HSN: 382

NAME: CARBON TETRACHLORIDE

CAS-RN: 56-23-5

DATE: 20180416

Risk Values - Summary Table

Summary Risk Table for:CARBON TETRACHLORIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Oral: Non-Cancer
green check
--
--
--
--
--
--
green check
--
green check
Oral: Cancer
green check
--
green check
--
--
--
--
green check
--
green check
Inhalation: Non-Cancer
green check
--
--
--
--
--
--
green check
--
green check
Inhalation: Cancer
green check
--
green check
--
--
--
--
green check
--
green check
green check = Chemical evaluated and ITER data online.


Noncancer Oral Risk Values Table:

ITER Noncancer Oral Risk Table for: CARBON TETRACHLORIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Risk Value Namechronic MRL
--
--
--
--
--
--
TDI
--
RfD
Risk Value*NA
--
--
--
--
--
--
4E-3
--
4E-3
Year2005
--
--
--
--
--
--
2000
--
2010
Base(Experimental)*NA
--
--
--
--
--
--
NOAEL 1
--
BMDL2X 5.46
Basis(Adjusted)*NA
--
--
--
--
--
--
NA
--
BMDL2X-ADJ 3.9
Uncertainty FactorNA
--
--
--
--
--
--
250
--
1000
Critical Organ or EffectNA
--
--
--
--
--
--
liver
--
elevated serum SDH activity
SpeciesNA
--
--
--
--
--
--
rat
--
rat
StudyNA
--
--
--
--
--
--
multiple
--
Bruckner et al., 1986
Biomonitoring Blood
--
--
--
--
--
--
--
--
--
7E-02
Biomonitoring Urine
--
--
--
--
--
--
--
--
--
--
View Specific:Click here
--
--
--
--
--
--
Click here
--
Click here
*In mg/kg body weight per day, unless otherwise specified.


Noncancer Oral Synopsis:

ATSDR, RIVM, and U.S. EPA evaluated the noncancer oral toxicity data for carbon tetrachloride. EPA derived a reference dose (RfD) of 0.004 mg/kg-day based on elevated serum sorbitol dehydrogenase (SDH) activity observed in rats exposed to carbon tetrachloride by oral gavage in corn oil 12 weeks (Bruckner et al., 1986). EPA used an increase in SDH activity 2 times the control mean, representing an increase in serum enzyme level considered to be biologically significant, as the benchmark response (BMR). The resulting 95\% confidence limit on this response (BMDL2X) is 5.46 mg/kg-day EPA adjusted this by 5/7 days to account for continuous exposure, resulting in a BMDL2X-ADJ of 3.9 mg/kg-day. EPA applied a composite uncertainty factor of 1000 (10 each for intra- and inter-species variability, and 3 each for use of a subchronic study and database deficiencies). RIVM derived a tolerable daily intake (TDI) of 0.004 mg/kg-day based on a NOAEL of 1 mg/kg-day for liver effects observed in rat subchronic studies. RIVM applied a composite uncertainty factor of 250. ATSDR did not derive a chronic oral minimal risk level (MRL) because no data were located on the effects of chronic-duration oral exposure in humans, and because serious effects were observed at the lowest tested doses in several animal bioassays and ATSDR does not base MRLs on doses at which serious effects occur. However, ATSDR did derive an intermediate MRL based on the same study as EPA.

The biomonitoring equivalent (BE) was derived by Aylward et al. (2010). A BE is the concentration or range of concentrations of a chemical in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline. BE values are most appropriately used as screening values to evaluate biomonitoring data in the context of existing risk assessments rather than for assessing data from individuals. BE values are derived through integration of available data on toxicokinetics with the toxicity data underlying the exposure guidelines (Hays et al. 2008). Values were derived using a previously-published physiologically based pharmacokinetic (PBPK) model (Aylward et al., 2008). Additional important information regarding the derivation, appropriate application, and limitations of BE values in the assessment of biomonitoring data is available in the published derivation (Aylward et al., 2008). Click on the green circle(s) for more information.

Noncancer Oral Specifics:

ATSDR

PEER:
The ATSDR Toxicological Profile has undergone internal agency reviews and has been externally reviewed by a peer review panel.

MOREI:
ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological Profile for Carbon Tetrachloride. U.S. Department of Health and Human Services, Public Health Service. August. Available at http://www.atsdr.cdc.gov/toxprofiles/tp30.html.

For the list of ATSDR minimal risk levels (MRLs), see http://www.atsdr.cdc.gov/mrls/index.html.

Noncancer Oral Specifics:

RIVM

PEER:
The RIVM toxicological profile has undergone internal reviews.

BIB:
Multiple studies as cited in:

ATSDR 1994. Toxicological Profile for Carbon Tetrachloride (Update). TP-93/02, Agency of Toxic Substances and Disease Registry, U.S. Department of Health &; Human Services, Public Health Service; Atlanta (GA), USA.

MOREI:
Baars AJ et al. 2001. Re-evaluation of human-toxicological maximum permissible risk levels. RIVM report no. 711701025, National Institute of Public Health and the Environment, Bilthoven, The Netherlands, March 2001, p 188-192. Available at http://www.rivm.nl/bibliotheek/rapporten/711701025.pdf or at http://www.rivm.nl/en/ (click on Search, type "711701025", then click on document).

Previous source document:

Vermeire, TG, ME van Apeldoorn, JC de Fouw and PJCM Janssen. "Voorstel voor de humaan-toxicologische onderbouwing van C-(toetsings)warden" (In Dutch). RIVM report no. 725201005. National Institute of Public Health and the Environment, Bilthoven, The Netherlands, February 1991, p 132-133. Report can be ordered from RIVM (see http://www.rivm.nl/en/ click on Publications, then click on "How to order" for instructions).

Noncancer Oral Specifics:

U.S.EPA

PEER:
This document has been reviewed by EPA scientists, interagency reviewers from other federal agencies and White House offices, and the public, and peer reviewed by independent scientists external to the EPA. A summary and EPA's disposition of the comments received from the independent external peer reviewers and from the public is included in Appendix A of the Toxicological Review of Carbon Tetrachoride (U.S. EPA, 2010).

BIB:
Bruckner, J.V., W.F. MacKenzie, S. Muralidhara, et al. 1986. Oral toxicity of carbon tetrachloride: acute, subacute and subchronic studies in rats. Fundam. Appl. Toxicol. 6:16-34.

U.S. EPA. 2010. Toxicological Review of Carbon Tetrachloride (CAS No. 56-23-5). In Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. EPA/635/R-08/005F. Available at http://www.epa.gov/iris/toxreviews/0020tr.pdf

MOREI:
Details on this chemical's assessment are available on U.S. EPA's Integrated Risk Information System (IRIS).

U.S. EPA, 2010. Integrated Risk Information System (IRIS). Online. National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris/subst/0020.htm

Aylward, L.L., LaKind, J.S., Hays, S.M. 2008. Biomonitoring Equivalents (BE) dossier for trihalomethanes. 2008 Oct;58 (1):33-44. PubMed PMID: 18579267.

Aylward L.L., Kirman C.R., Blount B.C., Hays S.M. 2010. Chemical-specific screening criteria for interpretation of biomonitoring data for volatile organic compounds (VOCs) application of steady-state PBPK model solutions. Regul Toxicol Pharmacol. 2010 Oct;58(1):33-44. PubMed PMID: 20685286.

Hays S.M., Aylward L.L., LaKind J.S., Bartels M.J., Barton H.A., Boogaard P.J., Brunk C., DiZio S., Dourson M., Goldstein D.A., Lipscomb J., Kilpatrick M.E., Krewski D., Krishnan K., Nordberg M., Okino M., Tan Y.M., Viau C., Yager J.W. 2008. Guidelines for the derivation of Biomonitoring Equivalents: report from the Biomonitoring Equivalents Expert Workshop. 2008 Aug;51(3 Suppl):S4-15. PubMed PMID: 18583008.


Cancer Oral Risk Values Table:

ITER Cancer Oral Risk Table for: CARBON TETRACHLORIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Risk Value NameNA
--
NA
--
--
--
--
CR(oral)
--
RSD
Risk Value*NA
--
NA
--
--
--
--
NA
--
1.4E-4
Year2005
--
1999
--
--
--
--
2000
--
2010
ClassificationNA
--
2B
--
--
--
--
NA
--
see below
Target OrganNA
--
NA
--
--
--
--
NA
--
liver
SpeciesNA
--
NA
--
--
--
--
NA
--
mouse
StudyNA
--
NA
--
--
--
--
NA
--
Nagano et al., 2007b; JBRC, 1998
Biomonitoring Blood
--
--
--
--
--
--
--
--
--
2.3E-03
Biomonitoring Urine
--
--
--
--
--
--
--
--
--
--
View Specific:Click here
--
Click here
--
--
--
--
Click here
--
Click here
*In mg/kg body weight per day, unless otherwise specified.


Cancer Oral Synopsis:

ATSDR, IARC, RIVM, and U.S. EPA evaluated the oral carcinogenicity data for carbon tetrachloride. Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), EPA considers carbon tetrachloride to be "likely to be carcinogenic to humans" by all routes of exposure based on: (1) inadequate evidence of carcinogenicity in humans and (2) sufficient evidence in animals by oral and inhalation exposure, i.e., hepatic tumors in multiple species (rat, mouse, and hamster) and pheochromocytomas (adrenal gland tumors) in mice. EPA derived an oral slope factor (SF) of 7E-2 per (mg/kg)-day based on incidence of hepatocellular adenoma or carcinoma observed in a mouse inhalation study, using PBPK modeling to conduct the route-to-route extrapolation. Note that EPA based both the inhalation unit risk (IUR) and the oral SF on the same inhalation study (Nagano et al., 2007b), but used different tumor data as the point-of-departure for each quantitative estimate. While it may appear counterintuitive that the use of data from a single inhalation bioassay (Nagano et al., 2007b) could result in the use of different data sets for estimating cancer potency by the oral and inhalation routes, EPA explained that this was the result of using PBPK modeling of different dose metrics for the liver and adrenal gland that could result in different relationships between environmental exposure and internal dose within a species (i.e., rat in the current bioassay) and across species (i.e., rats and humans). For comparison purposes on ITER, TERA converted the EPA slope factor to a dose at the 1 in 100,000 (E-5) risk level by dividing 1E-5 by the slope factor of 7E-2 per (mg/kg)-day, resulting in a risk specific dose (RSD) of 1.4E-4 mg/kg-day.

IARC classified carbon tetrachloride as possibly carcinogenic to humans (Group 2B), based on inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. The IARC evaluation considers the evidence of carcinogenicity in humans and experimental animals, as well as other data relevant to the evaluation of carcinogenicity and its mechanisms. IARC does not generally develop risk values or other estimates of potency.

RIVM concluded that carbon tetrachloride has no mutagenic properties and that carcinogenicity of carbon tetrachloride is only apparent at doses that also cause hepatotoxicity. Therefore, cancer can be addressed using a NOAEL approach. ATSDR has published a Toxicological Profile for Carbon Tetrachloride. Although ATSDR discusses the carcinogenicity data in its Toxicological Profiles, it does not currently assess cancer potency or perform cancer risk assessments.

The biomonitoring equivalent (BE) was derived by Aylward et al. (2010). A BE is the concentration or range of concentrations of a chemical in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline. BE values are most appropriately used as screening values to evaluate biomonitoring data in the context of existing risk assessments rather than for assessing data from individuals. BE values are derived through integration of available data on toxicokinetics with the toxicity data underlying the exposure guidelines (Hays et al. 2008). Values were derived using a previously-published physiologically based pharmacokinetic (PBPK) model (Aylward et al., 2008). Additional important information regarding the derivation, appropriate application, and limitations of BE values in the assessment of biomonitoring data is available in the published derivation (Aylward et al., 2008). Click on the green circle(s) for more information.

Cancer Oral Specifics:

ATSDR

PEER:
The ATSDR Toxicological Profile has undergone internal agency reviews and has been externally reviewed by a peer review panel.

MOREI:
ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological Profile for Carbon Tetrachloride. U.S. Department of Health and Human Services, Public Health Service. August. Available at http://www.atsdr.cdc.gov/toxprofiles/tp30.html.

For the list of ATSDR minimal risk levels (MRLs), see http://www.atsdr.cdc.gov/mrls/index.html.

Cancer Oral Specifics:

IARC

PEER:
Each IARC evaluation is developed by an international working group of experts, which meets to discuss and finalize the monograph text and to formulate the evaluations. Working Group members are chosen on the basis of their knowledge and experience, with due regard given to avoid situations where financial or other interests might affect the outcome of their work. The members of a Working Group are invited to serve in their individual capacities as scientists, and not as representatives of their governments or of any organization with which they are affiliated. Representatives of national and international agencies are also invited to the meetings, and others may attend as observers.

MOREI:
International Agency for Research on Cancer (IARC) Monographs. Re-Evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. 1999. Volume 71, page 422. Summaries &; Evaluations available at http://monographs.iarc.fr/ENG/Monographs/vol71/index.php

Additional information about the IARC Monographs (including ordering information and links to other Monographs) can be found at http://monographs.iarc.fr/

Cancer Oral Specifics:

RIVM

PEER:
The RIVM toxicological profile has undergone internal reviews.

MOREI:
Baars AJ et al. 2001. Re-evaluation of human-toxicological maximum permissible risk levels. RIVM report no. 711701025, National Institute of Public Health and the Environment, Bilthoven, The Netherlands, March 2001, p 188-192. Available at http://www.rivm.nl/bibliotheek/rapporten/711701025.pdf or at http://www.rivm.nl/en/ (click on Search, type "711701025", then click on document).

Previous source document:

Vermeire, TG, ME van Apeldoorn, JC de Fouw and PJCM Janssen. "Voorstel voor de humaan-toxicologische onderbouwing van C-(toetsings)warden" (In Dutch). RIVM report no. 725201005. National Institute of Public Health and the Environment, Bilthoven, The Netherlands, February 1991, p 132-133. Report can be ordered from RIVM (see http://www.rivm.nl/en/ click on Publications, then click on "How to order" for instructions).

Cancer Oral Specifics:

U.S.EPA

PEER:
This document has been reviewed by EPA scientists, interagency reviewers from other federal agencies and White House offices, and the public, and peer reviewed by independent scientists external to the EPA. A summary and EPA's disposition of the comments received from the independent external peer reviewers and from the public is included in Appendix A of the Toxicological Review of Carbon Tetrachoride (U.S. EPA, 2010).

BIB:
JBRC (Japan Bioassay Research Center). 1998. Subchronic inhalation toxicity and carcinogenicity studies of carbon tetrachloride in F344 rats and BDF1 mice (Studies Nos. 0020, 0021, 0043, and 0044). Kanagawa, Japan Industrial Safety and Health Association, Japan Bioassay Research Center, Kanagawa, Japan. Unpublished report to the Ministry of Labor. Hirasawa Hadano Kanagawa, 257 Japan.

Nagano, K., T. Sasaki, Y. Umeda, et al. 2007b. Inhalation carcinogenicity and chronic toxicity of carbon tetrachloride in rats and mice. Inhal. Tox. 19:1089-1103.

U.S. EPA. 2005a. Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Available at http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=116283

U.S. EPA. 2010. Toxicological Review of Carbon Tetrachloride (CAS No. 56-23-5). In Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. EPA/635/R-08/005F. Available at http://www.epa.gov/iris/toxreviews/0020tr.pdf

MOREI:
Details on this chemical's assessment are available on U.S. EPA's Integrated Risk Information System (IRIS).

U.S. EPA, 2010. Integrated Risk Information System (IRIS). Online. National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris/subst/0020.htm

Aylward, L.L., LaKind, J.S., Hays, S.M. 2008. Biomonitoring Equivalents (BE) dossier for trihalomethanes. 2008 Oct;58 (1):33-44. PubMed PMID: 18579267.

Aylward L.L., Kirman C.R., Blount B.C., Hays S.M. 2010. Chemical-specific screening criteria for interpretation of biomonitoring data for volatile organic compounds (VOCs) application of steady-state PBPK model solutions. Regul Toxicol Pharmacol. 2010 Oct;58(1):33-44. PubMed PMID: 20685286.

Hays S.M., Aylward L.L., LaKind J.S., Bartels M.J., Barton H.A., Boogaard P.J., Brunk C., DiZio S., Dourson M., Goldstein D.A., Lipscomb J., Kilpatrick M.E., Krewski D., Krishnan K., Nordberg M., Okino M., Tan Y.M., Viau C., Yager J.W. 2008. Guidelines for the derivation of Biomonitoring Equivalents: report from the Biomonitoring Equivalents Expert Workshop. 2008 Aug;51(3 Suppl):S4-15. PubMed PMID: 18583008.


Noncancer Inhalation Risk Values Table:

ITER Noncancer Inhalation Risk Table for: CARBON TETRACHLORIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Risk Value Namechronic MRL
--
--
--
--
--
--
TCA
--
RfC
Risk Value*1.9E-1 (0.03 ppm)
--
--
--
--
--
--
6E-2
--
1E-1
Year2005
--
--
--
--
--
--
2000
--
2010
Base(Experimental)*NOAEL 32 (5 ppm)
--
--
--
--
--
--
NOAEC 31
--
NA
Basis(Adjusted)*NOAEL(HEC) 5.8 (0.9 ppm)
--
--
--
--
--
--
NOAEC 6.4
--
BMCL10(HEC) 14.3
Uncertainty Factor30
--
--
--
--
--
--
100
--
100
Critical Organ or Effectliver
--
--
--
--
--
--
liver
--
liver
Speciesrat
--
--
--
--
--
--
rat
--
rat
StudyJapan Bioassay Research Center, 1998
--
--
--
--
--
--
multiple
--
Nagano et al., 2007b; JBRC, 1998
Biomonitoring Blood
--
--
--
--
--
--
--
--
--
2E-01
Biomonitoring Urine
--
--
--
--
--
--
--
--
--
--
View Specific:Click here
--
--
--
--
--
--
Click here
--
Click here
*In mg/kg body weight per day, unless otherwise specified.


Noncancer Inhalation Synopsis:

ATSDR, RIVM, and U.S. EPA evaluated the noncancer inhalation toxicity data for carbon tetrachloride. EPA derived a reference concentration (RfC) of 0.1 mg/m3 based on the observation of fatty changes in the livers of rats following chronic inhalation exposure (Nagano et al., 2007b; JBRC, 1998). EPA used BMD modeling to analyze the data and PBPK modeling to estimate human equivalent concentrations, resulting in a point of departure of BMCL10(HEC) of 14.3 mg/m3. EPA applied a total uncertainty factor of 100 (10 for intrahuman variability and 3 each for extrapolation from animals to humans and database deficiencies).

ATSDR derived a chronic inhalation minimal risk level (MRL) of 0.03 ppm (0.19 mg/m3) (1 ppm= 6.39 mg/m3) based on a NOAEL of 5 ppm for liver effects in rats. A NOAEL(HEC) was calculated by multiplying the duration-adjusted NOAEL of 0.9 ppm (5 ppm x 6 hours/24 hours x 5 days/7 days) by the ratio of the rat and human blood:gas partition coefficients (1.7). Because the ratio was greater than 1, a default value of 1 was applied, resulting in a NOAEL(HEC) of 0.9 ppm (5.8 mg/m3). The NOAEL(HEC) was divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans using dosimetric adjustment and 10 for human variability). The resulting MRL is equal to 0.19 mg/m3.

RIVM derived a tolerable concentration in air (TCA) based on an adjusted NOAEC of 6.4 mg/m3 for liver toxicity identified in a subchronic study in rats; the resulting TCA is 0.06 mg/m3. Although all three organizations appear to have derived values based on the same critical effect and study, different approaches in developing the point of departure and choice of uncertainty factor account for the differences in the values derived by each organization.

The biomonitoring equivalent (BE) was derived by Aylward et al. (2010). A BE is the concentration or range of concentrations of a chemical in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline. BE values are most appropriately used as screening values to evaluate biomonitoring data in the context of existing risk assessments rather than for assessing data from individuals. BE values are derived through integration of available data on toxicokinetics with the toxicity data underlying the exposure guidelines (Hays et al. 2008). Values were derived using a previously-published physiologically based pharmacokinetic (PBPK) model (Aylward et al., 2008). Additional important information regarding the derivation, appropriate application, and limitations of BE values in the assessment of biomonitoring data is available in the published derivation (Aylward et al., 2008). Click on the green circle(s) for more information.

Noncancer Inhalation Specifics:

ATSDR

DCE:
See MRL Worksheet in Toxicological Profile, Appendix A, pp. A-5 through A-7. Available at http://www.atsdr.cdc.gov/toxprofiles/tp30-a.pdf.

QEST:
See MRL Worksheet in Toxicological Profile, Appendix A, pp. A-5 through A-7. Available at http://www.atsdr.cdc.gov/toxprofiles/tp30-a.pdf.

PEER:
The ATSDR Toxicological Profile has undergone internal agency reviews and has been externally reviewed by a peer review panel.

BIB:
Japan Bioassay Research Center. 1998. Subchronic inhalation toxicity and carcinogenicity studies of carbon tetrachloride in F344 rats and BDF1 mice (Studies Nos. 0020, 0021, 0043, and 0044). Kanagawa, Japan Industrial Safety and Health Association, Japan Bioassay Research Center (Unpublished report to the Ministry of Labor). Hirasawa Hadano Kanagawa, 257 Japan. (In 2001, T. Matsushima provided additional data tables for these studies: organ weights, hematology, serum chemistry, urinalysis).

Methods published in:

Nagano K, Nishizawa T, Yamamoto S et al. 1998. Inhalation carcinogenesis studies of six halogenated hydrocarbons in rats and mice. In: Advances in the prevention of occupational respiratory diseases. Chiyotani K, Hosoda Y, Aizawa Y, eds. Elsevier Science B.V., 741-746.

MOREI:
ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological Profile for Carbon Tetrachloride. U.S. Department of Health and Human Services, Public Health Service. August. Available at http://www.atsdr.cdc.gov/toxprofiles/tp30.html.

For the list of ATSDR minimal risk levels (MRLs), see http://www.atsdr.cdc.gov/mrls/index.html.

Noncancer Inhalation Specifics:

RIVM

PEER:
The RIVM toxicological profile has undergone internal reviews.

BIB:
Multiple studies as cited in:

ATSDR 1994. Toxicological Profile for Carbon Tetrachloride (Update). TP-93/02, Agency of Toxic Substances and Disease Registry, U.S. Department of Health &; Human Services, Public Health Service; Atlanta (GA), USA.

MOREI:
Baars AJ et al. 2001. Re-evaluation of human-toxicological maximum permissible risk levels. RIVM report no. 711701025, National Institute of Public Health and the Environment, Bilthoven, The Netherlands, March 2001, p 188-192. Available at http://www.rivm.nl/bibliotheek/rapporten/711701025.pdf or at http://www.rivm.nl/en/ (click on Search, type "711701025", then click on document).

Previous source document:

Vermeire, TG, ME van Apeldoorn, JC de Fouw and PJCM Janssen. "Voorstel voor de humaan-toxicologische onderbouwing van C-(toetsings)warden" (In Dutch). RIVM report no. 725201005. National Institute of Public Health and the Environment, Bilthoven, The Netherlands, February 1991, p 132-133. Report can be ordered from RIVM (see http://www.rivm.nl/en/ click on Publications, then click on "How to order" for instructions).

Noncancer Inhalation Specifics:

U.S.EPA

PEER:
This document has been reviewed by EPA scientists, interagency reviewers from other federal agencies and White House offices, and the public, and peer reviewed by independent scientists external to the EPA. A summary and EPA's disposition of the comments received from the independent external peer reviewers and from the public is included in Appendix A of the Toxicological Review of Carbon Tetrachoride (U.S. EPA, 2010).

BIB:
JBRC (Japan Bioassay Research Center). 1998. Subchronic inhalation toxicity and carcinogenicity studies of carbon tetrachloride in F344 rats and BDF1 mice (Studies Nos. 0020, 0021, 0043, and 0044). Kanagawa, Japan Industrial Safety and Health Association, Japan Bioassay Research Center, Kanagawa, Japan. Unpublished report to the Ministry of Labor. Hirasawa Hadano Kanagawa, 257 Japan.

Nagano, K., T. Sasaki, Y. Umeda, et al. 2007b. Inhalation carcinogenicity and chronic toxicity of carbon tetrachloride in rats and mice. Inhal. Tox. 19:1089-1103.

U.S. EPA. 2010. Toxicological Review of Carbon Tetrachloride (CAS No. 56-23-5). In Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. EPA/635/R-08/005F. Available at http://www.epa.gov/iris/toxreviews/0020tr.pdf

MOREI:
Details on this chemical's assessment are available on U.S. EPA's Integrated Risk Information System (IRIS).

U.S. EPA, 2010. Integrated Risk Information System (IRIS). Online. National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris/subst/0020.htm

Aylward, L.L., LaKind, J.S., Hays, S.M. 2008. Biomonitoring Equivalents (BE) dossier for trihalomethanes. 2008 Oct;58 (1):33-44. PubMed PMID: 18579267.

Aylward L.L., Kirman C.R., Blount B.C., Hays S.M. 2010. Chemical-specific screening criteria for interpretation of biomonitoring data for volatile organic compounds (VOCs) application of steady-state PBPK model solutions. Regul Toxicol Pharmacol. 2010 Oct;58(1):33-44. PubMed PMID: 20685286.

Hays S.M., Aylward L.L., LaKind J.S., Bartels M.J., Barton H.A., Boogaard P.J., Brunk C., DiZio S., Dourson M., Goldstein D.A., Lipscomb J., Kilpatrick M.E., Krewski D., Krishnan K., Nordberg M., Okino M., Tan Y.M., Viau C., Yager J.W. 2008. Guidelines for the derivation of Biomonitoring Equivalents: report from the Biomonitoring Equivalents Expert Workshop. 2008 Aug;51(3 Suppl):S4-15. PubMed PMID: 18583008.


Cancer Inhalation Risk Values Table:

ITER Cancer Inhalation Risk Table for: CARBON TETRACHLORIDE
Risk Value Parameter OrganizationATSDRHealth CanadaIARCIPCSIPRVITER PRNSF IntlRIVMTCEQU.S.EPA
Risk Value NameNA
--
NA
--
--
--
--
CR(inhal)
--
RSC
Risk Value*NA
--
NA
--
--
--
--
NA
--
1.7E-3
Year2005
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1999
--
--
--
--
2000
--
2010
ClassificationNA
--
2B
--
--
--
--
NA
--
see below
Target OrganNA
--
NA
--
--
--
--
NA
--
pheochromocytoma
SpeciesNA
--
NA
--
--
--
--
NA
--
mouse
StudyNA
--
NA
--
--
--
--
NA
--
Nagano et al., 2007b; JBRC, 1998
Biomonitoring Blood
--
--
--
--
--
--
--
--
--
3.2E-03
Biomonitoring Urine
--
--
--
--
--
--
--
--
--
--
View Specific:Click here
--
Click here
--
--
--
--
Click here
--
Click here
*In mg/kg body weight per day, unless otherwise specified.


Cancer Inhalation Synopsis:

ATSDR, IARC, RIVM, and U.S. EPA evaluated the inhalation carcinogenicity data for carbon tetrachloride. Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), EPA considers carbon tetrachloride to be "likely to be carcinogenic to humans" by all routes of exposure based on: (1) inadequate evidence of carcinogenicity in humans and (2) sufficient evidence in animals by oral and inhalation exposure, i.e., hepatic tumors in multiple species (rat, mouse, and hamster) and pheochromocytomas (adrenal gland tumors) in mice. EPA derived an inhalation unit risk (IUR) of 6E-6 per (ug/m3) based on the incidence of pheochromocytomas observed in male mice following chronic inhalation exposure. EPA used PBPK modeling to estimate the human equivalent concentrations. Note that EPA based both the IUR and the oral slope factor on the same inhalation study (Nagano et al., 2007b), but used different tumor data as the point-of-departure for each quantitative estimate. While it may appear counterintuitive that the use of data from a single inhalation bioassay (Nagano et al., 2007b) could result in the use of different data sets for estimating cancer potency by the oral and inhalation routes, EPA explained that this was the result of using PBPK modeling of different dose metrics for the liver and adrenal gland that could result in different relationships between environmental exposure and internal dose within a species (i.e., rat in the current bioassay) and across species (i.e., rats and humans). For comparison purposes on ITER, TERA converted the EPA unit risk to a concentration at the 1 in 100,000 (E-5) risk level by dividing 1E-5 by the unit risk of 6E-6 per (ug/m3) (and by an additional 1000 to convert to mg/m3). The resulting risk specific concentration (RSC) is 1.7E-3 mg/m3.

IARC classified carbon tetrachloride as possibly carcinogenic to humans (Group 2B), based on inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. The IARC evaluation considers the evidence of carcinogenicity in humans and experimental animals, as well as other data relevant to the evaluation of carcinogenicity and its mechanisms. IARC does not generally develop risk values or other estimates of potency.

RIVM concluded that carbon tetrachloride has no mutagenic properties and that carcinogenicity of carbon tetrachloride is only apparent at doses that also cause hepatotoxicity. Therefore, cancer can be addressed using a NOAEL approach. ATSDR has published a Toxicological Profile for Carbon Tetrachloride. Although ATSDR discusses the carcinogenicity data in its Toxicological Profiles, it does not currently assess cancer potency or perform cancer risk assessments.

The biomonitoring equivalent (BE) was derived by Aylward et al. (2010). A BE is the concentration or range of concentrations of a chemical in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline. BE values are most appropriately used as screening values to evaluate biomonitoring data in the context of existing risk assessments rather than for assessing data from individuals. BE values are derived through integration of available data on toxicokinetics with the toxicity data underlying the exposure guidelines (Hays et al. 2008). Values were derived using a previously-published physiologically based pharmacokinetic (PBPK) model (Aylward et al., 2008). Additional important information regarding the derivation, appropriate application, and limitations of BE values in the assessment of biomonitoring data is available in the published derivation (Aylward et al., 2008). Click on the green circle(s) for more information.

Cancer Inhalation Specifics:

ATSDR

PEER:
The ATSDR Toxicological Profile has undergone internal agency reviews and has been externally reviewed by a peer review panel.

MOREI:
ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological Profile for Carbon Tetrachloride. U.S. Department of Health and Human Services, Public Health Service. August. Available at http://www.atsdr.cdc.gov/toxprofiles/tp30.html.

For the list of ATSDR minimal risk levels (MRLs), see http://www.atsdr.cdc.gov/mrls/index.html.

Cancer Inhalation Specifics:

IARC

PEER:
Each IARC evaluation is developed by an international working group of experts, which meets to discuss and finalize the monograph text and to formulate the evaluations. Working Group members are chosen on the basis of their knowledge and experience, with due regard given to avoid situations where financial or other interests might affect the outcome of their work. The members of a Working Group are invited to serve in their individual capacities as scientists, and not as representatives of their governments or of any organization with which they are affiliated. Representatives of national and international agencies are also invited to the meetings, and others may attend as observers.

MOREI:
International Agency for Research on Cancer (IARC) Monographs. Re-Evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. 1999. Volume 71, page 422. Summaries &; Evaluations available at http://monographs.iarc.fr/ENG/Monographs/vol71/index.php

Additional information about the IARC Monographs (including ordering information and links to other Monographs) can be found at http://monographs.iarc.fr/

Cancer Inhalation Specifics:

RIVM

PEER:
The RIVM toxicological profile has undergone internal reviews.

MOREI:
Baars AJ et al. 2001. Re-evaluation of human-toxicological maximum permissible risk levels. RIVM report no. 711701025, National Institute of Public Health and the Environment, Bilthoven, The Netherlands, March 2001, p 188-192. Available at http://www.rivm.nl/bibliotheek/rapporten/711701025.pdf or at http://www.rivm.nl/en/ (click on Search, type "711701025", then click on document).

Previous source document:

Vermeire, TG, ME van Apeldoorn, JC de Fouw and PJCM Janssen. "Voorstel voor de humaan-toxicologische onderbouwing van C-(toetsings)warden" (In Dutch). RIVM report no. 725201005. National Institute of Public Health and the Environment, Bilthoven, The Netherlands, February 1991, p 132-133. Report can be ordered from RIVM (see http://www.rivm.nl/en/ click on Publications, then click on "How to order" for instructions).

Cancer Inhalation Specifics:

U.S.EPA

PEER:
This document has been reviewed by EPA scientists, interagency reviewers from other federal agencies and White House offices, and the public, and peer reviewed by independent scientists external to the EPA. A summary and EPA's disposition of the comments received from the independent external peer reviewers and from the public is included in Appendix A of the Toxicological Review of Carbon Tetrachoride (U.S. EPA, 2010).

BIB:
JBRC (Japan Bioassay Research Center). 1998. Subchronic inhalation toxicity and carcinogenicity studies of carbon tetrachloride in F344 rats and BDF1 mice (Studies Nos. 0020, 0021, 0043, and 0044). Kanagawa, Japan Industrial Safety and Health Association, Japan Bioassay Research Center, Kanagawa, Japan. Unpublished report to the Ministry of Labor. Hirasawa Hadano Kanagawa, 257 Japan.

Nagano, K., T. Sasaki, Y. Umeda, et al. 2007b. Inhalation carcinogenicity and chronic toxicity of carbon tetrachloride in rats and mice. Inhal. Tox. 19:1089-1103.

U.S. EPA. 2005a. Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Available at http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=116283

U.S. EPA. 2010. Toxicological Review of Carbon Tetrachloride (CAS No. 56-23-5). In Support of Summary Information on the Integrated Risk Information System (IRIS), National Center for Environmental Assessment, Washington, DC. EPA/635/R-08/005F. Available at http://www.epa.gov/iris/toxreviews/0020tr.pdf

MOREI:
Details on this chemical's assessment are available on U.S. EPA's Integrated Risk Information System (IRIS).

U.S. EPA, 2010. Integrated Risk Information System (IRIS). Online. National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris/subst/0020.htm

Aylward, L.L., LaKind, J.S., Hays, S.M. 2008. Biomonitoring Equivalents (BE) dossier for trihalomethanes. 2008 Oct;58 (1):33-44. PubMed PMID: 18579267.

Aylward L.L., Kirman C.R., Blount B.C., Hays S.M. 2010. Chemical-specific screening criteria for interpretation of biomonitoring data for volatile organic compounds (VOCs) application of steady-state PBPK model solutions. Regul Toxicol Pharmacol. 2010 Oct;58(1):33-44. PubMed PMID: 20685286.

Hays S.M., Aylward L.L., LaKind J.S., Bartels M.J., Barton H.A., Boogaard P.J., Brunk C., DiZio S., Dourson M., Goldstein D.A., Lipscomb J., Kilpatrick M.E., Krewski D., Krishnan K., Nordberg M., Okino M., Tan Y.M., Viau C., Yager J.W. 2008. Guidelines for the derivation of Biomonitoring Equivalents: report from the Biomonitoring Equivalents Expert Workshop. 2008 Aug;51(3 Suppl):S4-15. PubMed PMID: 18583008.

NO Revision History: