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Selenium sulfide
CASRN 7446-34-6
Contents
0458
Selenium sulfide; CASRN 7446-34-6
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Selenium sulfide
File On-Line 03/01/1991
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 07/01/1993
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Selenium sulfide
CASRN -- 7446-34-6
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Selenium sulfide
CASRN -- 7446-34-6
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Selenium sulfide
CASRN -- 7446-34-6
Last Revised -- 07/01/1993
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
NOTE: This assessment is also for selenium disulfide (CASRN 7488-56-4).
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- B2; probable human carcinogen
Basis -- Based on inadequate data from human studies and sufficient evidence
in animals. When administered orally, selenium sulfide produced
hepatocellular carcinomas in both sexes of F344 rats and female B6C3F1 mice
and alveolar/bronchiolar carcinomas or adenomas in female B6C3F1 mice.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Data on the possible carcinogenicity of selenium sulfide in
humans are inadequate. Some human data for selenium and various selenium
compounds are, however, available. Several investigators have studied the
association between serum selenium and the risk of cancer through prospective,
case-control and nested case-control studies. Analysis of blood serum levels
indicated that patients with cancer, particularly gastrointestinal cancer,
prostatic cancer, or Hodgkin's lymphoma, had significantly lower blood
selenium levels than healthy patients (Shamberger et al., 1973; Salonen et
al., 1984; Kok et al., 1987; Willet et al., 1983; Willet and Stampfer, 1986).
The risk of cancer for men (Kok et al., 1987) or for all subjects (Willet et
al., 1983) in the lowest quintile of serum selenium was twice that of subjects
with higher levels.
Geographic correlational studies have compared cancer mortality in areas
of high vs. low levels of naturally occurring selenium. Shamberger and Frost
(1969) reported that an inverse relationship existed between cancer death
rates and the selenium concentrations in foliage plants of several Canadian
provinces. The human cancer death rate in provinces with selenium-containing
plants was 122.2 +/- 7.8 (presumably per 100,000 population although this was
not specified), while in the provinces devoid of these plants, the human death
rate was 139.9 +/- 4.0.
In an ecological study Shamberger and Willis (1971) reported that there
was a correlation between decreased cancer death rates in humans and an
increase in the selenium in the forage crops in California. In high-selenium
areas (selenium 0.11 ppm of forage crops) the cancer death rate per 100,000
was 141.2. In the medium-selenium areas (0.05-0.10 ppm) the cancer death rate
was 190.1. In low-selenium areas (0.02-0.05 ppm) the cancer death rate was
233.0. Shamberger and Willis (1971) also investigated the ratio of observed
to expected cancer death rates by anatomic site for men in 17 paired cities
including high- and low-selenium areas. The anatomic sites that would come
into contact with dietary selenium, such as pharynx, esophagus, stomach,
bladder and intestine, showed a SUBSTantially lower rate ratio in the high-
selenium cities than in the low-selenium cities. Other ecological and
prospective studies have correlated an increased incidence of colon, breast
and other forms of cancer in humans in geographic areas where selenium is
deficient and a lowered cancer incidence with higher selenium concentrations
(Schrauzer and Ishmael, 1974; Shamberger, 1976; Schrauzer et al., 1976;
Jansson et al., 1978; Yang et al., 1983).
In a study of approximately 300 employees exposed to selenium (form not
specified) in a rectifier (electronics) process over a 26-year period, only 17
deaths occurred, 6 of which were due to cancer (Glover, 1970). This number,
however, is not statistically different from the 5.1 deaths expected based on
national mortality rates. The source of the mortality rates was not
specified. Several toxic effects including pulmonary irritation, epigastric
pain and dermal irritation and dermatitis were associated with selenium
exposure in men, but no carcinogenic effect was reported.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. NCI (1980a) conducted a bioassay of selenium sulfide on F344
rats and B6C3F1 mice. Selenium sulfide (a mixture of selenium monosulfide and
selenium disulfide) in 0.5% aqueous carboxymethyl cellulose was administered
by gavage at 3 or 15 mg/kg/day to F344 rats (50/sex/group) 7 days/week for 103
weeks. Survivors were sacrificed at 104-105 weeks. Controls (50/sex/group)
consisted of an untreated group and a group receiving the vehicle only.
Body weights were slightly decreased relative to vehicle controls
(approximately 10%) in high-dose male and female rats, suggesting an MTD had
been achieved. Survival was comparable (approximately 78%) between treated
groups and vehicle controls. A significant dose-related trend was seen in the
incidence of hepatocellular carcinoma or neoplastic nodules in males and
females. A statistically significant increase in the incidence of
hepatocellular carcinomas and combined hepatocellular carcinoma or neoplastic
nodules was observed in high-dose males and females relative to their
respective vehicle controls. In males, incidence of hepatocellular carcinoma
was 0/50, 0/50 and 14/49, and the incidence of hepatocellular carcinoma or
neoplastic nodules was 1/50, 0/50 and 24/49 for the vehicle control, low-, and
high-dose groups, respectively. In females, the incidence of hepatocellular
carcinoma was 0/50, 0/50 and 21/50, and the incidence of hepatocellular
carcinoma or neoplastic nodules was 1/50, 0/50 and 37/50 for vehicle control,
low-, and high-dose groups, respectively.
In male rats, there was a statistically significant dose-related increase
in the incidence of lymphoma or leukemia. The incidence in the treated groups
was significantly higher than the vehicle-control group; however, the
untreated-control group was not included in the statistical analysis, and the
incidence of lymphoma or leukemia in untreated controls was 21/49 (43%)
compared with 7/50 (14%), 15/50 (30%), and 17/49 (35%) for the vehicle
control, low-dose and high-dose groups, respectively. Because the incidence
of these tumors was lower in the low- and high-dose groups than in the
untreated controls, their occurrence in male rats cannot be clearly related to
administration of selenium sulfide.
In male rats, incidence of testicular interstitial-cell tumors showed a
statistically significant dose-related trend (41/50, 82% vehicle control;
45/50, 90% low dose; 47/49, 96% high dose) and the elevation in the high-dose
group was statistically significant relative to vehicle controls. The
untreated control incidence was 42/48 (88%). No historical records for this
laboratory in which aqueous carboxymethyl cellulose was used as a vehicle are
available for comparison. However, NCI reports that interstitial-cell tumors
occur in 75-100% of aged control male F344 rats.
Female rats showed a statistically significant dose-related decrease in
pituitary chromophobe adenoma (23/50, 14/49, 11/48).
Selenium sulfide (a mixture of selenium monosulfide and selenium
disulfide) in 0.5% aqueous carboxymethyl cellulose was administered at 20 or
100 mg/kg/day by gavage to B6C3F1 mice (50/sex/group) 7 days/week for 103
weeks (NCI, 1980a). Survivors were sacrificed at 104-105 weeks. Controls
(50/sex) consisted of an untreated group and a group receiving the vehicle.
Body weights and survival of the treated mice were comparable with those of
the vehicle control groups, suggesting an MTD may not have been reached.
Survival at termination was approximately 60-70% for males and approximately
78-86% for females.
The incidence of alveolar/bronchiolar carcinoma in female mice (0/49,
1/50, 4/49 for control, low-dose and high-dose females, respectively) showed a
statistically significant dose-related increase. The incidence of
alveolar/bronchiolar carcinomas or adenomas in females also showed a
statistically significant dose-related elevation. The incidence in the high-
dose group was statistically significantly increased above vehicle controls
and untreated controls. Incidence of alveolar/bronchiolar carcinomas or
adenomas in the untreated controls, vehicle controls, low-dose, and high-dose
groups was 2/50 (4%), 0/49, 3/50 (6%) and 12/49 (24%), respectively. The
incidence of these tumors in other vehicle control groups maintained in the
same room ranged from 2-12% (selenium sulfide untreated control females were
4%). NCI concluded the lung tumors in female mice were related to
administration of selenium sulfide, but there was a high variability of these
tumors.
In males, incidence of alveolar/bronchiolar carcinomas or adenomas (4/50,
10/50, 13/50 for control, low-dose and high-dose males, respectively) showed a
statistically significant dose-related elevation and was significant in the
high-dose group only when compared with the vehicle controls. When compared
with the untreated control males (9/48, 18%), the incidence of
alveolar/bronchiolar carcinomas or adenomas in treated male mice was not
statistically significant. Because it uses a Bonferoni adjustment for
pairwise comparisons, which has a more stringent significance criterion, NCI
concluded that the incidence of lung tumors in male mice could not be clearly
related to selenium sulfide administration.
In male mice, the incidence of lymphoma or leukemia (4/50, 12/50, 8/50 in
the control, low- and high-dose groups, respectively) was statistically
significantly elevated only in the low-dose group relative to vehicle
controls. The incidence of hepatocellular carcinoma alone (15/50, 11/50,
23/50) and when combined with adenomas (15/50, 14/50, 23/50) showed a
significant positive trend, but pairwise comparisons were not statistically
significant.
Incidence of hepatocellular carcinomas alone or when combined with
adenomas showed a statistically significant dose-related increase in female
mice. Incidence of hepatocellular carcinoma alone (0/49, 1/50, 22/49 in the
control, low- and high-dose groups, respectively) and hepatocellular carcinoma
or adenoma (0/49, 2/50, 25/49) was statistically significantly elevated in the
high-dose females relative to vehicle control females.
Because selenium sulfide is used as an antidandruff agent in shampoos, NCI
conducted two bioassays to assess possible carcinogenicity by the dermal
route. In the first study, a suspension of selenium sulfide in 0.5% aqueous
carboxymethyl cellulose was applied to the clipped backs of ICR Swiss mice
(50/sex/group) at 0, 0.5 or 1.0 mg/animal three times weekly for 86 weeks
(NCI, 1980b). The mice were housed individually. Body weights and mortality
were comparable between treated and control mice, although mortality was high
in all groups after 52 weeks and the study was terminated after 88 weeks.
Survival at termination was approximately 10-20% for all groups. NCI
attributed most of the deaths to multiple organ amyloidosis, especially that
of the liver, kidney and spleen.
Incidence of alveolar/bronchiolar carcinoma or adenoma in female mice
(2/50, 4% control; 4/49, 8% low dose; 8/49, 16% high dose) showed a
statistically significant dose-related increase and was elevated in the high-
dose animals when compared with vehicle controls. However, the incidence of
these tumors in untreated controls (9/49, 18%) was greater than the vehicle
control group or the dosed groups. The time-to-tumor onset in the high-dose
group was 25 weeks, whereas in the vehicle controls the first tumor was
observed at 86 weeks. In female mice a statistically significant dose-related
increase was reported in the total hemangiomas or hemangiosarcomas incidence
for all sites combined. The incidence was 1/50, 0/50, 1/50 and 4/50 for the
untreated, vehicle, low-dose and high-dose groups, respectively. No tumors
were found in male mice. While an MTD did not appear to be reached, skin
irritation (hyperkeratosis and acanthosis) at the application site suggests
higher doses might not have been tolerated. Under the conditions of this
bioassay, dermal application of selenium sulfide produced an equivocal
carcinogenic effect in ICR Swiss mice, but the study was limited by the
relatively short lifespan of this strain of mouse.
In the second bioassay (NCI, 1980c), Selsun shampoo, which contains 2.5%
selenium sulfide, was applied to the clipped backs of ICR Swiss mice
(50/sex/group). Doses of 0.05 mL of 25% or 50% Selsun in distilled water
(0.313 or 0.625 mg selenium sulfide/animal) were applied three times weekly
for 86 weeks. Vehicle controls were clipped and treated with distilled water;
untreated controls were clipped only. The mice were housed individually.
Mean body weights and mortality were comparable between groups, although
mortality was high in all groups after 52 weeks and the study was terminated
after 88 weeks. Survival at termination was approximately 10-20% for all
groups. NCI attributed most of the deaths to multiple organ amyloidosis,
especially that of the liver, kidney and spleen.
In male mice, alveolar/bronchiolar carcinomas or adenomas occurred with a
significant dose-related trend. Incidences in the high-dose group (9/48, two
of which were carcinomas) and in the low-dose group (7/50, all adenomas) were
statistically significantly higher than the incidence in the vehicle control
group (1/49). The time to observation of the first tumor was 49, 68, 87 and
53 weeks for the high-dose, low-dose, vehicle control and untreated control
groups, respectively. NCI concluded that comparison of matched vehicle-
control groups with the high-dose group indicates the possibility of an
association of the administration of Selsun with the occurrence of lung
tumors. However, since alveolar/bronchiolar adenomas have been reported as
common tumors in aged Swiss mice, the incidences of these tumors observed
among male mice could not be clearly related to dermally-applied Selsun.
Tumor incidences in treated female mice were comparable to controls. While an
MTD did not appear to be reached, skin irritation (hyperkeratosis and
acanthosis) at the application site suggests higher doses might not have been
tolerated. The study is limited by the short lifespan of the animals.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Although selenium sulfide has not been assayed for genotoxicity, other
selenium compounds have given conflicting results in genotoxicity assays.
These results have been reviewed in U.S. EPA (1989a,b) and in the Selenium and
Compounds IRIS assessment.
Selenium is an essential micronutrient for several species, including
humans, and is part of several enzymes, such as glutathione peroxidase, an
enzyme involved in cellular defense against oxidative damage, and heme
oxidase. While low doses of selenium are essential, high doses of selenium or
a deficiency of dietary selenium may produce toxicity, such as a carcinogenic
response. Under some conditions selenium may be protective against tumor
development.
Bioavailability of selenium is dependent on numerous factors, including
the intake levels, chemical form and nutritional status. Organic forms of
selenium are more bioavailable than inorganic forms; selenates and selenites
are the inorganic forms more readily absorbed. Selenium sulfide is less
soluble in water than sodium selenate and selenite, but the extent to which
selenium sulfide is absorbed dermally or through the gastrointestinal tract
has not been fully elucidated (U.S. EPA, 1989b).
Exposure to selenium sulfide is primarily through the use of antidandruff
shampoos and pharmaceuticals. The greatest daily exposure to selenium is via
food (U.S. EPA, 1989b).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1989a,b
The 1989 Health and Environmental Effects Document on Selenium and Compounds
has received OHEA review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 11/09/1989, 03/07/1990, 05/03/1990
Verification Date -- 05/03/1990
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Selenium sulfide
CASRN -- 7446-34-6
Last Revised -- 03/01/1991
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfC REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Glover, J.R. 1970. Selenium and its industrial toxicology. Industr. Med.
Surg. 39: 26-30.
Jansson, B., M.M. Jacobs and A.C. Griffin. 1978. Gastrointestinal cancer:
Epidemiology and experimental studies. Adv. Exp. Med. Biol. 91: 305-322.
Kok, F.J., A.M. De Bruijn, A. Hofman, R. Vermeeren and H.A. Valkenburg. 1987.
Is serum selenium a risk factor for cancer in men only? Am. J. Epidemiol.
125(1): 12-16.
NCI (National Cancer Institute). 1980a. Bioassay of selenium sulfide
(gavage) for possible carcinogenicity. NCI Tech. Report Ser. No. 194. NTP
No. 80-17.
NCI (National Cancer Institute). 1980b. Bioassay of selenium sulfide (dermal
study) for possible carcinogenicity. NCI Tech. Report Ser. No. 197. NTP No.
80-18.
NCI (National Cancer Institute). 1980c. Bioassay of Selsun for possible
carcinogenicity. NCI Tech. Report Ser. No. 199. NTP No. 80-19.
Salonen, J.T., G. Alfthan, J.K. Huttunen and P. Puska. 1984. Association
between serum selenium and the risk of cancer. Am. J. Epidemiol. 120(3):
342-349.
Schrauzer, G.N. and D. Ishmael. 1974. Effects of selenium and of arsenic on
the genesis of spontaneous mammary tumors in inbred C3H mice. Ann. Clin. Lab.
Sci. 4(6): 441-447.
Schrauzer, G.N., D.A. White and C.J. Schneider. 1976. Inhibition of the
genesis of spontaneous mammary tumors in C3H mice: Effects of selenium and of
selenium-antagonistic elements and their possible role in human breast cancer.
Bioinorg. Chem. 6(3): 265-270.
Shamberger, R.J. 1976. Selenium in health and disease. Proceedings of the
Symposium on Selenium-Tellurium in the Environment. Industrial Health
Foundation, Inc., Pittsburgh, PA. p. 253-267.
Shamberger, R.J. and D.V. Frost. 1060. Possible protection effect of
selenium against human cancer. Canad. Med. Assoc. J. 100: 682.
Shamberger, R.J. and C.E. Willis. 1971. Selenium distribution and human
cancer mortality. Crit. Rev. Clin. Lab. Sci. 2: 211-221.
Shamberger, R.J., E. Rukovena, A.K. Longfield et al. 1973. Antioxidants and
cancer. I. Selenium in the blood of normals and cancer patients. J. Natl.
Cancer Inst. 50: 863-870.
U.S. EPA. 1989a. Evaluation of the Potential Carcinogenicity of Selenium
Sulfide (Selenium Disulfide). Prepared by the Carcinogen Assessment Group,
Office of Health and Environmental Assessment for the Office of Emergency and
Remedial Response, Office of Solid Waste and Emergency Response, Washington,
DC. OHEA-C-073-174.
U.S. EPA. 1989b. Health and Environmental Effects Document on Selenium and
Compounds. Prepared by the Environmental Criteria and Assessment Office,
Office of Health and Environmental Assessment, Cincinnati, OH for the Office
of Solid Waste, Washington, DC.
Willitt, W.C., B.F. Polk, J.S. Morris et al. 1983. Prediagnostic serum
selenium and risk of cancer. Lancet. 2: 130-134.
Yang, G., S. Wang, R. Zhou and S. Sun. 1983. Endemic selenium intoxication
of humans in China. Am. J. Clin. Nutr. 37: 872-881.
_VII. REVISION HISTORY
Substance Name -- Selenium sulfide
CASRN -- 7446-34-6
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1991 II. Carcinogenicity assessment on-line
03/01/1991 VI. Bibliography on-line
01/01/1992 IV. Regulatory Action section on-line
07/01/1993 II.D.3. Primary contact's phone number changed
VIII. SYNONYMS
Substance Name -- Selenium sulfide
CASRN -- 7446-34-6
Last Revised -- 03/01/1991
7446-34-6
Selenium sulfide
HSDB 679
NCI-C50033
Selenium monosulfide
Selenium sulphide
Selensulfid [German]
SULFUR SELENIDE
7488-56-4
Selenium sulfide
Caswell No. 732A
Disulfure de selenium [French]
Disulfuro de selenio [Spanish]
EPA Pesticide Chemical Code 072003
Exsel
Seleen
Selenium disulfide
Selenium disulphide
Selsun
Selsun Blue
Sulfur selenide
UN 2657
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0458.HTM
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