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1,4-Dioxane (CASRN 123-91-1)

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Note: A TOXICOLOGICAL REVIEW is available for this chemical in Adobe PDF Format (419 pp, 8.52M).  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 program must be configured properly so the PDF displays within the browser window. If your browser and Adobe program need configuration, please go to EPA's PDF page for instructions. In addition, there are hyperlinks to the reference citations throughout this document that will take you to the HERO database (Health and Environmental Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of developing science assessments.

0326

1,4-Dioxane; CASRN 123-91-1

Human health assessment information on a chemical substance is included in IRIS only after a comprehensive review of toxicity data by U.S. EPA health scientists from several program offices, regional offices, and the Office of Research and Development. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the positions that were reached during the review process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website at www.epa.gov/iris/backgrd.html.

STATUS OF DATA FOR 1,4-Dioxane

File First On-Line 08/22/1988

Category (section)
Status
Last Revised
Chronic Oral RfD Assessment (I.A.) on-line 08/11/2010
Chronic Inhalation RfC Assessment (I.B.) on-line 09/20/2013
Carcinogenicity Assessment (II.) on-line 09/20/2013

_I.  HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS

__I.A.  REFERENCE DOSE (RfD) FOR CHRONIC ORAL EXPOSURE

Substance Name – 1,4-Dioxane
CASRN – 123-91-1
Section I.A. Last Revised – 08/11/2010

The RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The RfD is intended for use in risk assessments for health effects known or assumed to be produced through a nonlinear (presumed threshold) mode of action. It is expressed in units of mg/kg-day. Please refer to the guidance documents at www.epa.gov/iris/backgrd.html for an elaboration of these concepts. Because RfD values can be derived for the noncarcinogenic health effects of substances that are also carcinogens, it is essential to refer to other sources of information concerning the carcinogenicity of this chemical 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.

There was no previous oral RfD for 1,4-dioxane on IRIS.

___I.A.1. CHRONIC ORAL RfD SUMMARY

Critical Effect
Point of Departure
UF
Chronic RfD
Liver and kidney toxicity

Chronic oral male rat study

Kociba et al. (1974)
NOAEL: 9.6 mg/kg-day
300
0.03 mg/kg-day

___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)

Liver and kidney toxicity were the primary noncancer health effects associated with exposure to 1,4-dioxane in humans and laboratory animals. Occupational exposure to 1,4-dioxane has resulted in hemorrhagic nephritis and centrilobular necrosis of the liver (Johnstone, 1959; Barber, 1934). In animals, liver and kidney degeneration and necrosis were observed frequently in acute oral and inhalation studies (JBRC, 1998a; Drew et al., 1978; David, 1964; Kesten et al., 1939; Laug et al., 1939; Schrenk and Yant, 1936; de Navasquez, 1935; Fairley et al., 1934). Liver and kidney effects were also observed following chronic oral exposure to 1,4-dioxane in animals (Kano et al., 2009; JBRC, 1998b; Yamazaki et al., 1994; NCI, 1978; Kociba et al., 1974; Argus et al., 1973; Argus et al., 1965) [see summary Table 4-25 in the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013)].

In the available chronic studies, (Kociba et al., 1974) reported the most sensitive effects in the liver and kidney based on a NOAEL of 9.6 mg/kg-day and a LOAEL of 94 mg/kg-day in male Sherman rats. Kociba et al. (1974) reported toxic effects of hepatocellular degeneration and necrosis in the liver, while liver lesions reported in other studies (JBRC, 1998b; Argus et al., 1973) appeared to be related to the carcinogenic process. Kociba et al. (1974) also reported renal tubule epithelial cell degenerative changes and necrosis in the kidney which was supported by data in NCI (1978) and Argus et al. (1973); however, kidney toxicity was observed in these studies at higher doses. For degenerative liver effects resulting from 1,4-dioxane exposure, the Kociba et al. (1974) study represents the most sensitive effect and dataset observed in a chronic bioassay. As a result, Kociba et al. (1974) was chosen as the principal study for the derivation of the RfD.

Kociba et al. (1974) conducted a 2-year study in which four groups of 6-8-week-old Sherman rats (60/sex/dose level) were administered 1,4-dioxane in drinking water at levels of 0 (controls), 0.01, 0.1, or 1.0% for up to 716 days. Based on water consumption and BW data for specific exposure groups, Kociba et al. (1974) calculated mean daily doses of 9.6, 94, and 1,015 mg/kg-day for male rats and 19, 148, and 1,599 mg/kg-day for female rats during days 114-198 for the 0.01, 0.1, and 1.0% concentration levels, respectively. Rats were observed daily for clinical signs of toxicity, and BWs were measured twice weekly during the first month, weekly during months 2-7, and biweekly thereafter. Water consumption was recorded at three different time periods during the study: days 1-113, 114-198, and 446-460. Blood samples were collected from a minimum of five male and five female control and high-dose rats during the 4th, 6th, 12th, and 18th months of the study and at termination. Each blood sample was analyzed for packed cell volume, total erythrocyte count, hemoglobin, and total and differential WBC counts. Additional endpoints evaluated included organ weights (brain, liver, kidney, testes, spleen, and heart) and gross and microscopic examination of major tissues and organs (brain, bone and bone marrow, ovaries, pituitary, uterus, mesenteric lymph nodes, heart, liver, pancreas, spleen, stomach, prostate, colon, trachea, duodenum, kidneys, esophagus, jejunum, testes, lungs, spinal cord, adrenals, thyroid, parathyroid, nasal turbinates, and urinary bladder).

Histopathological lesions were restricted to the liver and kidney from the mid- and high-dose groups and consisted of variable degrees of renal tubular epithelial and hepatocellular degeneration and necrosis (no quantitative incidence data were provided). Rats from these groups also showed evidence of hepatic regeneration, as indicated by hepatocellular hyperplastic nodule formation and evidence of renal tubular epithelial regenerative activity (observed after 2 years of exposure). These changes were not seen in controls or in low-dose rats. The authors determined a NOAEL of 9.6 mg/kg-day and a LOAEL of 94 mg/kg-day for 1,4-dioxane based on the liver and kidney effects in male rats.

Methods of Analysis. Kociba et al. (1974) did not provide quantitative incidence or severity data for liver and kidney degeneration and necrosis. Benchmark dose (BMD) modeling could not be performed for this study, and the NOAEL for liver and kidney degeneration (9.6 mg/kg-day in male rats) was used as the point of departure (POD) in deriving the RfD for 1,4-dioxane.

Other datasets and alternative POD values were also considered as the basis for the 1,4-dioxane RfD, including incidence data reported for cortical tubule degeneration in male and female rats (NCI, 1978) and liver hyperplasia (JBRC, 1998b). The BMDL10 values of 22.3 mg/kg-day and 23.8 mg/kg-day from the (NCI, 1978) and (JBRC, 1998b) studies, respectively, are about double the NOAEL (9.6 mg/kg-day) observed by Kociba et al. (1974).

___I.A.3. UNCERTAINTY FACTORS

UF = 300
          = 10 (UFA) × 10 (UFH) × 1 (UFS) × 1 (UFL) × 3 (UFD)

A default interspecies UF of 10 (UFA) was used to account for pharmacokinetic and pharmacodynamic differences between rats and humans. Existing PBPK models could not be used to derive an oral RfD for 1,4-dioxane.

A default interindividual variability UF of 10 (UFH) was used to account for variation in sensitivity within human populations because there is limited information on the degree to which humans of varying gender, age, health status, or genetic makeup might vary in the disposition of, or response to, 1,4-dioxane.

An UF to extrapolate from a subchronic to a chronic (UFS) exposure duration was not necessary (e.g., UFS = 1) because the RfD was derived from a study using a chronic exposure protocol.

An UF to extrapolate from a LOAEL to a NOAEL (UFL) was not necessary (e.g., UFL = 1) because the RfD was based on a NOAEL. Kociba et al. (1974) was a well-conducted, chronic drinking water study with an adequate number of animals. Histopathological examination was performed for many organs and tissues, but clinical chemistry analysis was not performed. NOAEL and LOAEL values were derived from the study based on liver and kidney toxicity.

An UF of 3 for database deficiencies (UFD) was applied due to the lack of a multigeneration reproductive toxicity study.

___I.A.4. ADDITIONAL STUDIES/COMMENTS

The predominant noncancer effect of chronic oral exposure to 1,4-dioxane is degenerative effects in the liver and kidney. For degenerative liver effects resulting from 1,4-dioxane exposure, the Kociba et al. (1974) study represents the most sensitive effect and dataset observed in a chronic bioassay.

Kidney toxicity as evidenced by glomerulonephritis (Argus et al., 1965; Argus et al., 1973) and degeneration of the cortical tubule (CAA, 1990; NCI, 1978; Kociba et al., 1974) has also been observed in response to chronic exposure to 1,4-dioxane. Degenerative effects were observed in the kidney at the same dose level as effects in the liver (Kociba et al., 1974).

Rhinitis and inflammation of the nasal cavity were reported in both the NCI (1978) (mice only, dose ≥ 380 mg/kg-day) and JBRC (1998a) studies (≥ 274 mg/kg-day in rats, >278 mg/kg-day in mice).  JBRC (1998a)reported nasal inflammation in rats (NOAEL 55 mg/kg-day, LOAEL 274 mg/kg-day) and mice (NOAEL 66 mg/kg-day, LOAEL 278 mg/kg-day).

Studies in experimental animals have also found that relatively high doses of 1,4-dioxane (1,000 mg/kg-day) during gestation can produce delayed ossification of the sternebrae and reduced fetal BWs (Giavini et al., 1985). 

For more detail on Susceptible Populations, exit to the toxicological review, Section 4.8 (PDF)

___I.A.5. CONFIDENCE IN THE CHRONIC ORAL RfD

Study - Medium
Database - Medium
RfD - Medium

The overall confidence in the RfD is medium. Confidence in the principal study (Kociba et al., 1974) is medium. The 2-year drinking water study is a well-conducted, peer-reviewed study that used 3 dose groups plus a control. The study had adequate group sizes (60 rats/sex/dose group) and investigated multiple target organs.

Confidence in the oral database is medium due to the lack of a multigeneration reproductive toxicity study.

Reflecting medium confidence in the principal study and medium confidence in the database, confidence in the RfD is medium.

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 CHRONIC ORAL RfD

Source Document – Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013)

This document has been provided for review to EPA scientists, interagency reviewers from other federal agencies and the Executive Office of the President, and the public, and peer reviewed by independent scientists external to 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 1,4-Dioxane (U.S. EPA, 2013). To review this appendix, exit to the Toxicological Review, Appendix A, Summary of External Peer Review and Public Comments and Disposition (PDF).

Agency Completion Date - 08/11/2010

___I.A.7. EPA CONTACTS

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email address).

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__I.B. REFERENCE CONCENTRATION (RfC) FOR CHRONIC INHALATION EXPOSURE

Substance Name — 1,4-Dioxane
CASRN — 123-91-1
Section I.B. Last Revised — 09/20/2013

The RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The RfC considers toxic effects for both the respiratory system (portal of entry) and for effects peripheral to the respiratory system (extrarespiratory effects). The inhalation RfC (generally expressed in units of mg/m3) is analogous to the oral RfD and is similarly intended for use in risk assessments for health effects known or assumed to be produced through a nonlinear (presumed threshold) mode of action.

Inhalation RfCs are derived according to Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994). Because RfCs can also be derived for the noncarcinogenic health effects of substances that are carcinogens, it is essential to refer to other sources of information concerning the carcinogenicity of this chemical substance. The U.S. EPA has evaluated this substance for potential human carcinogenicity, a summary of that evaluation is contained in Section II of this file.

__I.B.1. CHRONIC INHALATION RfC SUMMARY

Critical Effect
Point of Departure*
UF
Chronic RfC
Atrophy and respiratory metaplasia of the olfactory epithelium

Chronic inhalation male rat study

Kasai et al. (2009)
LOAEL: 50 ppm
LOAEL PODADJ: 8.9 ppm
LOAEL PODHEC: 32.2 mg/m3
1,000
3×10-2 mg/m3

*Conversion Factors and Assumptions - Rats in the principal study were exposed for 6 hours/day, 5 days/week, for 104 weeks. The POD associated with intermittent exposure was adjusted to continuous exposure by multiplying the POD by 6/24 hours and 5/7 days resulting in the PODADJ of 8.9 ppm. This ppm value was converted to mg/m3 using the chemical-specific conversion factor of 1 ppm = 3.6 mg/m3. Additionally, the POD was adjusted to reflect the human equivalent concentration (HEC) by application of a chemical-specific dosimetric adjustment factor (DAF) of 1.12 resulting in the PODHEC of 32.2 mg/m3

___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)

Four inhalation studies in animals were identified in the literature; two, 13 week subchronic studies in laboratory animals (Kasai et al., 2008; Fairley et al., 1934) and two, 2 year chronic studies in rats (Kasai et al., 2009; Torkelson et al., 1974). Nasal, liver, and kidney toxicity were the primary noncancer health effects of inhalation exposure to 1,4-dioxane in rodents (see summary Table 4-26 in the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013).

The chronic Kasai et al. (2009) study was selected as the principal study for the derivation of the RfC. Groups of male 6 week old F344/DuCrj rats (50/group) were exposed via inhalation to nominal concentrations of 0 (clean air), 50, 250, and 1,250 ppm (0, 180, 900, and 4,500 mg/m3, respectively) of vaporized 1,4-dioxane (>99% pure) for 6 hours/day, 5 days/week, for 104 weeks (2 years) in whole body inhalation chambers (Kasai et al., 2009). At the time of death or at the end of the 2-years of exposure the authors examined multiple organ systems. Based on the noncancer database for 1,4-dioxane, this study demonstrated exposure concentration related effects for histopathological lesions at a lower concentration (50 ppm) compared to the subchronic Kasai et al. study (2008). The 2 year bioassay (Kasai et al., 2009) did not observe effects in both sexes, but the use of only male rats was proposed by the study authors as justified by data illustrating the absence of induced mesotheliomas in female rats following exposure to 1,4-dioxane in drinking water (Yamazaki et al., 1994). Additionally, a similar pattern of effects was observed after oral exposure to 1,4-dioxane (Kano et al., 2009; JBRC, 1998b) as observed in the Kasai et al. (2009) 2 year inhalation study.

Nonneoplastic lesions from the Kasai et al. (2009) study that were statistically increased as compared to control were considered candidates for the critical effect. The candidate endpoints included centrilobular necrosis of the liver, squamous cell metaplasia of nasal respiratory epithelium, squamous cell hyperplasia of nasal respiratory epithelium, respiratory metaplasia of nasal olfactory epithelium, sclerosis in lamina propria of nasal cavity, and two degenerative nasal lesions, that is, atrophy of nasal olfactory epithelium and hydropic change in the lamina propria. Despite statistical increases at the low and mid exposure concentrations (50 and 250 ppm, respectively), incidences of nuclear enlargement of respiratory epithelium (nasal cavity), olfactory epithelium (nasal cavity), and proximal tubule (kidney) were not considered candidates for the critical effect, since nuclear enlargement as a specific morphologic diagnosis is not considered by EPA to be an adverse effect of exposure to 1,4-dioxane.

Methods of Analysis. Benchmark dose (BMD) modeling methodology (U.S. EPA, 2012) was used to analyze the candidate endpoints identified for 1,4-dioxane. BMDs and BMDLs were able to be determined for centrilobular necrosis, squamous cell metaplasia and hyperplasia of the respiratory epithelium, and hydropic change of lamina propria. Due to poor fit or substantial model uncertainty, BMD model results were inadequate for the following nasal lesions: atrophy (olfactory epithelium), respiratory metaplasia (olfactory epithelium), and sclerosis (lamina propria). Consequently, the NOAEL/LOAEL approach was used to determine potential PODs for these endpoints.

Other endpoints in Kasai et al. (2009) were considered as alternative POD values in the derivation of the RfC, including incidence data reported for centrilobular necrosis in the liver and other respiratory effects. Alternative PODs are shown in Table 5-4 and Figure 5-5 of the Toxicological Review for 1,4-Dioxane (U.S. EPA, 2013).

___I.B.3. UNCERTAINTY FACTORS

UF = 1,000

      = 3 (UFA) × 10 (UFH) × 1 (UFS) × 10 (UFL) × 3 (UFD)

An interspecies UF of 3 (UFA) was used for animal to human extrapolation to account for pharmacodynamic differences between species. This uncertainty factor is comprised of two separate areas of uncertainty to account for differences in the toxicokinetics and toxicodynamics of animals and humans. In this assessment, the toxicokinetic uncertainty was accounted for by the calculation of a HEC and application of a dosimetric adjustment factor as outlined in the RfC methodology (U.S. EPA, 1994). As the toxicokinetic differences are thus accounted for, only the toxicodynamic uncertainties remain, and an UFA of 3 is retained to account for this uncertainty.

A default interindividual variability UF of 10 (UFH) was used to account for variation in sensitivity within human populations because there is limited information on the degree to which humans of varying gender, age, health status, or genetic makeup might vary in the disposition of, or response to, 1,4-dioxane. A recent modeling study by Valcke and Krishnan (2011) assessed the impact of exposure duration and concentration on the human kinetic adjustment factor and estimated the neonate to adult 1,4-dioxane blood concentration ratio to be 3.2. Thus, a full factor of 10 was used to account for differences between adults and neonates, as well as other differences in gender, age, health status, or genetics that might result in a different disposition of, or response to, 1,4-dioxane.

An UF to extrapolate from a subchronic to a chronic (UFS) exposure duration was not necessary (e.g., UFS = 1) because the RfC was derived from a study using a chronic exposure protocol.

An UF of 10 (UFL) was used to extrapolate from a LOAEL to a NOAEL because a LOAEL was used as the POD. A NOAEL for atrophy and respiratory metaplasia of the olfactory epithelium was not identified in the study by Kasai et al. (2009).

An UF of 3 for database deficiencies (UFD) was applied due to the lack of a multigeneration reproductive toxicity study.

___I.B.4. ADDITIONAL STUDIES/COMMENTS

Prior to the Kasai et al. (Kasai et al., 2009; Kasai et al., 2008) studies, two other studies were available for consideration in the derivation of inhalation toxicity values: one subchronic study (Fairley et al., 1934) and one chronic inhalation study (Torkelson et al., 1974). In the subchronic study, rabbits, guinea pigs, rats, and mice (3-6/species/group) were exposed to 1,000, 2,000, 5,000, or 10,000 ppm of 1,4-dioxane vapor for 1.5 hours two times a day for 5 days, 1.5 hours for one day, and no exposure on the seventh day. Animals were exposed until death occurred or were sacrificed after various durations of exposure (3-202.5 hours). Detailed dose-response information was not provided; however, severe liver and kidney damage and acute vascular congestion of the lungs were observed at concentrations ≥ 1,000 ppm. Kidney damage was described as patchy degeneration of cortical tubules with vascular congestion and hemorrhage. Liver lesions varied from cloudy hepatocyte swelling to large areas of necrosis.

Torkelson et al. (1974) performed a chronic inhalation study in which male and female Wistar rats (288/sex) were exposed to 111 ppm 1,4-dioxane vapor for 7 hours/day, 5 days/week for 2 years. Control rats (192/sex) were exposed to filtered air. No significant effects were observed on BWs, survival, organ weights, hematology, clinical chemistry, or histopathology. Because Fairley et al. (1934) identified a free-standing LOAEL only, and Torkelson et al. (1974) identified a free-standing NOAEL only, neither study was sufficient to characterize the inhalation risks of 1,4-dioxane.

For more detail on Susceptible Populations, exit to the toxicological review, Section 4.8 (PDF).

___I.B.5. CONFIDENCE IN THE CHRONIC INHALATION RfC

Study — Medium
Database — Medium
RfC — Medium

The overall confidence in the RfC is medium. Confidence in the principal study (Kasai et al., 2009) is medium. The 2-year inhalation study is a well-conducted, peer-reviewed study that used 3 dose groups plus a control. The study had adequate group sizes (50 rats/dose group) and investigated multiple target organs; however, the study did only used male rats and did not investigate chronic effects in females.

Confidence in the database is medium due to the lack of supporting studies and a multigeneration reproductive toxicity study.

Reflecting medium confidence in the principal study and medium confidence in the database, confidence in the RfC is medium.

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 CHRONIC INHALATION RfC

Source Document – Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013)

This document has been provided for review to EPA scientists, interagency reviewers from other federal agencies and the Executive Office of the President, and the public, and peer reviewed by independent scientists external to 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 1,4-Dioxane (U.S. EPA, 2013). To review this appendix, exit to the Toxicological Review, Appendix A, Summary of External Peer Review and Public Comments and Disposition (PDF).

Agency Completion Date - 09/20/2013

___I.B.7. EPA CONTACTS

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email address).

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_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE

Substance Name — 1,4-Dioxane
CASRN — 123-91-1
Last Revised — 09/20/2013

This section 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 and inhalation exposure. Users are referred to Section I of this file for information on long-term toxic effects other than carcinogenicity.

The rationale and methods used to develop the carcinogenicity information in IRIS are described in the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) and the Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens (U.S. EPA, 2005b). The quantitative risk estimates are derived from the application of a low-dose extrapolation procedure, and are presented in two ways to better facilitate their use. First, route-specific risk values are presented. The "oral slope factor" is a plausible upper bound on the estimate of risk per mg/kg-day of oral exposure. Similarly, a "unit risk" is a plausible upper bound on the estimate of risk per unit of concentration, either per µg/L drinking water (see Section II.B.1.) or per µg/m3 air breathed (see Section II.C.1.). Second, the estimated concentration of the chemical substance in drinking water when associated with cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000 is also provided.

A cancer assessment for 1,4-dioxane via the oral route of exposure was posted on the IRIS databse in 2010. At that time, 1,4-dioxane was classified as a likely human carcinogen, based on the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). This update adds an inhalation unit risk (IUR) to that assessment, and the weight-of-evidence cancer classification remains the same.

A previous cancer assessment for 1,4-dioxane was posted on the IRIS database in 1988. At that time, 1,4-dioxane was classified as a B2 carcinogen (probable human carcinogen), based on inadequate human data and sufficient evidence of carcinogenicity in animals (induction of nasal cavity and liver carcinomas in multiple strains of rats, liver carcinomas in mice, and gall bladder carcinomas in guinea pigs). An oral cancer slope factor (CSF) of 1.1 × 10-2 (mg/kg-day)-1 was derived from the tumor incidence data for nasal squamous cell carcinoma in male rats exposed to 1,4-dioxane in drinking water for 2 years (NCI, 1978). The linearized multistage extra risk procedure was used for linear low dose extrapolation. An inhalation unit risk (IUR) was not previously derived.

__II.A. EVIDENCE FOR HUMAN CARCINOGENICITY

___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION

In accordance with the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 1,4-dioxane is characterized as "likely to be carcinogenic to humans." This characterization is based on the following findings: (1) inadequate evidence of carcinogenicity in humans, and (2) sufficient evidence in animals (i.e., hepatic tumors in multiple species [three strains of rats, two strains of mouse, and in guinea pigs]; mesotheliomas of the peritoneum, mammary, and nasal tumors have also been observed in rats following 2 years of oral exposure to 1,4- dioxane).

There is adequate evidence of liver carcinogenicity in several 2-year bioassays conducted in three strains of rats, two strains of mice, and in guinea pigs (Kano et al., 2009; Kasai et al., 2009; JBRC, 1998b; Yamazaki et al., 1994; NCI, 1978; Kociba et al., 1974; Argus et al., 1973; Hoch-Ligeti and Argus, 1970; Hoch-Ligeti et al., 1970; Argus et al., 1965). Additionally, tumors of the peritoneum (Kano et al., 2009; Kasai et al., 2009; JBRC, 1998b; Yamazaki et al., 1994), mammary (Kano et al., 2009; Kasai et al., 2009; JBRC, 1998b; Yamazaki et al., 1994), and nasal cavitiy (Kano et al., 2009; Kasai et al., 2009; JBRC, 1998b; Yamazaki et al., 1994; NCI, 1978; Kociba et al., 1974; Argus et al., 1973; Hoch-Ligeti et al., 1970), as well as kidney, Zymbal gland, and subcutaneous tissue (Kasai et al., 2009) have been observed in rats due to exposure to 1,4-dioxane. Studies in humans are inconclusive regarding evidence for a causal link between occupational exposure to 1,4-dioxane and increased risk for cancer; however, only two studies were available and these were limited by small cohort size and a small number of reported cancer cases (Buffler et al., 1978; Thiess et al., 1976).

U.S. EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) indicate that for tumors occurring at a site other than the initial point of contact, the weight of evidence for carcinogenic potential may apply to all routes of exposure that have not been adequately tested at sufficient doses. An exception occurs when there is convincing information (e.g., toxicokinetic data) that absorption does not occur by other routes. Information available on the carcinogenic effects of 1,4-dioxane via the oral route demonstrates that tumors occur in tissues remote from the site of absorption. Information on the carcinogenic effects of 1,4-dioxane via the dermal route in humans and animals is absent. Based on the observance of systemic tumors following oral and inhalation exposure, and in the absence of information to indicate otherwise, it is assumed that an internal dose will be achieved regardless of the route of exposure. Therefore, 1,4-dioxane is "likely to be carcinogenic to humans" by all routes of exposure.

A MOA hypothesis involving sustained proliferation of spontaneously transformed liver cells has some support from data indicating that 1,4-dioxane acts as a tumor promoter in mouse skin and rat liver bioassays (Lundberg et al., 1987; King et al., 1973). Dose-response and temporal data support the occurrence of cell proliferation and hyperplasia prior to the development of liver tumors (JBRC, 1998b; Kociba et al., 1974) in the rat model. However, the dose-response relationship for induction of hepatic cell proliferation has not been characterized, and it is unknown if it would reflect the dose-response relationship for liver tumors in the 2-year rat and mouse studies. Conflicting data from rat and mouse bioassays (JBRC, 1998b; Kociba et al., 1974) suggest that cytotoxicity may not be a required precursor event for 1,4-dioxane-induced cell proliferation. Liver tumors were observed in female rats and female mice in the absence of lesions indicative of cytotoxicity (Kano et al., 2009; JBRC, 1998b; NCI, 1978). Thus, data regarding a plausible dose response and temporal progression from cytotoxicity and cell proliferation to eventual liver tumor formation are not available. The MOA by which 1,4 dioxane produces liver, nasal, peritoneal (mesotheliomas), and mammary gland tumors is not conclusive, and the available data do not support any hypothesized carcinogenic MOA for 1,4 dioxane

For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF).

For more detail on Susceptible Populations, exit to the toxicological review, Section 4.8 (PDF)

___II.A.2. HUMAN CARCINOGENICITY DATA

Human studies of occupational exposure to 1,4-dioxane were inconclusive to assess the evidence of carcinogenicity of 1,4-dioxane (see Section 4.1 in the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013). In each case, the cohort size and number of reported cases were of limited size (Buffler et al., 1978; Thiess et al., 1976).

___II.A.3. ANIMAL CARCINOGENICITY DATA

Three chronic drinking water bioassays provided incidence data for liver tumors in rats and mice, and nasal cavity, peritoneal, and mammary gland tumors in rats only (Kano et al., 2009; JBRC, 1998b; Yamazaki et al., 1994; NCI, 1978; Kociba et al., 1974). With the exception of the NCI (1978) study, the incidence of nasal cavity tumors was generally lower than the incidence of liver tumors in exposed rats. The Kano et al. (2009) drinking water study was chosen as the principal study for derivation of an oral cancer slope factor (CSF) for 1,4-dioxane. This study used three dose groups in addition to controls and characterized the dose-response relationship at lower exposure levels, as compared to the high doses employed in the NCI (1978) bioassay. The Kociba et al. (1974) study also used three low dose exposure groups; however, the study authors only reported the incidence of hepatocellular carcinoma, which may underestimate the combined incidence of rats with adenoma or carcinoma. In addition to increased incidence of liver tumors, chosen as the most sensitive target organ for tumor formation, the Kano et al. (2009) study also noted increased incidence of peritoneal and mammary gland tumors. Nasal cavity tumors were also seen in high-dose male and female rats; however, the incidence of nasal tumors was much lower than the incidence of liver tumors in both rats and mice.

As described in detail in Section 4.2.1.2.6 and Appendix E of the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013), the Japanese Bioassay Research Center conducted a 2-year drinking water study on the effects of 1,4-dioxane in both sexes of rats and mice. The results from that study were reported several times, once as conference proceedings (Yamazaki et al., 1994), once as a detailed laboratory report (JBRC, 1998b), and once as a published manuscript (Kano et al., 2009). As a result of the most recent publication (Kano et al., 2009), the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2010) was updated and the data in the new publication was considered. Although the data contained in the reports varied, the differences were minor and did not affect the conclusions of this assessment. The variations included: (1) the level of detail on dose information reported; (2) categories for incidence data reported (e.g., all animals or sacrificed animals); and (3) analysis of non- and neoplastic lesions.

A chronic bioassay of 1,4-dioxane by the inhalation route reported by Kasai et al. (2009) provides data adequate for dose response modeling and was subsequently chosen as the study for the derivation of an IUR for 1,4-dioxane. In this bioassay, groups of 50 male F344 rats were exposed to either 0, 50, 250 or 1,250 ppm 1,4-dioxane, 6 hours/day, 5 days/week, for 2 years (104 weeks). In male F344 rats, 1,4-dioxane produced a statistically significant increase in incidence and/or a statistically significant dose response trend for the following tumor types: hepatomas, nasal squamous cell carcinomas, renal cell carcinomas, peritoneal mesotheliomas, mammary gland fibroadenomas, Zymbal gland adenomas, and subcutis fibromas (Kasai et al., 2009).

___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY

Several carcinogenicity bioassays have been conducted for 1,4-dioxane in mice, rats, and guinea pigs (Kano et al., 2009; Kasai et al., 2009; JBRC, 1998b; Yamazaki et al., 1994; NCI, 1978; Kociba et al., 1974; Torkelson et al., 1974; Argus et al., 1973; Hoch-Ligeti and Argus, 1970; Hoch-Ligeti et al., 1970; Argus et al., 1965). Liver tumors have been observed following drinking water exposure in male Wistar rats (Argus et al., 1965), male guinea pigs (Hoch-Ligeti and Argus, 1970), male Sprague Dawley rats (Argus et al., 1973; Hoch-Ligeti et al., 1970), male and female Sherman rats (Kociba et al., 1974), female Osborne-Mendel rats (NCI, 1978), male and female F344/DuCrj rats (Kano et al., 2009; Kasai et al., 2009; JBRC, 1998b; Yamazaki et al., 1994), male and female B6C3F1 mice (NCI, 1978), and male and female Crj:BDF1 mice (Kano et al., 2009; JBRC, 1998b; Yamazaki et al., 1994). In the earliest cancer bioassays, the liver tumors were described as hepatomas (Argus et al., 1973; Hoch-Ligeti and Argus, 1970; Hoch-Ligeti et al., 1970; Argus et al., 1965); however, later studies made a distinction between hepatocellular carcinoma and hepatocellular adenoma (Kano et al., 2009; Kasai et al., 2009; JBRC, 1998b; Yamazaki et al., 1994; NCI, 1978). Both tumor types have been seen in rats and mice exposed to 1,4-dioxane. Kociba et al. (1974) noted evidence of liver toxicity at or below the dose levels that produced liver tumors but did not report incidence data for these effects. Hepatocellular degeneration and necrosis were observed in the mid- and high-dose groups of male and female Sherman rats exposed to 1,4-dioxane, while tumors were only observed at the highest dose. Hepatic regeneration was indicated in the mid- and high-dose groups by the formation of hepatocellular hyperplastic nodules. Findings from JBRC (1998b) also provided evidence of liver hyperplasia in male F344/DuCrj rats at a dose level below the dose that induced a statistically significant increase in tumor formation.

Nasal cavity tumors were also observed in Sprague Dawley rats (Argus et al., 1973; Hoch-Ligeti et al., 1970), Osborne-Mendel rats (NCI, 1978), Sherman rats (Kociba et al., 1974), and F344/DuCrj rats (Kano et al., 2009; Kasai et al., 2009; JBRC, 1998b; Yamazaki et al., 1994). Most tumors were characterized as squamous cell carcinomas. Nasal tumors were not elevated in B6C3F1 or Crj:BDF1 mice. JBRC (1998b) was the only study that evaluated nonneoplastic changes in nasal cavity tissue following prolonged exposure to 1,4-dioxane in the drinking water. Histopathological lesions in female F344/DuCrj rats were suggestive of toxicity and regeneration in this tissue (i.e., atrophy, adhesion, inflammation, nuclear enlargement, and hyperplasia and metaplasia of respiratory and olfactory epithelium). Some of these effects occurred at a lower dose (83 mg/kg-day) than that shown to produce nasal cavity tumors (429 mg/kg-day) in female rats. Reexamination of tissue sections from the NCI (1978) bioassay suggested that the majority of nasal tumors were located in the dorsal nasal septum or the nasoturbinate of the anterior portion of the dorsal meatus. Nasal tumors were not observed in an inhalation study in Wistar rats exposed to 111 ppm for 5 days/week for 2 years (Torkelson et al., 1974).

Tumor initiation and promotion studies in mouse skin and rat liver suggested that 1,4-dioxane does not initiate the carcinogenic process, but instead acts as a tumor promoter (Lundberg et al., 1987; Bull et al., 1986; King et al., 1973) [see Section 4.2.3 in the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013)].

In addition to the liver and nasal tumors observed in several studies, a statistically significant increase in mesotheliomas of the peritoneum was seen in male rats from the Kano et al. (2009) (also (JBRC, 1998b; Yamazaki et al., 1994) and Kasai et al. (2009). Female rats dosed with 429 mg/kg-day in drinking water for 2 years also showed a statistically significant increase in mammary gland adenomas (Kano et al., 2009; JBRC, 1998b; Yamazaki et al., 1994) A significant increase in the incidence of these tumors was not observed in other chronic oral bioassays of 1,4-dioxane (NCI, 1978; Kociba et al., 1974). Additional statistically significant increases in other tumor types were observed in male F344 rats exposed to 0, 50, 250 or 1,250 ppm 1,4-dioxane, 6 hours/day, 5 days/week, for 2 years (104 weeks) including renal cell carcinomas, peritoneal mesotheliomas, mammary gland fibroadenomas, Zymbal gland adenomas, and subcutis fibromas (Kasai et al., 2009).

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__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE

___II.B.1. SUMMARY OF RISK ESTIMATES

____II.B.1.1.  Oral Slope Factor:  1 × 10-1 per mg/kg-day

The derivation of the oral slope factor 1 × 10-1 per mg/kg-day is based on the incidence of hepatocellular adenomas and carcinomas in female mice exposed to 1,4-dioxane in drinking water for 2 years (Kano et al., 2009). The dose metric used in the current estimate of the human equivalent dose (HED) is the applied or external dose because a PBPK model was determined not to be suitable for species extrapolation (see Appendix B of the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013). The rat BMDL50 of 32.93 mg/kg-day represents the POD used to calculate the BMDL50HED of 4.95 mg/kg-day.

The oral slope factor is derived from the BMDL50HED, the 95% lower bound on the exposure associated with a 50% extra cancer risk, by dividing the risk (as a fraction) by the BMDL50HED, and represents an upper bound, continuous lifetime exposure risk estimate:

BMDL50HED, lower 95% bound on exposure at 50% extra risk – 4.95 mg/kg-day

BMD50HED, central estimate of exposure at 50% extra risk – 7.51 mg/kg-day

The slope of the linear extrapolation from the central estimate is 0.5/
(7.51 mg/kg-day) = 7 × 10-2 per mg/kg-day

The slope factor for 1,4-dioxane should not be used with exposures exceeding the point of departure (BMDL50HED = 4.95 mg/kg-day), because above this level the fitted dose-response model better characterizes what is known about the carcinogenicity of 1,4-dioxane.

____II.B.1.2.  Drinking Water Unit Risk*:  2.9 × 10-6 per µg/L

Drinking Water Concentrations at Specified Risk Levels

Risk Level
Lower Bound on Concentration Estimate*
E-4 (1 in 10,000)
35 µg/L
E-5 (1 in 100,000)
3.5 µg/L
E-6 (1 in 1,000,000)
0.35 µg/L

*The unit risk and concentration estimates assume water consumption of 2 L/day by a 70 kg human.

____II.B.1.3. Extrapolation Method

Log-logistic model with linear extrapolation from the POD (BMDL50HED) associated with 50% extra cancer risk.

The log-logistic model provided the best-fit to the female mouse liver tumor data Kano et al. (2009) female data as indicated by the AIC and p-value as was chosen as the best-fitting model to carry forward in the analysis; however, this model resulted in a BMDL10 much lower than the response level at the lowest dose in the study (Kano et al., 2009). Thus, the log-logistic model was also run for BMR values of 30 and 50%. Using a higher BMR value resulted in BMDL values closer to the lowest observed response data, and a BMR of 50% was chosen to carry forward in the analysis.

___II.B.2. DOSE-RESPONSE DATA

Tumor Type – hepatocellular adenoma and carcinoma
Test Species – female BDF1 mouse
Route – Oral, drinking water
References – Kano et al. (2009)

Incidence of liver tumors in female BDF1 female mice exposed to 1,4-dioxane in drinking water for 2 years
Tumor Dose (mg/kg-day)
0 66 278 964
Hepatocellular adenoma or carcinoma 5/50 35/50a 41/50a 46/50a,b

aSignificantly different from control by Fisher's exact test (p < 0.01.)

bStatistically significant trend for increased tumor incidence by Peto's test (p < 0.01).

Source: Kano et al. (2009)

Oral Cancer Slope Factor (CSF) using linear low-dose extrapolation approach and interspecies extrapolation
Tumor Dose groups modeled BMD50
mg/kg-day
BMDL50
mg/kg-day
BMDHED
mg/kg-day
BMDLHED
mg/kg-day
Oral SF
(mg/kg-day)-1
Female mouse hepatocellular adenoma or carcinoma 0, 66, 278, 964 mg/kg-day 49.88 32.93 7.51 4.95 0.10

___II.B.3. ADDITIONAL COMMENTS

Supplementary information not required.

___II.B.4. DISCUSSION OF CONFIDENCE

Relevance to humans. The oral CSF was derived using the tumor incidence in the liver of female mice. A thorough review of the available toxicological data available for 1,4-dioxane provides no scientific justification to propose that the liver adenomas and carcinomas observed in animal models following exposure to 1,4-dioxane are not plausible in humans. Liver adenomas and carcinomas were considered plausible outcomes in humans due to exposure to 1,4-dioxane.

Choice of low-dose extrapolation approach. The possibilities for the low-dose extrapolation of tumor risk from exposure to 1,4-dioxane, or any chemical, are linear or nonlinear, but is dependent upon a plausible MOA(s) for the observed tumors. The MOA is a key consideration in clarifying how risks should be estimated for low-dose exposure. Exposure to 1,4-dioxane has been observed in animal models to induce multiple tumor types, including liver adenomas and carcinomas, nasal carcinomas, mammary adenomas and fibroadenomas, and mesotheliomas of the peritoneal cavity (Kano et al., 2009). MOA information that is available for the carcinogenicity of 1,4-dioxane has largely focused on liver adenomas and carcinomas, with little or no MOA information available for the remaining tumor types. In Section 4.7.3 of the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013), hypothesized MOAs, other than a mutagenic MOA, were explored due to the lack of mutagenicity observed in genetic toxicology tests performed for 1,4-dioxane. The available evidence in support of the hypothesized MOAs for 1,4-dioxane is not conclusive. In the absence of a MOA(s) for the observed tumor types associated with exposure to 1,4-dioxane, a linear low-dose extrapolation approach was used to estimate human carcinogenic risk associated with 1,4-dioxane exposure.

In the studies evaluated (Kano et al., 2009; NCI, 1978; Kociba et al., 1974), the multistage model provided good descriptions of the incidence of a few tumor types in male (nasal cavity) and female (hepatocellular and nasal cavity) rats and in male mice (hepatocellular) exposed to 1,4-dioxane via ingestion (see Appendix D of the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013) for additional details). However, the multistage model did not provide an adequate fit for female mouse liver tumor dataset based upon the following (U.S. EPA, 2012):

By default, the BMDS software imposes constraints on the values of certain parameters of the models. When these constraints were imposed, the multistage model and most other models did not fit the incidence data for female mouse liver adenomas or carcinomas, even after dropping the highest dose group.

The log-logistic model was selected because it was the only model that provided an adequate fit to the female mouse liver tumor data (Kano et al., 2009). A BMR of 50% was used because it is proximate to the response at the lowest dose tested and the BMDL50 was estimated by applying appropriate parameter constraints to the selected model, consistent with the BMD Technical Guidance Document (U.S. EPA, 2012).

The human equivalent oral CSF estimated from liver tumor datasets with statistically significant increases ranged from 4.2 × 10-4 to 1.0 × 10-1 per mg/kg-day, a range of about three orders of magnitude, with the upper and lower extremes coming from the combined male and female data for hepatocellular carcinomas (Kociba et al., 1974) and the female mouse liver adenoma and carcinoma dataset (Kano et al., 2009).

Dose metric. 1,4-Dioxane is known to be metabolized in vivo. However, it is unknown whether a metabolite or the parent compound, or some combination of parent compound and metabolites, is responsible for the observed carcinogenicity. If the actual carcinogenic moiety is proportional to administered exposure, then use of administered exposure as the dose metric is the least biased choice. On the other hand, if this is not the correct dose metric, then the impact on the CSF and IUR is unknown.

Interspecies extrapolation. An adjustment for cross-species scaling (BW0.75) was applied to address toxicological equivalence of internal doses between each rodent species and humans, consistent with the U.S. EPA's 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). It is assumed that equal risks result from equivalent constant lifetime exposures.

Statistical uncertainty at the POD. Parameter uncertainty can be assessed through confidence intervals. Each description of parameter uncertainty assumes that the underlying model and associated assumptions are valid. For the log-logistic model applied to the female mouse data, there is a reasonably small degree of uncertainty at the 50% excess incidence level (the POD for linear low-dose extrapolation), as indicated by the proximity of the BMDLHED (4.95 mg/kg-day) to the BMDHED (7.51 mg/kg-day).

Bioassay selection. The study by Kano et al. (2009) was used for development of an oral CSF. This was a well-designed study, conducted in both sexes in two species with a sufficient number of animals per dose group. The number of test animals allocated among three dose levels and an untreated control group was adequate, with examination of appropriate toxicological endpoints in both sexes of rats and mice. Alternative bioassays (Kociba et al., 1974) are available and were fully considered for the derivation of the oral CSF.

Choice of species/gender. The oral CSF for 1,4-dioxane was derived using the tumor incidence data for the female mouse, which was thought to be more sensitive than male mice or either sex of rats to the carcinogenicity of 1,4-dioxane. While all data, from both species and sexes reported from the Kano et al. (2009) study, were suitable for deriving an oral CSF, the female mouse data represented the most sensitive indicator of carcinogenicity in the rodent model. The lowest exposure level (66 mg/kg-day [animal dose] or 10 mg/kg-day [HED]) observed a considerable and significant increase in combined liver adenomas and carcinomas. Additional testing of doses within the range of control and the lowest dose (66 mg/kg-day [animal dose] or 10 mg/kg-day [HED]) could refine and reduce uncertainty for the oral CSF.

Human population variability. The extent of inter-individual variability in 1,4-dioxane metabolism has not been characterized. A separate issue is that the human variability in response to 1,4-dioxane is also unknown. Data exploring whether there is differential sensitivity to 1,4-dioxane carcinogenicity across life stages is unavailable. This lack of understanding about potential differences in metabolism and susceptibility across exposed human populations thus represents a source of uncertainty. Also, the lack of information linking a MOA for 1,4-dioxane to the observed carcinogenicity is a source of uncertainty.

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____II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE

__II.C.1. Summary of Risk Estimates

__II.C.1.1. Inhalation Unit Risk: 5 × 10-6 (µg/m3)-1

The derivation of the inhalation unit risk 5 × 10-6 per µg/m3 is based on combined tumor incidence in male rats exposed to 1,4-dioxane in via inhalation for 2 years (Kasai et al., 2009). The dose metric used in the current estimate of the human equivalent concentration (HEC) is the applied or inhaled concentration because a PBPK model was determined not to be suitable for species extrapolation (see Appendix B of the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013). The rat multitumor BMCL10 of 30.3 ppm represents the POD used to calculate the BMCLHEC of 19.5 mg/m3.

The inhalation unit risk is derived from the BMCLHEC, the 95% lower bound on the exposure associated with a 10% extra cancer risk, by dividing the risk (as a fraction) by the BMCLHEC, and represents an upper bound, continuous lifetime exposure risk estimate:

BMCL10HEC, lower 95% bound on exposure at 10% extra risk — 19.5 mg/m3

BMC10HEC, central estimate of exposure at 10% extra risk — 26.0 mg/m3

The slope of the linear extrapolation from the central estimate is 0.1/
(26.0 mg/m3) = 4 × 10-6 per µg/m3

The inhalation unit risk for 1,4-dioxane should not be used with exposures exceeding the point of departure (BMCL10HEC = 19.5 mg/m3), because above this level the fitted dose-response model better characterizes what is known about the carcinogenicity of 1,4-dioxane.

__II.C.1.2. Extrapolation Method

Multi-tumor dose-response model with linear extrapolation from the POD (BMCL10HEC) associated with 10% extra cancer risk. Statistically significant dose response trends for the increase in tumors with increasing dose was observed for the nasal cavity squamous cell carcinomas, hepatomas, renal cell carcinomas, peritoneal mesotheliomas, mammary gland fibroadenomas, and Zymbal gland adenomas. All of these tumors were considered to be of independent origin and included in the multi-tumor analysis.

__II.C.2. Dose-Response Data for Carcinogenicity

Tumor Types — multiple (nasal, liver, kidney, peritoneal, mammary gland, and Zymbal gland)
Test species — male F344 rats
Route — Inhalation
Reference — Kasai et al. (2009)

Incidence of tumors in F344 male rats exposed to 1,4-dioxane for 104 weeks (6 hours/day, 5 days/week)
Tumor Type Animal Exposure (ppm)
0 50 250 1,250
Nasal cavity squamous cell carcinoma 0/50 0/50 1/50 6/50a,b
Hepatocellular adenoma or carcinomae 1/50 2/50 4/50 22/50a,c
Renal cell carcinoma 0/50 0/50 0/50 4/50a
Peritoneal mesothelioma 2/50 4/50 14/50c 41/50a,c
Mammary gland fibroadenoma 1/50 2/50 3/50 5/50d
Mammary gland adenoma 0/50 0/50 0/50 1/50
Zymbal gland adenoma 0/50 0/50 0/50 4/50a
Subcutis fibroma 1/50 4/50 9/50c 5/50

aStatistically significant trend for increased tumor incidence by Peto's test (p ≤ 0.01).

bTumor incidence significantly elevated compared with that in controls by Fisher's exact test (p ≤ 0.05).

cTumor incidence significantly elevated compared with that in controls by Fisher's exact test (p ≤ 0.01).

dStatistically significant trend for increased tumor incidence by Peto's test (p ≤ 0.05).

eProvided via email from Dr. Tatsuya Kasai (JBRC) to Dr. Reeder Sams (U.S. EPA) on 12/23/2008 (2008). Statistics were not reported for these data by study authors, so statistical analyses were conducted by EPA.

Source: Kasai et al. (2009) and Kasai (2008)

Inhalation Unit Risk (IUR) using linear low-dose extrapolation approach and interspecies extrapolation
Tumor
Dose groups modeled
BMC10 mg/m3
BMCL10 mg/m3
BMCHEC mg/m3
BMCLHEC mg/m3
Inhalation Unit Risk (µg/m3)-1
Multiple – F344 male rats 0, 50, 250, 1,250 ppm (0, 180, 900, or 4,500 mg/m3) 40.4 30.3 26.0 19.5 5.0 × 10-6

__II.C.3. Additional Comments

Supplementary information not required.

__II.C.4. Discussion of Confidence

Relevance to humans. The derivation of the inhalation unit risk is based on the tumor incidence at multiple sites in male rats. There is no information on 1,4-dioxane to indicate that the observed rodent tumors are irrelevant to humans. Further, no data exist to guide quantitative adjustment for differences in sensitivity among rodents and humans. In the absence of information to indicate otherwise and considering similar cell types are prevalent throughout the respiratory tract of rats and humans, the nasal, liver, renal, peritoneal, mammary gland, Zymbal gland and subcutis tumors were considered relevant to humans.

Choice of low-dose extrapolation approach. The possibilities for the low-dose extrapolation of tumor risk from exposure to 1,4-dioxane, or any chemical, are linear or nonlinear, but is dependent upon a plausible MOA(s) for the observed tumors. The MOA is a key consideration in clarifying how risks should be estimated for low-dose exposure. Exposure to 1,4-dioxane has been observed in animal models to induce multiple tumor types, including liver adenomas and carcinomas, nasal carcinomas, mammary adenomas and fibroadenomas, and mesotheliomas of the peritoneal cavity (Kano et al., 2009). MOA information that is available for the carcinogenicity of 1,4-dioxane has largely focused on liver adenomas and carcinomas, with little or no MOA information available for the remaining tumor types. In Section 4.7.3 of the Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013), hypothesized MOAs, other than a mutagenic MOA, were explored due to the lack of mutagenicity observed in genetic toxicology tests performed for 1,4-dioxane. The available evidence in support of the hypothesized MOAs for 1,4-dioxane is not conclusive. In the absence of sufficient information to support a MOA(s) for the observed tumor types associated with exposure to 1,4-dioxane, a linear low-dose extrapolation approach was used to estimate human carcinogenic risk associated with 1,4-dioxane exposure.

The BMDS multistage cancer model provided adequate fits for the tumor incidence data following a 2 year inhalation exposure to 1,4-dioxane by male rats (Kasai et al., 2009), thus the BMDS MS_Combo multi-tumor model was used to determine a BMCL10.

Interspecies extrapolation. Differences in the anatomy of the upper respiratory tract and resulting differences in absorption or in local respiratory system effects are sources of uncertainty in the inhalation cancer assessment. However, since similar cell types are prevalent throughout the respiratory tract of both rats and humans, the tumors are considered biologically plausible and relevant to humans.

Statistical uncertainty at the POD. Parameter uncertainty can be assessed through confidence intervals. Each description of parameter uncertainty assumes that the underlying model and associated assumptions are valid. For the multistage, multi-tumor model applied for the male rat inhalation dataset, there is a reasonably small degree of uncertainty at the 10% extra risk level (the POD for linear low dose extrapolation).

Bioassay selection. The study by Kasai et al. (2009) was used for derivation of an inhalation unit risk. This was a well designed study, conducted in male rats with a sufficient number (N=50) of animals per dose group. Three dose levels plus an untreated control group were examined following exposure to 1,4-dioxane via inhalation for 2 years.

Choice of species/gender. Male F344 rat data were used to estimate risk following inhalation of 1,4-dioxane. Kano et al. (2009) showed that male rats were more sensitive than female rats to the effects of 1,4-dioxane following oral administration; therefore, male rats were chosen to be studies in the 2 year bioassay conducted by the same laboratory (Kasai et al., 2009). The sensitivity and tumorigenic response of female rats or male or female mice following inhalation of 1,4-dioxane is unknown. Since female mice were the most sensitive gender and species examined in the Kano et al. (2009) oral study, female mice may also be more sensitive to the inhalation of 1,4-dioxane which would result in a greater risk.

Human population variability. The extent of inter-individual variability in 1,4-dioxane metabolism has not been characterized. A separate issue is that the human variability in response to 1,4-dioxane is also unknown. Data exploring whether there is differential sensitivity to 1,4-dioxane carcinogenicity across life stages is unavailable. This lack of understanding about potential differences in metabolism and susceptibility across exposed human populations thus represents a source of uncertainty. Also, the lack of information linking a MOA for 1,4-dioxane to the observed carcinogenicity is a source of uncertainty.

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__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)

___II.D.1. EPA DOCUMENTATION

Source Document – Toxicological Review of 1,4-Dioxane (U.S. EPA, 2013)

This document has been provided for review to EPA scientists, interagency reviewers from other federal agencies and the Executive Office of the President, and the public, and peer reviewed by independent scientists external to 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 1,4-Dioxane (U.S. EPA, 2013). To review this appendix, exit to the Toxicological Review, Appendix A, Summary of External Peer Review and Public Comments and Disposition (PDF).

Agency Completion Date - 09/20/2013

___II.D.2. EPA REVIEW

Agency Completion Date Oral – 08/11/2010

Agency Completion Date Inhalation – 09/20/2013

___II.D.3. EPA CONTACTS

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202) 566-1676 (phone), (202) 566-1749 (fax), or hotline.iris@epa.gov (email address).

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_III.  [reserved]
_IV.  [reserved]
_V.  [reserved]


_VI.  Bibliography

Substance Name — 1,4-Dioxane
CASRN — 123-91-1
Section VI. Last Revised — 08/11/2010

__VI.A. Oral RfD References

Argus, MF; Arcos, JC; Hoch-Ligeti, C. (1965). Studies on the carcinogenic activity of protein-denaturing agents: Hepatocarcinogenicity of dioxane. J Natl Cancer Inst 35: 949-958.

Argus, MF; Sohal, RS; Bryant, GM; Hoch-Ligeti, C; Arcos, JC. (1973). Dose-response and ultrastructural alterations in dioxane carcinogenesis. Influence of methylcholanthrene on acute toxicity. Eur J Cancer 9: 237-243. http://dx.doi.org/10.1016/0014-2964(73)90088-1

Barber, H. (1934). Haemorrhagic nephritis and necrosis of the liver from dioxan poisoning. Guy's Hosp Rep 84: 267-280.

CAA. Clean Air Act, as amended by Pub. L. No. 101-549, section 604: Phase-out of production and consumption of class I substances, 42 USC § 7671c (1990).

David, H. (1964). Electron-microscopic findings in dioxan-dependent nephrosis in rat kidneys. Beitr Pathol Anat 130: 187-212.

de Navasquez, S. (1935). Experimental tubular necrosis of the kidneys accompanied by liver changes due to dioxane poisoning. J Hyg 35: 540-548.

Drew, RT; Patel, JM; Lin, FN. (1978). Changes in serum enzymes in rats after inhalation of organic solvents singly and in combination. Toxicol Appl Pharmacol 45: 809-819. http://dx.doi.org/10.1016/0041-008X(78)90172-2

Fairley, A; Linton, EC; Ford-Moore, AH. (1934). The toxicity to animals of 1:4 dioxan. J Hyg 34: 486-501. http://dx.doi.org/10.1017/S0022172400043266

Giavini, E; Vismara, C; Broccia, ML. (1985). Teratogenesis study of dioxane in rats. Toxicol Lett 26: 85-88. http://dx.doi.org/10.1016/0378-4274(85)90189-4

JBRC (Japan Bioassay Research Center). (1998a). Two-week studies of 1,4-dioxane in F344 rats and BDF1 mice (drinking water studies). Kanagawa, Japan.

JBRC (Japan Bioassay Research Center). (1998b). Two-year studies of 1,4-dioxane in F344 rats and BDF1 mice (drinking water). Kanagawa, Japan.

Johnstone, RT. (1959). Death due to dioxane? AMA Arch Ind Health 20: 445-447.

Kano, H; Umeda, Y; Kasai, T; Sasaki, T; Matsumoto, M; Yamazaki, K; Nagano, K; Arito, H; Fukushima, S. (2009). Carcinogenicity studies of 1,4-dioxane administered in drinking-water to rats and mice for 2 years. Food Chem Toxicol 47: 2776-2784. http://dx.doi.org/10.1016/j.fct.2009.08.012

Kesten, HD; Mulinos, MG; Pomerantz, L. (1939). Pathologic effects of certain glycols and related compounds. Arch Pathol 27: 447-465.

Kociba, RJ; McCollister, SB; Park, C; Torkelson, TR; Gehring, PJ. (1974). 1,4-dioxane. I. Results of a 2-year ingestion study in rats. Toxicol Appl Pharmacol 30: 275-286. http://dx.doi.org/10.1016/0041-008X(74)90099-4

Laug, EP; Calvery, HO; Morris, HJ; Woodard, G. (1939). The toxicology of some glycols and derivatives. J Ind Hyg Toxicol 21: 173-201.

NCI (National Cancer Institute). (1978). Bioassay of 1,4-dioxane for possible carcinogenicity. (78-1330 NCICGTR-80). Bethesda, MD. http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr080.pdf (124 pp, 3.33M)

Schrenk, HH; Yant, WP. (1936). Toxicity of dioxan. J Ind Hyg Toxicol 18: 448-460.

U.S. EPA (U.S. Environmental Protection Agency). (2013). Toxicological review of 1,4-Dioxane (with inhalation update) (CAS No. 123-91-1) in support of summary information on the Integrated Risk Information System (IRIS) [EPA Report]. (EPA-635/R-11/003-F). Washington, DC.

Valcke, M; Krishnan, K. (2011). Assessing the impact of the duration and intensity of inhalation exposure on the magnitude of the variability of internal dose metrics in children and adults. Inhal Toxicol 23: 863-877. http://dx.doi.org/10.3109/08958378.2011.609918

Yamazaki, K; Ohno, H; Asakura, M; Narumi, A; Ohbayashi, H; Fujita, H; Ohnishi, M; Katagiri, T; Senoh, H; Yamanouchi, K; Nakayama, E; Yamamoto, S; Noguchi, T; Nagano, K; Enomoto, M; Sakabe, H. (1994). Two-year toxicological and carcinogenesis studies of 1,4-dioxane in F344 rats and BDF1 mice. In K Sumino; S Sato; NG Shinkokai (Eds.), Proceedings: Second Asia-Pacific Symposium on Environmental and Occupational Health 22-24 July, 1993: Kobe (pp. 193-198). Kobe, Japan: Kobe University School of Medicine, International Center for Medical Research.

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__VI.B. Inhalation RfC References

Fairley, A; Linton, EC; Ford-Moore, AH. (1934). The toxicity to animals of 1:4 dioxan. J Hyg 34: 486-501. http://dx.doi.org/10.1017/S0022172400043266

Giavini, E; Vismara, C; Broccia, ML. (1985). Teratogenesis study of dioxane in rats. Toxicol Lett 26: 85-88. http://dx.doi.org/10.1016/0378-4274(85)90189-4

JBRC (Japan Bioassay Research Center). (1998b). Two-year studies of 1,4-dioxane in F344 rats and BDF1 mice (drinking water). Kanagawa, Japan.

Kano, H; Umeda, Y; Kasai, T; Sasaki, T; Matsumoto, M; Yamazaki, K; Nagano, K; Arito, H; Fukushima, S. (2009). Carcinogenicity studies of 1,4-dioxane administered in drinking-water to rats and mice for 2 years. Food Chem Toxicol 47: 2776-2784. http://dx.doi.org/10.1016/j.fct.2009.08.012

Kasai, T; Kano, H; Umeda, Y; Sasaki, T; Ikawa, N; Nishizawa, T; Nagano, K; Arito, H; Nagashima, H; Fukushima, S. (2009). Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats. Inhal Toxicol 21: 889-897. http://dx.doi.org/10.1080/08958370802629610

Kasai, T; Saito, M; Senoh, H; Umeda, Y; Aiso, S; Ohbayashi, H; Nishizawa, T; Nagano, K; Fukushima, S. (2008). Thirteen-week inhalation toxicity of 1,4-dioxane in rats. Inhal Toxicol 20: 961-971. http://dx.doi.org/10.1080/08958370802105397

Torkelson, TR; Leong, BKJ; Kociba, RJ; Richter, WA; Gehring, PJ. (1974). 1,4-Dioxane. II. Results of a 2-year inhalation study in rats. Toxicol Appl Pharmacol 30: 287-298. http://dx.doi.org/10.1016/0041-008X(74)90100-8

U.S. EPA (U.S. Environmental Protection Agency). (1994). Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry [EPA Report]. (EPA/600/8-90/066F). Research Triangle Park, NC. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993

U.S. EPA (U.S. Environmental Protection Agency). (2012). Benchmark dose technical guidance. (EPA/100/R-12/001). Washington, DC: Risk Assessment Forum. http://www.epa.gov/raf/publications/pdfs/benchmark_dose_guidance.pdf (99 pp, 1.08M)

U.S. EPA (U.S. Environmental Protection Agency). (2013). Toxicological review of 1,4-Dioxane (with inhalation update) (CAS No. 123-91-1) in support of summary information on the Integrated Risk Information System (IRIS) [EPA Report]. (EPA-635/R-11/003-F). Washington, DC.

Valcke, M; Krishnan, K. (2011). Assessing the impact of the duration and intensity of inhalation exposure on the magnitude of the variability of internal dose metrics in children and adults. Inhal Toxicol 23: 863-877. http://dx.doi.org/10.3109/08958378.2011.609918

Yamazaki, K; Ohno, H; Asakura, M; Narumi, A; Ohbayashi, H; Fujita, H; Ohnishi, M; Katagiri, T; Senoh, H; Yamanouchi, K; Nakayama, E; Yamamoto, S; Noguchi, T; Nagano, K; Enomoto, M; Sakabe, H. (1994). Two-year toxicological and carcinogenesis studies of 1,4-dioxane in F344 rats and BDF1 mice. In K Sumino; S Sato; NG Shinkokai (Eds.), Proceedings: Second Asia-Pacific Symposium on Environmental and Occupational Health 22-24 July, 1993: Kobe (pp. 193-198). Kobe, Japan: Kobe University School of Medicine, International Center for Medical Research.

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__VI.C. Carcinogenicity Assessment References

Argus, MF; Arcos, JC; Hoch-Ligeti, C. (1965). Studies on the carcinogenic activity of protein-denaturing agents: Hepatocarcinogenicity of dioxane. J Natl Cancer Inst 35: 949-958.

Argus, MF; Sohal, RS; Bryant, GM; Hoch-Ligeti, C; Arcos, JC. (1973). Dose-response and ultrastructural alterations in dioxane carcinogenesis. Influence of methylcholanthrene on acute toxicity. Eur J Cancer 9: 237-243. http://dx.doi.org/10.1016/0014-2964(73)90088-1

Buffler, PA; Wood, SM; Suarez, L; Kilian, DJ. (1978). Mortality follow-up of workers exposed to 1,4-dioxane. J Occup Environ Med 20: 255-259.

Bull, RJ; Robinson, M; Laurie, RD. (1986). Association of carcinoma yield with early papilloma development in SENCAR mice. Environ Health Perspect 68: 11-17.

Hoch-Ligeti, C; Argus, MF. (1970). Effect of carcinogens on the lung of guinea pigs. In P Nettlesheim; MG HannaJr; JW DeatherageJr (Eds.), Morphology of Experimental Respiratory Carcinogenesis: Proceedings of a Biology Division, Oak Ridge National Laboratory, Conference held in Gatlinburg, Tennessee, May 13-16, 1970 (pp. 267-279). Oak Ridge, TN: United States Atomic Energy Comission, Division of Technical Information. http://www.ntis.gov/search/product.aspx?ABBR=CONF700501

Hoch-Ligeti, C; Argus, MF; Arcos, JC. (1970). Induction of carcinomas in the nasal cavity of rats by dioxane. Br J Cancer 24: 164-167.

JBRC (Japan Bioassay Research Center). (1998b). Two-year studies of 1,4-dioxane in F344 rats and BDF1 mice (drinking water). Kanagawa, Japan.

Kano, H; Umeda, Y; Kasai, T; Sasaki, T; Matsumoto, M; Yamazaki, K; Nagano, K; Arito, H; Fukushima, S.(2009). Carcinogenicity studies of 1,4-dioxane administered in drinking-water to rats and mice for 2 years. Food Chem Toxicol 47: 2776-2784. http://dx.doi.org/10.1016/j.fct.2009.08.012

Kasai, T. (2008). 1,4-Dioxane toxicity studies. Available online

Kasai, T; Kano, H; Umeda, Y; Sasaki, T; Ikawa, N; Nishizawa, T; Nagano, K; Arito, H; Nagashima, H; Fukushima, S. (2009). Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats. Inhal Toxicol 21: 889-897. http://dx.doi.org/10.1080/08958370802629610

King, ME; Shefner, AM; Bates, RR. (1973). Carcinogenesis bioassay of chlorinated dibenzodioxins and related chemicals. Environ Health Perspect 5: 163-170.

Kociba, RJ; McCollister, SB; Park, C; Torkelson, TR; Gehring, PJ. (1974). 1,4-dioxane. I. Results of a 2-year ingestion study in rats. Toxicol Appl Pharmacol 30: 275-286. http://dx.doi.org/10.1016/0041-008X(74)90099-4

Lundberg, I; Hogberg, J; Kronevi, T; Holmberg, B. (1987). Three industrial solvents investigated for tumor promoting activity in the rat liver. Cancer Lett 36: 29-33. http://dx.doi.org/10.1016/0304-3835(87)90099-1

NCI (National Cancer Institute). (1978). Bioassay of 1,4-dioxane for possible carcinogenicity. (78-1330 NCICGTR-80). Bethesda, MD. http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr080.pdf (124 pp, 3.33M)

Thiess, AM; Tress, E; Fleig, I. (1976). Arbeitsmedizinische Untersuchungsergebnisse von Dioxan-exponierten Mitarbeitern [Industrial-medical investigation results in the case of workers exposed to dioxane]. Arbeitsmedizin, Sozialmedizin, Umweltmedizin 11: 35-46.

Torkelson, TR; Leong, BKJ; Kociba, RJ; Richter, WA; Gehring, PJ. (1974). 1,4-Dioxane. II. Results of a 2-year inhalation study in rats. Toxicol Appl Pharmacol 30: 287-298. http://dx.doi.org/10.1016/0041-008X(74)90100-8

U.S. EPA (U.S. Environmental Protection Agency). (2005a). Guidelines for carcinogen risk assessment [EPA Report]. (EPA/630/P-03/001F). Washington, DC: Risk Assessment Forum. http://www.epa.gov/cancerguidelines/

U.S. EPA (U.S. Environmental Protection Agency). (2005b). Supplemental guidance for assessing susceptibility from early-life exposure to carcinogens [EPA Report] (pp. 1125-1133). (EPA/630/R-03/003F). Washington, DC. http://www.epa.gov/cancerguidelines/guidelines-carcinogen-supplement.htm

U.S. EPA (U.S. Environmental Protection Agency). (2010). Toxicological review of 1,4-Dioxane (CAS No. 123-91-1) in support of summary information on the Integrated Risk Information System (IRIS) [EPA Report]. (EPA-635/R-09-005-F). Washington, DC. http://www.epa.gov/iris/toxreviews/0326tr.pdf (417 pp, 3.7M)

U.S. EPA (U.S. Environmental Protection Agency). (2012). Benchmark dose technical guidance. (EPA/100/R-12/001). Washington, DC: Risk Assessment Forum. http://www.epa.gov/raf/publications/pdfs/benchmark_dose_guidance.pdf (99 pp, 1.08M)

U.S. EPA (U.S. Environmental Protection Agency). (2013). Toxicological review of 1,4-Dioxane (with inhalation update) (CAS No. 123-91-1) in support of summary information on the Integrated Risk Information System (IRIS) [EPA Report]. (EPA-635/R-11/003-F). Washington, DC.

Yamazaki, K; Ohno, H; Asakura, M; Narumi, A; Ohbayashi, H; Fujita, H; Ohnishi, M; Katagiri, T; Senoh, H; Yamanouchi, K; Nakayama, E; Yamamoto, S; Noguchi, T; Nagano, K; Enomoto, M; Sakabe, H. (1994). Two-year toxicological and carcinogenesis studies of 1,4-dioxane in F344 rats and BDF1 mice. In K Sumino; S Sato; NG Shinkokai (Eds.), Proceedings: Second Asia-Pacific Symposium on Environmental and Occupational Health 22-24 July, 1993: Kobe (pp. 193-198). Kobe, Japan: Kobe University School of Medicine, International Center for Medical Research.

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_VII.  Revision History

Substance Name — 1,4-Dioxane
CASRN — 123-91-1
File First On-Line — 08/22/1998

Date
Section
Description
08/22/1988 II. Carcinogen summary on-line
08/11/2010 I., II., VI. RfD and cancer assessment updated; RfC discussion added.
08/12/2010 NA Archived review drafts and comments from the development of this assessment are available.
09/20/2013 Added RfC and inhalation cancer assessment.
09/21/2013 NA Archived review drafts and comments from the development of this assessment are available. Archived version of the 2010 final oral assessment is available (U.S. EPA, 2010).

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_VIII. Synonyms

Substance Name — 1,4-Dioxane
CASRN — 123-91-1
Section VIII. Last Revised — 09/20/2013

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