exposures in a residential population in China.

For more detail on other Haza rd Identification Issues, exit to the toxicological review, Section 4.7 (PDF)

. __I.A.5. Confidence in the Oral RfD Study — Low Database — Low RfD — Low The overall confidence in this RfD assessment is low. Confidence in the chosen study is low because of the small number of animals tested, the small numbe r of parameters measured, and the lack of toxic effect atthe highest dose tested. Confidence in the database is low because the su pporting studies are of equally low quality and the developmental toxicity endpoints are not well studied. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)

. __I.A.6. EPA Documentation and Review of the Oral RfD Source Document — U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comment s have been evaluated carefully and incorporated in finalization of thisIRIS Summary. A record of these comments is included as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information (a PDF document) on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxi cological review, Appendix A, External Peer Review -- Summary of Comments and Disposition (PDF)

. Other EPA Documentation — U.S. EPA. (1984) Health effects assessment for hexavalent chromium . Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste an d Emergency Response , Washington, DC. U.S. EPA. (1985) Drinking water he alth advisory for chromium. Prep ared by the Office of Health and Environmental Assessment, Environmental Criter ia and Assessment Office, Cincinnati, OH, for the Office of Drinking Wate r, Washington, DC (Draft). Agency consensus date -- 04/28/1998 

### http://www.epa.gov/iris/subst/0144.htmScreening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Chromium (VI) conducted in August 2003 did not identify any critical new stud ies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 202-566-1676. __I.A.7. EPA Contacts (Oral RfD) Please contact the IRIS Hotline for all questions co ncerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (fax), or hotline.iris@epa.gov(Internet address).

_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC) Chromium (VI) CASRN — 18540-29-9 Last Revised — 09/03/1998 The inhalation reference concentration (RfC) is anal ogous to the oral RfD and is likewise based on the assumption that thresholds exist for certai n toxic effects such as cellular necrosis. The inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral to the respirat ory system (extrarespiratory effect s). It is generally expressed in units of mg/m 3 . In general, the RfC is an estimate (wit h uncertainty spanning perhaps an order of magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an apprecia ble risk of deleterious e ffects during a lifetime. Inhalation RfCs were derived ac cording to the Interim Methods for Development of Inhalation Reference Doses (U.S. EPA, 1989) and subsequently, according toMethods for Derivation of Inhalation Reference Concentratio ns and Application of Inhalati on Dosimetry (U.S. EPA, 1994). RfCs can also be derived for the noncarcinoge nic health effects of substances that are carcinogens. Therefore, it is essential to refe r to other sources of information concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a summary of that evaluation will be contained in Section II of this file. __I.B.1. Inhalation RfC Summary Critical Effect Experimental Doses* UF MF RfC (1) Chromic acid mists and dissolved Cr (VI) aerosols: Nasal septum atrophy Human subchronic occupational study Lindberg and Hedenstierna, 1983 NOAEL: none LOAEL: 2E-3 mg/m 3 7.14 E-4 mg/m 3 (adj.) 90 1 8E-6 mg/m 3

(2) Cr(VI) particulates: Lactate dehydrogenase in bronchioalveolar lavage fluid Rat subchronic study Glaser et al., 1990 Malsch et al., 1994 BMD: 0.016 mg/m 3 0.034 mg/m 3 (adj.) 300 1 1E-4 mg/m 3 

### http://www.epa.gov/iris/subst/0144.htm*Conversion Factors and Assumptions — Breathing rate for 8-hour occupational exposure = 10 m 3 ; breathing rate for 24- hour continuous exposure = 20 m 3 ; occupational exposure = 5 days/week; continuous exposure = 7 days/week. RDDR (regional deposited dose ratio for particulates to account for differences between rats and humans) = 2.16 Nasal mucosal irritation, atro phy, and perforation have b een widely reported following occupational exposures to chro mic acid mists and dissolved he xavalent chromium aerosols. However, there is uncertainty re garding the relevance of occupati onal exposures to chromic acid mists and dissolved hexavalent chromium aero sols to exposures to Cr(VI) dusts in the environment. Lower respiratory effects have be en reported in labora tory animals following exposures to Cr(VI) dust s. However, these studies have not reported on nasal mucosal effects following the exposures. The uncertainties in the database have been addressed through the development of two RfCs; one based on nasal mu cosal atrophy following occupational exposures to chromic acid mists and dissolv ed hexavalent chromium aerosols , and a second based on lower respiratory effects following inhalation of Cr(VI) particulates in rats. __I.B.2. Principal and Supp orting Studies (Inhalation RfC)

(1) Chromic acid mists and dissolved Cr (VI) aerosols Three studies have focused on nasal mucosal ir ritation, atrophy, and perforation following occupational exposures to chro mic acid mists (Cohen et al., 1974; Lucas and Kramkowski, 1975; Lindberg and Hedenstierna, 1983). Of these, the st udy of Lindberg and Hedenstierna provides the most information on exposure levels and sympto ms reported by exposed workers. Respiratory symptoms, lung function, and changes in nasal se ptum were studied in 104 workers (85 males, 19 females) exposed in chrome plating plants . Workers were interviewed using a standard questionnaire for the assessment of nose, thro at, and chest symptoms. Nasal inspections and pulmonary function testing were performed as part of the study. The median exposure time for th e entire group of exposed subjec ts (104) in the study was 4.5 years (0.1-36 years). A total of 43 subjects exposed almost exclusively to chromic acid experienced a mean exposure timeof 2.5 years (0.2-23.6 years). The subjects exposed almost exclusively to chromic acid were divided into a low-ex posure group (8-hr TWA below 0.002 mg/m 3 , N=19) and a high-exposure group (8-hr TWA above 0.002 mg/m 3 , N=24). Exposure measurements using personal ai r samplers were performed for 84 subjects in the study on 13 different days. Exposure for th e remaining 20 workers was assumed to be similar to that measured for workers in the same area. Nineteen office employees were used as controls for nose and throat symptoms. A group of 119 automechanics whose lung function had been evaluated by similar techniqueswas selected as controls fo r lung functionmeasurements. Smoking habits of workers were evaluated as part of the study. At mean exposures below 0.002 mg/m 3 , 4/19 workers from the low-ex posure group of subjective nasal symptoms. Atrophied nasal mucosa were reported in 4/19 subjects from this group and 11/19 had smeary and crusty septal mucosa, which was statistically higher than controls. No one exposed to levels below 0.001 mg/m 3 complained of subject ive symptoms. At mean concentrations of 0.002 mg/m 3 or above, approximately one-third of the subjects had reddened, smeary, or crusty nasal mucosa. Atrophy was se en in 8/24 workers, which was significantly different from controls. Eight subjects had ul cerations in the nasal mucosa and five had perforations of the nasal septum . Atrophied nasal mucosa was not observed in any of the 19 controls, but smeary and crusty sept al mucosa occurred in 5/19 controls. 

### http://www.epa.gov/iris/subst/0144.htmShort-term effects on pulmonary function were ev aluated by comparing results of tests taken on Monday and Thursday among exposed groups and co ntrols. No significant changes were seen in the low-exposure group or th e control group. Nonsmokers in the high-exposure group experienced significant di fferences in pulmonary function me asurements from the controls, but the results were within normal limits.

The authors concluded that 8-hour mean exposures to chromic acid above 0.002 mg/m 3 may cause a transient decrease in lung function, and that short-term exposure s to greater than 0.02 mg/m 3 may cause septal ulceration an d perforation. Based on the results of this study, a LOAEL of 0.002 mg/m 3 can be identified for incidence of nasa l septum atrophy following exposure to chromic acid mists in chromeplating facilitie s. At TWA exposures greater than 0.002 mg/m 3 , nasal septum ulceration and perforatio ns occurred in addition to the atrophy reported at lower concentrations. The LOAEL is based on an 8-ho ur TWA occupational ex posure. The LOAEL is adjusted to account for cont inuous exposure according to the following equation: LOAELc = 0.002 mg/m 3 x (MVho/MVh) x 5 days/7 days where: LOAELc is the LOAEL for continuous exposure MVho is the breathing volume for an 8 hour occupational exposure (10 m 3 ) MVh is the breathing volume for a 24 hour continuous exposure (20 m 3 ) The LOAEL of 0.002 mg/m 3 based on a TWA exposure to chromi c acid is converted to a LOAEL for continuous exposure of 7.14 E-4 mg/m 3 . An uncertainty factor of 3 is applied to the LOAEL to extrapolate from a subchronic toa chronic exposure, an uncertai nty factor of 3 is applied to account for extrapolation from a LOAEL to a NOAEL, and an uncertainty fact or of 10 is applied to the LOAEL to account for interhuman variation. Th e total uncertainty factor applied to the LOAEL is 90. Application of the uncertainty fa ctor of 90 to the LOAEL of 7.14E-4 mg/m 3 generates an RfC of 8 E-6 mg/m 3 for upper respiratory effects caused by chromic acid mists and dissolved hexavalent chromium aerosols. (2) Cr (VI) Particulates: Two studies provide high-quality data on lowe r respiratory effects following exposures to chromium particulates (Glaser et al., 1985, 1990). Glaser et al. (1990) ex posed 8-week-old male Wistar rats to sodium dichroma te at 0.05 - 0.4 mg Cr(VI)/m 3 22 hr/day, 7 days/wk for 30-90 days. Chromium-induced effects occurred in a strong dose-dependent manner. The authors observed obstructive respiratory dyspnea and redu ced body weight follow ing subacute exposure at the higher dose levels. The me an 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/m 3 following both the subacute and subchronic exposu res. Accumulation of macropha ges 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, and albumin and lactate dehydrogenase (LDH) in bronchioalveolar lavage fluid (BALF) were increased following the exposure. The authors 

### http://www.epa.gov/iris/subst/0144.htmconcluded that chromium inha lation induced pneu mocyte toxicity and suggested that inflammation is essential for the induction of mo st chromium inhalation effects and may influence the carcinogenicity of Cr(VI) compounds. Glaser et al. (1985) exposed 5-week -old male Wistar rats to aero sols of sodium dichromate at concentrations ranging from 0.025 to 0.2 mg Cr(VI)/m 3 , 22 hr/day in subacute (28 day) or subchronic (90 day) protocols. Chromium-induced effects occurred in a dose-dependent manner. Lung and spleen weights were significantly in creased (p < 0.005) after both subacute and subchronic exposures at concen trations greater than 0.025 mg/m 3 . Differences in the mean total serum immunoglobulin werealso significant at exposures above 0.025 mg/m 3 , while exposures to aerosol concentrations greater than 0.1 mg/m 3 resulted in depression of the immune system stimulation. The immune stimulating effect of su bchronic exposure was not reversed after 2 mo of fresh air regeneration. Bronchoalveolar lavage (BAL) cell counts were significantly decreased following subchronic exposureto levels above 0.025 mg/m 3 chromium. The number of lymphocytes and granulocytes showed a slight but significant increase in the lavage fluids of the subacute and subchronically expose d groups. At subacute exposureconcentrations up to 0.05 mg/m 3 the phagocytic activity of the alveolar macrophages increased; however, subchronic exposure at 0.2 mg/m 3 decreased this function signific antly. The spleen T-lymphocyte subpopulation was stimulated by subchronic exposure to 0.2 mg/m 3 chromium, and serum contents of triglycerides and phos pholipids differed significantly from controls (p < 0.05) at this concentration. Together, these studies provide useful information on chromium exposure-related impacts including lung and spleen weight, LDH in BALF, protein in BALF, and albumin in BALF. The cellular content of BALF is considered representative of initial pulmonary injury and chronic lung inflammation, which may lead to the onset of pu lmonary fibrosis (Henderson, 1988). While these studies present dose-dependent re sults on sensitive indicators of lower respiratory toxicity, potential upper respiratory impacts resulting from the exposures were not addressed. Glaser et al. (1990) state that the upper respiratory tract was examined, but these da ta were not reported. One approach for development of an RfC using the data of Glaser et al. (1985, 1990) was offered by Malsch et al. (1994), who gene rated an inhalation RfC for ch romium dusts using a benchmark concentration (BMC) approach. The Agency develo ped its RfC for particulates based on this approach. After excluding exposures for periods of less than 90 days from the BMC analysis, Malsch et al. (1994) deve loped BMCs for lung weight, LDH in BALF, protein in BALF, albumin in BALF, and spleen weight. The Mals ch et al. (1994) analysis defi ned the benchmark concentration as the 95% lower confidence limit on the dose corresponding to a 10% relative change in the endpoint compared to the control. Dose-effect data were adjusted to account for discontinuous exposure (22 hr/day) and the maximum likelihood model was used to fit continuous data to a polynomial mean responseregression, yielding maximum li kelihood estimates of 0.036 - 0.078 mg/m 3 and BMCs of 0.016 - 0.067 mg/m 3 . Malsch et al. (1994) appl ied dosimetric adjustments and uncertainty factors to determine a RfC based on the following equation: RfC = BMC x RDDR UFAx UF Fx UF H

where: 

### http://www.epa.gov/iris/subst/0144.htm• RfCis the inhalation reference concentration

• BMCis the benchmark concentration (low er 95% confidence limit on thedose corresponding to a 10% relative change in the endpoint compared to the control)

• RDDR is the regional deposited dose ratio to account for pharmacokineticdifferences between species

• UF Ais a threefold uncertainty factor to account for pharmacodynamicdifferences not addressed by the RDDR

• UF Fis a threefold uncertainty factor to account for extrapolating from subchronic to chronic exposures; and

• UF H is a 10-fold uncertainty factor to account for the variation in sensitivity among members of the human population The RDDR factor is incorporated to account for differences in the deposi tion pattern of inhaled hexavalent chromium dusts in the respiratory tract of humans and the Wistar rat test animals (Jarabek et al., 1990). The RDDR of 2.1576 wa s determined based on the mass median aerodynamic diameter (0.28 μm for dose levels of 0.05-0.1 mg/m 3 and 0.39 for dose levels of 0.1-0.4 mg/m 3 ) and the geometric standard deviation (1.63 for dose levels of 0.05-0.1 mg/m 3 and 1.72 for dose levels of 0.1-0.4 mg/m 3 ) of the particulates reported in Glaser et al. (1990). A 3.16-fold uncertainty factor (midpoint between 1 and 10 on a log scale) was incorporated to account for the pharmacodynamic differences not a ccounted for by the RDDR. An additional 3.16- fold uncertainty factor was incorporated to acco unt for the less-than-lifetime exposure in Glaser et al. (1990), and a 10-fold uncertainty factor wa s applied to account for variation in the human population. A total uncertainty factor of 100 was applied to the BMC in addition to the RDDR. Glaser et al. (1990) reported th at LDH in BALF increa sed in a dose-dependent fashion from 0.05 to 0.4 mg/m 3 sodium dichromate, and this endpoint generated the lowest BMC (0.016 mg/m 3 ) and RfC (3.4 E-4 mg/m 3 ). LDH in BALF is considered the among the most sensitive indicators of potential lung toxicity (Hen derson, 1984, 1985, 1988; Beck et al ., 1982; Venet et al., 1985), as LDH is found extracellularly after cell damage and BALF is the closest siteto the original lung injury. LDH in BALF may also reflect chronic lu ng inflammation, which may lead to pulmonary fibrosis through prevention of the normal repair of lung tissue (Henderson, 1988).

Several uncertainties must be a ddressed with regard to the BMC and RfC developed by Malsch et al. (1994). Potentially important en dpoints, including upper airway effects and potential renal or immunological toxicity, were not addressed in the Glaser et al. (1985, 1990) studies and could not be included in the BMC analysis. While LDH in BALF resulted in the lowest BMC and RfC, all of the effects noted in Glaser et al. (1985, 1990) can be considered indicative of an inflammatory response, and might be eq ually suited to development of the RfC. LDH in BALF did not generate the best fit on the regression cu rve of the endpoints considered in the BMC analysis. In addition, the threefold uncertainty factor accounting for the use of a subchronic study may not be sufficiently protective for long-term effects. Wh ile the analysis acknowledged the importance of particle size and airway deposition in the de velopment of the RDDR, the potential impact of different particle sizes in respiratory toxicityby hexavalent chromium particulates was not addressed. Several of these uncertainties were conservatively addressed in the analysis of Malsch et al. (1994). LDH in BALF generated the lowest estimateof the BMC from the effects noted by Glaser et al. (1985, 1990). This effect can be considered to be indicative of cell da mage that occurs prior to fibrosis, as LDH appears in BALF following cell lysis. While the Malsch et al. (1994) analysis demonstrated a relatively poor curve fit for thisendpoint, the model gene rated a conservative fit in the data that is unlikely to overestimate the BMC. LDH in BALF as repo rted in Glaser et al. (1990) is considered to be an acceptable endpoint for developmen t of an RfC for inhalation of 

### http://www.epa.gov/iris/subst/0144.htmhexavalent chromium particulat es, and Malsch et al. (1994) us ed a reasonable approach for development of a BMC based on this endpoint. The threefold uncertainty factor used by Malsch et al. (1994) to account for the subchronic study is insufficient for development of the RfC for inhalation of chromium particulates. Glaser et al. (1985) demonstrated that at the end of the 90-day exposure period , chromium was still accumulating in the lung tissue of the test an imals, suggesting that lower long-term exposures might lead to accumulation of a critical concen tration in the lung. Subchronic studies also may not adequately predict the presen ce of inflammatory effects from lower long-term exposures. The Agency has therefore determined that a 10-fold uncertainty factor accounting for the use of a subchronic study is more appropriate in this casefor the development of an RfC for inhalation of chromium particulates. Selection of a threefold uncertainty factor to account for the pharmacodynamic differences not accounted for by the RDDR, an ad ditional 10-fold uncertainty factor to account for the less-thanlifetime exposure in Glas er et al. (1990), and a 10-fold uncertai nty factor to account for variation in the human population generate s a total uncertainty factor of 300. Application of the total uncertainty factor of 300 and the RDDR of 2.1576 to the BMC generated by Malsch et al. (1994) based on LDH in BALF (Glaser et al., 1990) results in an RfC of 1 E-4 mg/m 3 for inhalation of hexavalent chromium particulates. __I.B.3. Uncertainty and Modi fying Factors (Inhalation RfC) See discussion above. (1) Chromic acid mists and dissolved Cr (VI) aerosols: UF = 90. MF = 1. (2) Chromium (VI) particulates: UF = 300. MF = 1 __I.B.4. Additional Studie s/Comments (Inhalation RfC) There is considerable uncertainty with regard to the relevance of the nasal septum atrophy endpoint observed in the chromepl ating industry to exposure to hexavalent chromium in the environment. The effects were observed in ch romeplaters who were exposed to chromic acid mists near the plating baths. En vironmental exposures would most likely occur through contact with hexavalent chromium dusts, and exposures to chromic acid mists in the environment is considered to be unlikely. An additional uncertainty is related to the determination of dose in the Lindberg and Hedenstierna study. Nasal septum atrophy in this study was related to TWA exposures to chromic acid. The mostsignificant effects (nasal sept um perforation) were observed in workers who experienced peak excursions to levels considerably greater than the TWA. It is uncertain whether the peak excursion data or the TWAs are more appropriate for the determination of dose in this study. The RfC ba sed on the data of Lindberg and Hedenstierna (1983) should only be used toaddress exposures to chromic acid and dissolved hexavalent chromium aerosols. Nasal mucosal irritation, atro phy, and perforation have b een widely reported following occupational exposures to chro mic acid mists and dissolved he xavalent chromium aerosols. Glaser et al. (1990) did not repo rt on upper respiratory effects following exposure of rats to 

### http://www.epa.gov/iris/subst/0144.htmsodium dichromate. The RfC based on the data of Glaser et al. should only be used to address inhalation of Cr(VI) particulates. The RfCs in this IRIS Summary were added in 1998. The previous RfC section for hexavalent chromium in IRIS was empty.

For more detail on other Haza rd Identification Issues, exit to the toxicological review, Section 4.7 (PDF)

. __I.B.5. Confidence in the Inhalation RfC (1) Chromic acid mists and dissolved Cr (VI) aerosols: Study — Low Database — Low RfC -- Low The overall confidence in this RfC assessment is low. Confidence in the chosen study is low because of uncertainties regarding the exposure characterization and the role of direct contact for the critical effect. Confidence in the database is low because the supporting studies are equally uncertain regarding the ex posure characterization. (2) Chromium (VI) particulates: Study — Medium RfC — Medium The overall confidence in this RfC assessment is medium. Confidence in the chosen study is medium because of uncertaintie s regarding upper respiratory, reproductive, and renal effects resulting from the exposures. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)

. __I.B.6. EPA Documentation and Review of the Inhalation RfC Source Document — U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comment s have been evaluated carefully and incorporated in finalization of thisIRIS Summary. A record of these comments is included as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information (a PDF document) on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxi cological review, Appendix A, External Peer Review -- Summary of Comments and Disposition (PDF)

.

Agency Consensus Date — 04/28/1998 Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Chromium (VI) conducted in August 2003 did not identify any critical new stud ies. IRIS users who know of 

### http://www.epa.gov/iris/subst/0144.htmimportant new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 202-566-1676. __I.B.7. EPA Contacts (Inhalation RfC) Please contact the IRIS Hotline for all questions co ncerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (fax), or hotline.iris@epa.gov(Internet address).



### _II. Carcinogenicity Asse ssment for Lifetime Exposure Substance Name: Chromium (VI) CASRN: 18540-29-9 Last Revised — 09/03/1998 Section II provides information on three aspects of the carcinogenic assessment for the substance in question; the weight-of-evidence judgment of the likelihood that the substance is a human carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. The quantitative risk estimates are presented in three ways. The slope factor is the result of application of a low-dose extrap olation procedure and is presente d 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. The third form in which risk ispresented is a concentrat ion of the chemical in drinking water or air associated with cancer risk s of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000. The rationale and methods used to develop the ca rcinogenicity information in IRIS are described in The Risk Assessment Guide lines of 1986 (EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since the publication of EPA's more recent Proposed Guidelines for Carcinogen Risk A ssessment also utilize those Guid elines where indicated (Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for information on long-term toxic effects other than carcinogenicity. _II.A. Evidence for Human Carcinogenicity __II.A.1. Weight-of-Evid ence Characterization Under the current guidelines (EPA, 1986), Cr(VI) is classifi ed as Group A - known human carcinogen by the inhalation route of exposure. Carcinogenicity by the oral route of exposure cannot be determined and is classified as Group D. Under the proposed guidelines (EPA, 1996), Cr(V I) would be characteri zed as a known human carcinogen by the inhalation route of exposure on the following basis.

Hexavalent chromium is known to be carcinogenic in humans by the inhalation route of exposure. Results of occupational epidemiologic studies of chromium-exposed workers are consistent across investigators and study populations. Dose-response relationships have been established for chromium exposure and lung cancer. Chromium-exp osed workers are exposed to both Cr(III) and Cr(VI) compounds. Because only Cr(VI) has been found to be carcinogenic in animal studies, however, it was concluded that only Cr(VI) should be classified as a human carcinogen. Animal data are consistent with the human carcinogenicity data on hexavalent chromium. Hexavalent chromium compounds are carcinogenicin animal bioassays, producing the following tumor types: intramuscular injection site tumorsin rats and mice, intrapleural implant site tumors for various Cr(VI) compounds in rats, intrabronchial implantation site tumors for various 

### http://www.epa.gov/iris/subst/0144.htmCr(VI) compounds in rats, and subcutaneo us injection site sarcomas in rats. In vitro data are suggestive of a potentia l mode of action for hexavalent chromium carcinogenesis. Hexavalent chromium carcinogenes is may result from the formation of mutagenic oxidatitive DNA lesions following intracellular re duction to the trivalent form. Cr(VI) readily passes through cell membranes and is rapidly reduce d intracellularly to generate reactive Cr(V) and Cr(IV) intermediates and reactive oxygen sp ecies. A number of potentially mutagenic DNA lesions are formed during the reduction of Cr(VI). Hexavalent chromium is mutagenic in bacterial assays, yeasts, and V79 cells, and Cr(VI) compound s decrease the fidelity of DNA synthesis in vitro and produce unscheduled DNA synthesis asa consequence of DNA damage. Chromate has been shown to transform both primary cells and cell lines. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF)

. For more detail on other Haza rd Identification Issues, exit to the toxicological review, Section 4.7 (PDF)

. __II.A.2. Human Carcinogenicity Data Occupational exposure to chro mium compounds has been studied in the chromate production, chromeplating and chrome pigment, ferrochromium production, gold mining, leather tanning, and chrome alloy production industries. Workers in the chromate industry are exposed toboth trivalent and hexavalent compounds of chromium. Epidemiological studies of chromate production plants in Japan, Great Britain, West Germany, and the United States have revealed a correlation betw een occupational exposure to chromium and lung cancer, but the specific form of chromium responsibl e for the induction of cancer was not identified (Machle and Greg orius, 1948; Baejter, 1950a,b; Bidstrup, 1951; Mancuso and Hueper, 1951; Brinton et al., 1952; Bidstrup and Case, 1956; Todd, 1962; Taylor, 1966; Enterline, 1974; Mancuso, 1975; Ohsaki et al., 1978; Sanoand Mitohara, 1978; Hayes et al., 1979; Hill and Ferguson, 1979; Alderson et al., 1981; Haguenor et al., 1981; Satoh et al., 1981; Korallus et al., 1982; Frentzel-Beyme, 1983; Langard and Vigander, 1983; Watanabe and Fukuchi, 1984; Davies, 1984; Mancuso, 1997). Mancuso and Hueper (1951) conducted a proportion al mortality study of a cohort of chromate workers (employed for > l year from 1931-1949 in a Pa inesville, OH chromateplant) in order to investigate lung cancer associated with chromate production. Of the 2,931 deaths of males in the county where the plant is located, 34 (1.2%) we re due to respiratory cancer. Of the 33 deaths among the chromate workers, ho wever, 6 (18.2%) were due to respiratory cancer. Within the limitations of the study design, this report strongly suggested an increased incidence of respiratory cancer in the chromate-production plant. In an update of the Mancuso and Hueper (1 951) study, Mancuso (1975) followed 332 of the workers employed from 1931-1951 until 1974. By 1974, > 50% of this cohort had died. Of these men, 63.6%, 62.5%, and 58.3% of the cancer deaths for men employed from 1931-1932, 1933- 1934, and 1935-1937, respecti vely, were due to lung cancer. L ung cancer death rates increased by gradient of exposure to tota l chromium, and significant deposi tion of chromium was found in the lungs of workers long after the exposure ceased. Mancuso ( 1975) reported that these lung cancer deaths were related to insoluble (trivalent), soluble (hexavalent), and total chromium exposure, but the small numbers involved make identification of the specific form of chromium responsible for the lu ng cancer uncertain. 

### http://www.epa.gov/iris/subst/0144.htmMancuso (1997) recent ly updated this study, following the combined co hort of 332 workers until 1993. Of 283 deaths (85% of the cohort identified), 66 lung canc ers were found (23.3% of all deaths and 64.7% of all cancers). Lung cancer rates clearly increased by gradient level of exposure to total chromium. The relationship betw een gradient level of exposure and lung cancer rates is less clear for trivalent and hexavalent chromium. The rates of lu ng cancer within the cohort are consistent with thos e reported in Mancus o (1975), and provide further support for the cancer risk assessment based on those data. Studies of chrome pigment workers in the United States (Hayes et al., 1989), England (Davies, 1984, 1979, 1978), Norway (Langard and Vigander , 1983; Langard and Norseth, 1975), and in the Netherlands and Germany (Frentzel-Beyme, 1983) have consistent ly demonstrated an association between occu pational chromium exposure (predo minantly to Cr [VI]) and lung cancer. Several studies of the chromeplating industry havedemonstrated a positive relationship between cancer and exposure to chro mium compounds (Royle, 1975; Franchini et al., 1983; Sorahan et al., 1987). __II.A.3. Animal Carcinogenicity Data Animal data are consistent with the findings of human epidemiological studies of hexavalent chromium. Hexavalent chromium compounds were carcinogenic in animal assays producing the following tumor types: lung tumors following in halation of aerosols of sodium chromate and pyrolized Cr(VI)/Cr(III) oxide mixtures in rats(Glaser et al., 1986), lung tumors following intratracheal administration of so dium dichromate in rats (Steinho ff et al., 1983), intramuscular injection site tumors in Fischer 344 and Bethesda Black rats and in C57BL mice (Furst et al., 1976; Maltoni, 1974, 1976; Payne, 1960a; Hueper and Payne, 1959); intrap leural implant site tumors for various Cr(VI) compounds in Spragu e-Dawley and Bethesda Black rats (Payne, 1960b; Hueper 1961; Hueper and Payne, 1962), intrabronc hial implantation sitetumors for various Cr (VI) compounds in Wistar rats (Levy and Martin , 1983; Laskin et al., 1970; Levy, as quoted in NIOSH, 1975), and subcutaneous injection site sarcomas in Spra gue-Dawley rats (Maltoni, 1974, 1976). Inflammation is considered to be essential for the induction of most chromium respiratory effects and may influence the carcinogenicity of Cr(VI) co mpounds (Glaser et al., 1985). __II.A.4. Supporting Data for Carcinogenicity Metabolism and genotoxicity. Hexavalent chromium is rapidly taken up by cells through the sulfate transport system (Sugiyama, 1992). Once insi de the cell, Cr(VI) is quickly reduced to the trivalent form by cellular reductants, includin g ascorbic acid, glutathione and flavoenzymes (cytochrome P-450 and glutathione re ductase), and riboflavin (De Flora et al., 1989; De Flora et al., 1990; Sugiyama, 1992). The intracellular reduction of Cr(VI) generates reactive Cr(V) and Cr (IV) intermediates as well as hydroxyl free radicals (OH) and singlet oxygen ( 1 O 2 ) (Kawanishi et al., 1986). A variety of DNA lesions are formed duri ng the reduction of Cr(V I) to Cr(III), including DNA strand breaks, alkali-labile sites, DNA-protein and DNA-DNA crossl inks, and oxidative DNA damage, such as 8-oxo-deoxyguano sine (Klein et al., 1992; Klein et al., 1991; De Flora et al., 1990). The relative importance of the different chromium comple xes and oxidative DNA damage in the toxicity of Cr(VI) is unknown. A large number of chromium compounds have been assayed with in vitro genetic toxicology assays. In general, hexavalent chromium is mu tagenic in bacterial assays whereas trivalent 

### http://www.epa.gov/iris/subst/0144.htmchromium is not (Lofroth, 1978; Petrilli and De Flora, 1977, 1978). Likewise Cr(VI), but not Cr (III), was mutagenic in yeasts (Bonatti et al., 1976) and in V79 cells (Newbold et al., 1979). Cr (III) and (VI) compounds decrease the fidelity of DNA synthesis in vitro (L oeb et al., 1977), while Cr(VI) compounds inhibit replicative DNA synthesis in mammalian cells (Levis et al., 1978) and produce unscheduled DNA synthesis, presumably repair synthesis, as a consequence of DNA damage (Raffetto, 1977). Chromatehas been shown to transform both primary cells and cell lines (Fradkin et al., 1975; Tsuda and Kato, 1977; Cast o et al., 1979). Chromosomal effects produced by treatment with chromium compounds have be en reported by a number of authors; for example, both Cr(VI) and Cr(III) salts wereclastogenic for cultured human leukocytes (Nakamuro et al.,1978). In dogs (2/group) exposed to po tassium dichromate in drinking water at concentrations up to 11.2 ppm for 4 years, gross and microscopic ex amination of all major organs revealed no treatment-related lesions (Anwaret al., 1961). The small number of animals and the relatively short exposure duration relative to the lifespa n of the dog precludes a conclusion regarding a possible carcinogenic response. There are no other long-term studies of ingested Cr(VI). Cr(VI) is readily converted to Cr(III) in vivo, but there is noevidence that Cr(III) is oxidized to Cr(VI) in vivo. Cr(III) is an e ssential trace element.

_II.B. Quantitative Estimate of Carcin ogenic Risk from Oral Exposure The oral carcinogenicity of Cr(VI) cannot be de termined. No data were located in the available literature that suggested that Cr(VI) is ca rcinogenic by the oral route of exposure.

_II.C. Quantitative Estimate of Carcinog enic Risk from Inhalation Exposure __II.C.1. Summary of Risk Estimates ___ II.C.1.1. Air Unit Risk— 1.2E-2 per (μg/cu.m) Source: Mancuso, 1975 ___ II.C.1.2. Extrapolation Meth od — Multistage, extra risk Air Concentrations at Specified Risk Levels:

Risk Level Concentration E-4 (1 in 10,000) 8E-3 (μg/m 3 ) E-5 (1 in 100,000) 8E-4 (μg/m 3 ) E-6 (1 in 1,000,000) 8E-5 (μg/m 3 ) __II.C.2. Dose-Response Data for Carcinogenicity, Inhalation Exposure Tumor type -- lung cancer Test animals — human Route — inhalation, o ccupational exposure Source -- Mancuso, 1975 

### http://www.epa.gov/iris/subst/0144.htmSubject age (years) Exposure Level midrange (μg/m 3 ) Deaths From Lung Cancer Person-Years 50 5.66 25.27 46.83 3 6 6 1,345 931 299 60 4.68 20.79 39.08 4 5 5 1,063 712 211 70 4.41 21.29 2 4 401 345

__II.C.3. Additional Comm ents (Carcinogenicity, Inhalation Exposure) Mancuso (1997) recently updated the study of Mancuso (1975), following the combined cohort of 332 workers until 1993. Of 283 deaths (85% of th e cohort identified), 66 lung cancers were found (23.3% of all deaths and 64.7% of all cancers). Lung cancer rates clearly increased by gradient level of exposure to total chromium. The relationship between gradient level of exposure and lung cancer rates is less clear for trival ent and hexavalent chromium. The rates of lung cancer within the cohort are consistent with those reported in Ma ncuso (1975), and provide further support for the cancer riskassessment based on those data. The cancer mortality in Mancus o (1975) was assumed to be due to Cr(VI), which was further assumed to be no less than on e-seventh of total chromium. Itwas also assumed that the smoking habits of chromate workers were similar to those of the U.S. white male population. Trivalent chromium compounds have not been reported as carcinogenic by any route of administration. The unit risk should not be used if the air concentration exceeds 8E-1 μg/m3, since above this concentration the unit risk may not be appropriate. The carcinogenicity sectio n of this IRIS Summary was updated in 1998; however, the quantitative results have not been modified. __II.C.4. Discussion of Confidence (Carcinogenicity, In halation Exposure) Results of studies of chromium ex posure are consistent across inve stigators and countries. A dose relationship for lung tumors has been established. Theassumption that the ratio of Cr(III) to Cr (VI) is 6:1 may lead to a sevenfold underest imation of risk. The use of 1949 hygiene data (Bourne and Yee, 1950), which may underestimate worker ex posure, may result in an overestimation of risk. Further overestimation of risk may be due to the implicit assumption that the smoking habits of chromate workers were similar to those of the general white male population, since it is generally accepted that th e proportion of smokers is higher for industrial workers than for the general population.

_II.D. EPA Documentation, Review, and Contacts (C arcinogenicity Assessment) __II.D.1. EPA Documentation 

### http://www.epa.gov/iris/subst/0144.htmSource Document — U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comment s have been evaluated carefully and incorporated in finalization of thisIRIS Summary. A record of these comments is included as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information (a PDF document) on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxi cological review, Appendix A, External Peer Review -- Summary of Comments and Disposition (PDF)

. Other EPA Documentation — U.S. EPA. (1984) Health assessm ent document for chromium. Prepared by the Office of Health and Environ mental Assessment, Environmental Criteria and Assessment Office, Cincin nati, OH. EPA/600/8-83-014F. __II.D.2. EPA Review (Car cinogenicity Assessment) Agency consensus date -- 04/28/1998 Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Chromium (VI) conducted in August2003 did not identify any critic al new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 202-566-1676. __II.D.3. EPA Contacts (Carcinogenicity Assessment) Please contact the IRIS Hotline for all questions co ncerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (fax), or hotline.iris@epa.gov(Internet address).



### _III. [reserved] _IV. [reserved] _V. [reserved] _VI. Bibliography Chromium (VI) CASRN — 18540-29-9 Last Revised — 09/03/1998 _VI.A. Oral RfD References Anwar, RA; Langham, FF; Hoppert, CA; et al. (1961) Chronic toxicity studies. III. Ch ronic toxicity of cadmium and chromium in dogs. Arch Environ 3:456-460. Bruynzeel, DP; Hennipman, G; van Ketel, WG. (19 88) Irritant contact dermatitis and chromiumpassivated metal. Contact Derm 19:175-179. Burrows, D; Adams, RM. (1990) In: Occupation al skin disease, 2nd ed., Adams, RM, d. Philadelphia: W.B. Saunders, pp. 349-386. Cronin, E. (1980) Contact de rmatitis. New York: Church ill Livingstone, pp. 287-390. 

### http://www.epa.gov/iris/subst/0144.htmElbetieha, A; Al-Hamood, MH. (1997) Long-term exposure of male and female miceto trivalent and hexavalent chromium compounds: e ffect on fertility. Toxicology 116:19-47. Fregert, S. (1981) Chromium valencies and ce ment dermatitis. Br J Dermatol 105 (suppl. 21):7-9. Gruber, JE; Jennette, KW. (1978) Metabolism of the carcinogen chromate by rat liver microsomes. Biochem Biophy s Res Commun 82(2):700-706. Hunter, D. (1974) The diseas es of occupations, 5th ed. Boston: Little, Brown. Junaid, M; Murthy, RC; Saxena, DK . (1996) Embryotoxicity of ora lly administered chromium in mice: exposure during the period of organogenesis. Toxicol Lett 84:143-148. Kanojia, RK; Junaid, M; Murthy, RC. (1996) Chro mium induced teratogeni city in female rat. Toxicol Lett 89:207-213. MacKenzie, RD; Byerrum, RU; Decker, CF; et al. (1958) Chronic toxi city studies. II. Hexavalent and trivalent chromium administered in drinking water to rats. Am Med Assoc Arch Ind Health 18:232-234. National Toxicology Program (NTP). (1996a) Fina l Report. Potassium dich romate (hexavalent): The effects of potassium dichromate on Sprague- Dawley rats when admi nistered in the diet. December 13, 1996. National Toxicology Program (NTP). (1996b) Fina l Report. Potassium dichromate (hexavalent): The effects of potassium dichromatein BALB/c mice when administ ered in the diet. November 27, 1996. National Toxicology Program (NTP). (1997) Final Report. Potassium dichromate (hexavalent): Reproductive assessment by contin uous breeding when administered to BALB/c mice in the diet. February 18, 1997. Petrilli, FL; DeFlora, S. (1977) Toxicity and mutagencity of hexavalent chromium on Salmonella typhimurium. Appl Environ Microbiol 33(4):805-809. Petrilli, FL; DeFlora, S. (1978) Oxidation of inactive trival ent chromium to the mutagenic hexavalent form. Mutat Res 58(2-3):167-178. Polak, L. (1983) Immunology of chromium. In: Chromium: metabo lism and toxicity. Burrows, D, ed. Boca Raton, FL: CRC Press, pp. 51-135. Polak, L; Turk, JL; Frey, FR. ( 1973) Studies on contact hypersensi tivity to chromi um compounds. Progr Allergy 17:145-219. Spruit, D; van Neer, FCJ. (1966) Penetration rateof Cr(III) and Cr(VI). Dermatological 132:179- 182. U.S. Environmental Protection Agency (U.S. EPA). (1984) He alth effects assessment for hexavalent chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati , OH, for the Office of Solid 

### http://www.epa.gov/iris/subst/0144.htmWaste and Emergency Resp onse, Washington, DC. U.S. EPA. (1985) Drinking water he alth advisory for chromium. Prep ared by the Office of Health and Environmental Assessment, Environmental Criter ia and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC. U.S. EPA. (1998) Toxicologica l review of hexavalent ch romium. Available online at http://www.epa.gov/iris. Zhang, J; Li, X. (1987) Chromium pollution of soil and water in Jinzhou. J of Chinese Preventive Med 21:262-264.

_VI.B. Inhalation RfC References Beck, BD; Brain, JD; Boha nnon, DE. (1982) An in v ivo hamster bioassay to assess the toxicity of particles for the lungs. To xicol Appl Pharmacol 66:9-29. Cohen, SR; Davis, DM; Kramkowski, RS. (1974) Clin ical manifestations of chronic acid toxicity-- Nasal lesions in electroplateworkers. Cutis 13:558-568. Glaser, U; Hochrainer, D; Kloppe, H; et al. (1985) Low level chromi um (VI) inhalation effects on alveolar macrophages and immu ne function in Wistar ra ts. Arch Toxicol 57(4):250-256. Glaser, U; Hochrainer, D; Steinhof f, D. (1990) Investigation of irri tating properties of inhaled Cr (VI) with possible influence on its carcinogenic action. In: Environmental Hygiene II. Seemayer, NO; Hadnagy, W, eds. Berlin/New York: Springer-Verlag. Henderson, RF. (1984) Use of bronchoalveolar la vage to detect lung damage. Environ Health Perspect 56:115-129. Henderson, RF. (1988) Use of bronchoalveolar lava ge to detect lung dama ge. In: Toxicology of the lung. Gardner, DE; Crapo, JD; Ma saro, EJ, eds., New York: Raven Press. Henderson, RF; Benson, JM; Hahn , FF. (1985) New approaches for the evaluation of pulmonary toxicity: bronchoalveolar lavage fluid analysis. Fundam Ap pl Toxicol 5:451-458. Lees, PSJ; Gibb, HJ; Rooney, BC . (1995) Derivation of exposu re-response relationship for chromium from historic exposure data. 11th International Symposium of Epidemiology in Occupational Health, the Netherlands, September 1995. Lindberg, E; Hedensteirna, G. (1983) Chrome plating: Symptoms , finding in the upper airways and effects on lung function. Arch Environ Health 38:367-374. Lucas, JB; Kramkowski, RS. (1975) Health Hazard Evaluation Report No . 74-87-221. Cincinnati, OH. Health Hazard Evaluation Bran ch, U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Diseas e Control. National Institute for Occupational Safety and Health. Malsch, PA; Proctor, DM; Finley, BL. (1994) Esti mation of a chromium inhalation reference concentration using the benchmark dose method: a case study. Regul Toxicol Pharmacol 20:58- 82. 

### http://www.epa.gov/iris/subst/0144.htmU.S. EPA. (1998) Toxicologica l review of hexavalent ch romium. Available online at http://www.epa.gov/iris. Venet, A; Clavel, F; Israel-Biet, D; et al. (1985) Lung in acquired immune deficiency syndrome: Infectious and immunological stat us assessed by bronchioalveolar lavage. Bull Eur Physiopathol Respir 21:535-543.

_VI.C. CarcinogenicityAssessment References Alderson, MR; Rattan, NS; Bidstrup, L. (1981) He alth of workmen in the chromate-producing industry in Britain. Br J Ind Med 38:117-124. Baetjer, AM. (1950a) Pulmonary carcinoma in chro mate workers. In: A review of the literature and report of cases. Arch Ind Hyg Occup Med 2(5):487-504. Baetjer, AM. (1950b) Pulmonary carcinoma in ch romate workers. II. Incidence on basis of hospital records. Arch Ind Hyg Occup Med 2(5):505-516. Bidstrup, PL. (1951) Carcinoma of the lung in chromate workers. Br J Med 8:302-305. Bidstrup, PL; Case, RAM. (1956) Carcinoma of the lung in wo rkmen in the bichromates-producing industry in Great Britain. Br J Ind Med 13:260-264. Bonatti, S; Meini, M; Abbondandolo, A. (1976) Genetic effects of pota ssium dichromate in Schizosaccharomyces pomb e. Mutat Res 38:147-150. Bourne, HG, Jr; Yee, HT. (1950) Occupational cancer in a chro mate plant - an environmental appraisal. Ind Med Surg 19(12):563-567. Brinton, HP; Frasier, ES; Koven AL. (1952) Morb idity and mortality expe rience among chromate workers. Public Health Rep 67(9):835-847. Casto, BC; Meyers, J; Di Paolo, JA. (1979) Enhancement of vira l transformation for evaluation of the carcinogenic or mutagenic potential of inorganic metal salt s. Cancer Res 39:193-198. Davies, JM. (1978) Lung-cancer mortality in workers making chrome pigments. Lancet 1:384. Davies, JM. (1979) Lung cancer mortality of wo rkers in chromate pigm ent manufacture: An epidemiological survey. J Oil Chem Assoc 62:157-163. Davies, JM. (1984) Lung cancer mortality amon g workers making lead chromate and zinc chromate pigments at three Englis h factories. Br J Ind Med 41:158-169. De Flora, S; Wetterhahn, KE. ( 1989) Mechanisms of chromium meta bolism and genotoxicity. Life Chem Rep 7:169-244. De Flora, S; Bagnasco, M; Se rra, D; et al. (1990) Genotoxici ty of chromium compounds: a review. Mutat Res 238:99-172. Enterline, PE. (1974) Respiratory cancer am ong chromate workers. J Occup Med 16:523-526. 

### http://www.epa.gov/iris/subst/0144.htmFradkin, A; Janoff, A; La ne, BP; et al. (1975) In vitro transformation of BHK21 cells grown in the presence of calc ium chromate. Cancer Res 35:1058-1063. Frentzel-Beyme, R. (1983) Lung cancer mortality of workers employed in chromate pigment factories. A multicentric European epidemiolo gical study. J Cancer Res Clin Oncol 105:183-188. Furst, A; Schlauder, M; Sasmore, DP. (1976) Tumorigeni c activity of lead chromate. Cancer Res 36:1779-1783. Glaser, U; Hochrainer, D; Kloppe l, H; et al. (1986) Carcinogenic ity of sodium dichromate and chromium(VI/III) oxide aerosols inhaled bymale Wistar rats. Toxicology 42:219-232. Haguenor, JM; Dubois, G; Frimat, P; et al. (1981) Mortality due tobronch-pulmonary >cancer in a factory producing pigments based on lead and zi nc chromates. In: Preven tion of occupational cancer - International symposium, occupational safety and health series 46. Geneva , Switzerland: International Labour Offi ce, pp. 168-176. (French). Hayes, RB; Lilienfeld, AM ; Snell, LM. (1979) Morta lity in chromium chemical production workers: a prospective study. In t J Epidemiol 8(4):365-374. Hayes, RB; Sheffet, A; Spirtas, R. (1989) Cancer mortality among a cohort of chromium pigment workers. Am J Ind Med 16:127-133. Hill, WJ; Ferguson, WS. (1979) St atistical analysis of epidemio logical data from chromium chemical manufacturing pl ant. J Occup Med 21:103-106. Hueper, WC. (1961) Environmental carcinogen esis and cancers. Cancer Res 21:842-857. Hueper, WC; Payne, WW. (1962) Experimental studies in metal carc inogenesis: Chromium, nickel, iron, and arsenic. Arch Environ Health 5:445-462. Hill, WJ; Ferguson, WS. (1979) St atistical analysis of epidemio logical data from a chromium chemical manufacturing plan t. J Occup Med 21(2):103-106. Kawanishi, S; Inoue, S; Sano, S. (1986) Me chanism of DNA cleavageinduced by sodium chromate (VI) in the presence of hy drogen peroxide. J Biol Chem 261:5952-5958. Klein, CB; Frenkel, K; Costa, M. (1992) Chro mium mutagenesis in transgenic gpt+ Chinese hamster cell lines. Environ Mol Mutagen 19:29a. Klein, CB; Frenkel, K; Costa, M. (1991) The roleof oxidative processes in metal Carcinogenesis. Chem Res Toxicol 4:592-604. Korallus, U; Lange H; Ness, A; et al. (1982) Relationships between prec autionary measures and bronchial carcinoma mortality in the chromate-producing industry. Arbeitsmedizin, Socialmedizin, Preventivmedizin. 17(7):159-167. (German - Eng. summary) Langard, S; Norseth, T. (1975) A cohort study of bronchial carcinomas in workers producing chromate pigments. Br J Ind Med 32:62-65. Langard, S; Vigander, T. (1983) Occurrence of lung cancer in workers in producing chromium pigments. Br J Ind Med 40:71-74. 

### http://www.epa.gov/iris/subst/0144.htmLaskin, S; Kuschner, M; Drew, RT. (1970) Studie s in pulmonary carcinogenesis. In: Hanna, Jr., MG;, Nettesheim, P; and Gilbert, JR, eds. Levis, AG; Buttignol, M; Bianchi, V; et al. (1978) Effects of potassium dich romate on nucleic acid and protein syntheses and on prec ursor uptake in BHK fibroblasts. Cancer Res 38:110-116. Levy, LS; Martin, PA. (1983) The effects of a rang e of chromium-containing materials on rat lung. Sponsored by Dry Color Manufacturers' Association and others. (Unpublished) Loeb, LA; Sirover, MA; Agarwal, SS. (1977) Infideli ty of DNA synthesis as related to mutagenesis and carcinogenesis. Adv Exp Biol Med 91:103-115. Lofroth, G. (1978) The mutagenicity of hexa valent chromium is decreased by microsomal metabolism. Naturvi ssenschaften 65:207-208. Machle, W; Gregorius, F. (1948) Cancer of the re spiratory system in the United States chromateproducing industry. PublicHealth Rep 63(35):1114-1127. Maltoni, C. (1974) Occupati onal carcinogenesis. Excerp ta Med Int Congr Ser 322:19-26. Maltoni, C. (1976) Predictive value of carcin ogenesis bioassays. Ann NY Acad Sci 271:431-443. Mancuso, TF. (1975) Consideration of ch romium as an industrial carcinogen. International Conference on Heavy Metals in the Environment, Toronto, On tario, Canada, October 27-31. pp. 343-356. Mancuso, TF. (1997) Chromium asan industrial carcinogen: Part 1. Am J Ind Med 31:129-139. Mancuso, TF; Hueper, WC. (1951) Occupational ca ncer and other health Hazards in a chromate plant: A medical appraisal. In: Lung cancers in chromate workers. Ind Med Surg 20(8):358-363. Nakamuro, K; Yoshikawa, K; Sayato, Y; et al. (1978) Comparative studies of chromosomal aberration and mutagenicity of trivalent and hexavalent chromium. Mutat Res 58:175-181. Newbold, RF; Amos, J; Connell, JR. (1979) The cytotoxic, mutagenic and clastogenic effects of chromium-containing compounds on mammalian cells in culture. Mutat Res 67:55-63. National Institute for Occupa tional Safety and Health (N IOSH). (1975) Criteria for a recommended standard o ccupational exposure tochromium (VI). U.S. Department of Health, Education, and Welfare, Washington, DC. Ohsaki, Y; Abe, S; Kimura, K; et al. (1978) Lung cancer in Japanese ch romate workers. Thorax 33:372-374. Payne, WW. (1960a) The role of roasted chromite ore in the production of cancer. Arch Environ Health 1:20-26. Payne, WW. (1960b) Production of cancers in mice and rats by chromium compounds. Arch Ind Health 21:530-535. 

### http://www.epa.gov/iris/subst/0144.htmPetrilli, FL; DeFlora, S. (1977) Toxicity and muta genicity of hexavalent chromium on Salmonella typhimurium. Appl Environ Microbiol 33(4):805-809. Petrilli, FL; DeFlora, S. (1978) Oxidation of inactive trival ent chromium to the mutagenic hexavalent form. Mutat Res 58:167-178. Raffetto, G; Parodi, S; Parodi, C; et al. (1977) Direct interaction with cellular targets as the mechanism for chromium carc inogenesis. Tumori 63:503-512. Royle, H. (1975) Toxicity of chro mic acid in the chromium plat ing industry. Environ Res 10:141- 163. Sano, T; Mitohara, I. (1978) O ccupational cancer among chromi um workers. Jpn J Chest Dis 37 (2):90-101. Satoh, K; Fukuda, Y; Torii, K; et al. (1981) Epidemiologic study of workers engaged in the manufacture of chromium comp ounds. J Occup Med 23(12):835-838. Sorahan, T; Burgess, DC; Waterh ouse, JA. (1987) A mortality stud y of nickel/chromium platers. Br J Ind Med 44:250-258. Steinhoff, S; Gad, SC; Hatfield, GK; et al. (1983) Listing sodium dichroma te and soluble calcium chromate for carcinogenicity in rats. Bayer AG Institute of Toxicology. (Unpublished) Sugiyama, M. (1992) Role of physiological antioxid ants in chromium (VI)-induced cellular injury. Free Rad Biol Med 12:397-407. Taylor, FH. (1966) The relationship of mortality and duration of employme nt as reflected by a cohort of chromate workers. Am J Public Health 56(2):218-229. Todd, GE. (1962) Tobacco manufacturer's standing committee research pape rs. No. 1. Statistics of Smoking in the United Kingdom, 3rd ed. Tobacco Research Council, London. Tsuda, H; Kato, K. (1977) Chromosomal aberra tions and morphologica l transformation in hamster embryonic cells treated with potassium dichromate in vitro. Mutat Res 46:87-94. U.S. EPA. (1984) Health assessme nt document for chromium. Prepar ed by the Office of Health and Environmental Assessment, Environmental Crit eria and Assessment Office, Cincinnati, OH. EPA/600/8-83-014F. U.S. EPA. (1998) Toxicologica l review of hexavalent ch romium. Available online at http://www.epa.gov/iris. Watanabe, S; Fukuchi, Y. (1975) An epidemiolo gical survey on lung cancer in workers of a chromate-producing industry in Hokkaido, Ja pan. Presented at Inte rnational Congress on Occupational Health.



### _VII. Revision History http://www.epa.gov/iris/subst/0144.htmDate Chromium (VI) CASRN —18540-29-9 Section Description 09/30/1987 II.A.1. Citation corrected 03/01/1988 II.C.4. Confiden ce statement revised 03/01/1988 II.D.3. Co ntacts switched 03/01/1988 III.A. Health Advisory added 12/01/1989 I.B. Inhalation RfD now under review 06/01/1990 II.A.1. Basis - Text revised 06/01/1990 II.B. Text revised 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 06/01/1990 VI. Bibliography on-line 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 03/01/1991 II.A.1 Text revised 03/01/1991 II.A.4. Text revised 03/01/1991 II.B. Text revised 01/01/1992 I.A.7. Secondary contact change 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 06/01/1992 All CASRN corrected from 7440-47-3 to 18540-29-9 09/01/1994 I.A.6. Work group review date added 02/01/1995 I.A. RfD noted as pending change: Work Grp Mtg on 08/03/1994

08/01/1995 I.A., I.A.6., I.B. EPA's RfD/RfC and CRAVE workgroupswere discontinu ed in May 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions begi nning in September, 1995.

04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/01/1996 I.A.7. Secondary contact removed 09/03/1998 I., II., VI. Revised RfD, RfC, carcinogenicity assessment, refs. 10/28/2003 I.A.6., I.B.6., II.D.2. Screening-Level Literature Review Findings message has been added. 

### http://www.epa.gov/iris/subst/0144.htmIRIS Home Chronic HealthHazards for NonCarcinogenic Effects Reference Dose for Chronic Oral Exposure (RfD) • Oral RfD Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments • Confidence in the Oral RfD • EPA Documentation and Review

Reference Concentration for Chronic Inhalation

Exposure (RfC) • Inhalation RfC Summary • Principal and Supporting Studies • Uncertainty and Modifying Factors • Additional Studies/Comments • Confidence in the Inhalation RfC • EPA Documentation and Review Carcinogenicity Assessment for Lifetime Exposure Evidence for Human Carcinogenicity 

### _VIII. Synonyms Chromium (VI) CASRN —18540-29-9 Last Revised — 03/31/1987 • 18540-29-9 • 7440-47-3 • Chromic ion • Chromium • Chromium, ion • Chromium (VI) • Chromium (VI) ion 

### http://www.epa.gov/iris/subst/0144.htm• Weight-ofEvidence Characterization • Human Carcinogenicity Data • Animal Carcinogenicity Data • Supporting Data for Carcinogenicity Quantitative Estimate of Carcinogenic Risk from Oral Exposure

• Summary of Risk Estimates • Dose-Response Data • Additional Comments • Discussion of Confidence Quantitative Estimate of Carcinogenic Risk

from Inhalation Exposure • Summary of Risk Estimates • Dose-Response Data • Additional Comments • Discussion of Confidence • EPA Documentation, Review and, Contacts Bibliography Revision History Synonyms 

### http://www.epa.gov/iris/subst/0144.htm