United States
Environmental Protection
1=1 m m Agency
EPA/690/R-12/031F
Final
12-10-2012
Provisional Peer-Reviewed Toxicity Values for
Thiocyanic Acid
(CASRN 463-56-9, 80864-27-3)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Q. Jay Zhao, PhD, MPH, DABT, National Center for Environmental Assessment,
Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer-reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
l
Thiocyanic Acid
-------
TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS iii
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4
DERIVATION 01 PROVISIONAL VALUES 4
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 4
REFERENCES 4
APPENDIX A. PROVISIONAL SCREENING VALUES 7
APPENDIX B. PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
THIOCYANATES 10
li
Thiocyanic Acid
-------
COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
111
Thiocyanic Acid
-------
FINAL
12-10-2012
PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
THIOCYANIC ACID (CASRN 463-56-9, 80864-27-3)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.eov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
1
Thiocyanic Acid
-------
FINAL
12-10-2012
INTRODUCTION
Thiocyanic acid, also known as hydrogen thiocyanate or hydrogen rhodanide, belongs to
a class of chemicals called Thiocyanates (S-C=N). Thiocyanates are a group of compounds
formed from a combination of sulfur, carbon, and nitrogen (ATSDR, 2006). They occur
naturally in various foods and plants such as spinach, radish, celery, and cabbage (RIVM, 2001)
and are produced primarily from the reaction of free cyanide with sulphur (ATSDR, 2006). This
reaction occurs in the environment (for example, in industrial waste streams that contain
cyanide) and in the human body after cyanide is swallowed or absorbed (thiocyanate is the main
metabolite of free cyanide). Thiocyanates are known to affect the thyroid gland, reducing iodine
uptake and thereby reducing the ability of the gland to produce hormones that are necessary for
the normal function of the body (U.S. EPA, 2006). In the past, thiocyanate was used
therapeutically to treat severe hypertension, but the results of this therapy were inconsistent from
clinic to clinic, and even within a single study. Thiocyanate is believed to play a role in an
endogenous antibacterial system (lactoperoxidase/thiocyanate/hydrogen peroxide system)
present in milk. It has been added commercially to some milk preparations as an antibacterial
agent (U.S. EPA, 2006).
Table 1. Physicochemical Properties
Thiocyanic Acid (CASRN 463-56-9, 80864-27-3)a
Property (unit)
Value
Boiling point (°C)
146°C at 760 mm Hg
Melting point (°C)
5
Density (g/cm3)
1.126
Vapor pressure (mmHg at 25°C)
4.73
pH (unitless)
N/A
Solubility in water (g/100 mL at 25°C)
Good
Relative vapor density (air =1)
2.0
pKa (20°C)
1.1
Molecular weight (g/mol)
59.1
aValues from NIOSH (2006) and ChemSpider (2010).
No Reference Dose (RfD), Reference Concentration (RfC), or cancer assessment for
thiocyanic acid is included on the United States Environmental Protection Agency (U.S. EPA)
Integrated Risk Information System (IRIS) database (U.S. EPA, 201 la) or on the Drinking Water
Standards and Health Advisories List (U.S. EPA, 201 lb). No RfD or RfC values are reported in
the Health Effects Assessment Summary Tables (HEAST) (U.S. EPA, 201 lc). The Chemical
Assessments and Related Activities (CARA) list does not include any EPA documents for
thiocyanic acid (U.S. EPA, 1994). The toxicity of thiocyanic acid has not been reviewed by the
Agency for Toxic Substances and Disease Registry (ATSDR, 2011) or the World Health
2
Thiocyanic Acid
-------
FINAL
12-10-2012
Organization (WHO, 2011). However, some aspects of thiocyanate toxicity were discussed in
the ATSDR profile of cyanide because it is the main metabolite of cyanide (ATSDR, 2006). The
California Environmental Protection Agency (CalEPA, 2008, 2012) has not derived toxicity
values for exposure to thiocyanic acid. No occupational exposure limits for thiocyanic acid have
been derived by the American Conference of Governmental Industrial Hygienists
(ACGIH, 2011), the National Institute of Occupational Safety and Health (NIOSH, 2011), or the
Occupational Safety and Health Administration (OSHA, 2011).
The HEAST (U.S. EPA, 201 lc) does not report any cancer values for thiocyanic acid.
The International Agency for Research on Cancer (IARC, 2011) has not reviewed the
carcinogenic potential of thiocyanic acid. Thiocyanic acid is not included in the 12th Report on
Carcinogens (NTP, 2011). CalEPA (2012) has not derived a quantitative estimate of
carcinogenic potential for thiocyanic acid.
There are available data on thiocyanate salts (such as sodium, potassium, and ammonium
thiocyanate) that can potentially serve as suitable surrogates for thiocyanic acid. Most of the
relevant data on thiocyanate salts have been reviewed in a Provisional Peer Reviewed Toxicity
Value (PPRTV) document on the thiocyanates (U.S. EPA, 2006), which reports provisional
subchronic and chronic reference doses for thiocyanates of 0.0006 and 0.0002 mg/kg-day,
respectively. These provisional values are based on significant changes in thyroid function
(thyroxine concentration, triiodothyronine, and thyroid stimulating hormone in blood serum)
observed in a group of women exposed to thiocyanate in cow's milk for 5 years (Baneijee et al.,
1997). In calculating both the subchronic and chronic p-RfD values, the lowest-observed-
adverse-effect level (LOAEL) of 0.19 mg/kg-day from Banerjee et al. (1997) was used as the
point-of-departure for both the subchronic and chronic p-RfD values, with a cumulative
uncertainty factor of 300 and 1000 applied to the LOAEL, respectively. Confidence in the
principal study is low (U.S. EPA, 2006). The carcinogenic potential of thiocyanates has not been
reviewed (U.S. EPA, 2006). New toxicological studies on thiocyanates have been identified
which were published after the PPRTV publication date.
The Netherlands National Institute of Public Health and the Environment, Research for
Man and Environment (RIVM, 2001) established a Tolerable Daily Intake (TDI) of
0.011 mg/kg-day for thiocyanate (SCN ), This was based on the NOAEL from a 90-day human
study in which volunteers were exposed to milk containing SCN~ as sodium thiocyanate, using a
UF of 10 (Dahlberg et al., 1984).
Literature searches were conducted on sources published from 1900 through
September 2011 for studies relevant to the derivation of provisional toxicity values for
thiocyanic acid (CAS No. 463-56-9 and 80864-27-3). Searches were conducted using EPA's
Health and Environmental Research Online (HERO) database of scientific literature. HERO
searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane
Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations
Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing
Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR:
Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through
the National Service Center for Environmental Publications [NSCEP] and National
Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and
CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET
3
Thiocyanic Acid
-------
FINAL
12-10-2012
(Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC,
EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER,
LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and
TSCATS; Virtual Health Library; Web of Science (searches Current Content database among
others); World Health Organization; and Worldwide Science. The following databases outside
of HERO were searched for relevant health information: ACGIH, ATSDR, CalEPA, EPA IRIS,
EPA HEAST, EPA HEEP, EPA OW, EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and
RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
The literature search revealed no human or animal studies, either acute, short term, or
chronic, for thiocyanic acid.
DERIVATION OF PROVISIONAL VALUES
No subchronic and chronic p-RfD values can be derived because the literature search
revealed no human or animal studies, either acute, short term, or chronic, for thiocyanic acid.
However, there are available data on thiocyanate salts (such as sodium, potassium and
ammonium thiocyanate) which can potentially serve as suitable surrogates for thiocyanic acid.
Thiocyanic acid is a moderately strong acid, with a pKa of 1.1. In physiological conditions, it
would be mostly dissociated, and thus, exposure to thiocyanic acid is presumably comparable to
exposure to the thiocyanate anion. Thus, screening subchronic and chronic p-RfDs based on
previous PPRTV assessment on thiocyanates are provided in Appendix A.
Limitations in the available data preclude development of inhalation RfC and cancer
toxicity values.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Limitations in the available data preclude development of a WOE descriptor.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2011) Threshold limit
values for chemical substances and physical agents and biological exposure indices. Cincinnati,
OH: ACGIH. As cited in HSDB (Hazardous Substances Data Bank). Available online at
http://toxnet.nlm.nih.eov/cei-bin/sis/htmleen7HSDB. Accessed on 12/29/2011.
4
Thiocyanic Acid
-------
FINAL
12-10-2012
ATSDR (Agency for Toxic Substances and Disease Registry). (2006) Toxicological profile for
cyanide. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA.
Available online at http://www.atsdr.cdc.gov/ToxProfiles/tp8.pdf. Accessed on 12/29/2011.
ATSDR (Agency for Toxic Substances and Disease Registry). (2011) Toxicological profile
information sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Available online at http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed on
12/29/2011.
Baneijee, KK; Marimuthu, P; Bhattacharyya, P; et al. (1997) Effect of thiocyanate ingestion
through milk on thyroid hormone homeostasis in women. Brit .1 Nutr J8(5):679—681. (as cited
in U.S. EPA, 2006).
CalEPA (California Environmental Protection Agency). (2012) All OEHHA acute, 8-hour and
chronic reference exposure levels (chRELs) as on February2012. Office of Environmental
Health Hazard Assessment, Sacramento, CA. Available online at
http://www.oehha.ca.gov/air/allrels.html. Accessed on 11/28/2012.
CalEPA (California Environmental Protection Agency). (2011) OEHHA toxicity criteria
database. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available
online at http://www.oehha.ca.gov/riskAChemicalDB/index.asp. Accessed on 12/29/2011.
ChemSpider. (2010) Thiocyanic acid. The Royal Society of Chemistry (RSC). Available
online at http://www.chemspider.com/Chemical-Structure.760.html?rid=e8084690-3764-4230-
ba9f-d5b49f467818. Accessed on 11/04/2010.
Dahlberg, PA; Bergmark, A; et al. (1984) Intake of thiocyanate by way of milk and its possible
effect on thyroid function. Am J Clin Nutr 39(3):416-420. (as cited in U.S. EPA, 2006).
Dahlberg, PA; Bergmark, A; Eltom, M; et al. (1985) Effect of thiocyanate levels in milk on
thyroid function in iodine deficient subjects. Am J Clin Nutr 41(5): 1010-1014. (as cited in
U.S. EPA, 2006).
de Sousa, AB; Maiorka, PC; Goncalves, ID; et al. (2007) Evaluation of effects of prenatal
exposure to the cyanide and thiocyanate in wistar rats. Repro Toxicol 23(4):568-577
IARC (International Agency for Research on Cancer). (2011) Monographs on the evaluation of
carcinogenic risks to humans. Lyon, France: IARC. Available online at
http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed on 12/29/2011.
NIOSH (National Institute for Occupational Safety and Health). (2006) Thiocyanic acid.
International Chemical Safety Cards. ICSC 1671. Available online at
http://www.cdc.gov/niosh/ipcsneng/nengl671.html.
NIOSH (National Institute for Occupational Safety and Health). (2011) NIOSH pocket guide to
chemical hazards. Index of chemical abstracts service registry numbers (CAS No.). Center for
Disease Control and Prevention, U.S. Department of Health, Education and Welfare,
Atlanta, GA. Available online at http://www.cdc.gov/niosh/npg/npgdcas.html. Accessed on
12/29/2011.
5
Thiocyanic Acid
-------
FINAL
12-10-2012
NTP (National Toxicology Program). (2011) 12th Report on carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC.
OSHA (Occupational Safety and Health Administration). (2011) Air contaminants:
occupational safety and health standards for shipyard employment, subpart Z, toxic and
hazardous substances. U.S. Department of Labor, Washington, DC; OSHA Standard 1915.1000.
Available online at http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=
STANDARDS&p id=10286. Accessed on 12/29/2011.
RIVM (National Institute of Public Health and the Environment). (2001) Re-evaluation of
human-toxicological maximum permissible risk levels. RIVM report no. 711701025. Bilthoven,
The Netherlands: RIVM; pp. 86-95. Available online at
http://www.rivm.n1/bibliotheek/rapporten/711701025 .pdf.
Soto-Banco, B; Stegelmeier, BL; Pfister, JA; et al. (2008) Comparative effects of prolonged
administration of cyanide, thiocyanate and chokecherry {Primus virginiana) to goats. J Appl
Toxicol 28(3):356-363
U.S. EPA (Environmental Protection Agency). (1994) Chemical assessments and related
activities (CARA). Office of Health and Environmental Assessment, Washington, DC;
EPA/600/R-94/904. Available online at
http://nepis.epa. gov/Exe/ZyPURL.cgi?Dockev=6000 lG8L.txt.
U.S. EPA (Environmental Protection Agency). (2006) Provisional peer reviewed toxicity values
for thiocyanates. Office of Research and Development, National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (STSC), Cincinnati, OH.
Available online at http://hhpprtv.ornt.gov/quickview/pprtv.php?chemical Thiocvanate.
Accessed on 10/06/2010.
U.S. EPA (Environmental Protection Agency). (201 la) Integrated risk information system
(IRIS). Office of Research and Development, National Center for Environmental Assessment,
Washington, DC. Available online at http://www.epa.gov/iris/. Accessed on 12/29/2011.
U.S. EPA (Environmental Protection Agency). (201 lb) 2011 Edition of the drinking water
standards and health advisories. Office of Water, Washington, DC; EPA 820-R-l 1-002.
Available online at http://water.epa.gov/action/advisories/drinking/upload/dwstandards2011.pdf.
Accessed on 12/29/2011.
U.S. EPA (Environmental Protection Agency). (201 lc) Health effects assessment summary
tables (HEAST). Prepared by the Office of Research and Development, National Center for
Environmental Assessment, Cincinnati OH for the Office of Emergency and Remedial Response,
Washington, DC. Available online at http://epa-heast.ornl.gov/. Accessed on 12/29/2011.
WHO (World Health Organization). (2011) Online catalogs for the Environmental Health
Criteria series. Available online at http://www.who.int/ipcs/publications/ehc/en/. Accessed on
12/29/2011.
6
Thiocyanic Acid
-------
FINAL
12-10-2012
APPENDIX A. PROVISIONAL SCREENING VALUES
For reasons noted in the main PPRTV document, it is not possible to derive provisional
toxicity values for thiocyanic acid. However, information is available for this chemical which,
although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an Appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an Appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
Appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
DERIVATION OF SCREENING PROVISIONAL ORAL REFERENCE DOSE
Derivation of Screening Subchronic Provisional RfD (Screening Subchronic p-RfD)
Due to its low pKa value, thiocyanic acid would be likely dissociated in physiological
conditions. Therefore, it acts similarly as a thiocyanate anion. The screening subchronic p-RfD
is based on the subchronic p-RfD derived for thiocyanates (U.S. EPA, 2006). Appendix B
presents a detailed derivation of the p-RfDs for thiocyanates.
For thiocyanates, the available human data clearly identify both decreased blood pressure
and changes in thyroid function as sensitive effects of oral exposure to thiocyanates. However,
the effects on blood pressure were reported at doses generally ranging from 1.3-4.3 mg
(SCN)/kg-day (U.S. EPA, 2006), while effects on the thyroid occurred at exposure levels of
>0.19 mg (SCN)/kg-day in healthy subjects (Baneijee et al., 1997). Animal studies likewise
indicate that the thyroid is the most sensitive target of thiocyanate toxicity. However, the effect
levels are considerably greater in animal studies (on the order of 15-100 mg/kg-day) than in the
available human studies based on U.S. EPA (2006), even though an updated literature search
identified some lower effective doses (summarized below).
An updated literature review identified two new animal studies that evaluated thiocyanate
toxicity (Soto-Blanco et al., 2008; de Sousa et al., 2007) since 2006 to August 2011.
Soto-Blanco et al. (2008) reported that after 4 weeks of treatment with 4.5-mg potassium
thiocyanate (KSCN)/kg-day (equivalent to 2.6 mg [SCN]/kg-day) by gavage, female goats
(4 animals/group) had an increased number of vacuoles in the colloid of thyroid glands. In a
developmental (Trial A) and reproductive (Trial B) study (de Sousa et al., 2007), female Wister
rats received daily doses of 0.8, 2.4, or 24 mg (KSCN)/kg-day (equivalent to 0.48, 1.4, or 14 mg
[SCN]/kg-day) in drinking water from GDs 6-21 (Trial A), or GD 6 to 1 day after weaning
(PND 21). Dams and pups were examined for comprehensive developmental (Trial A) and
reproductive endpoints (Trial B), respectively. The most sensitive response observed in this
study was an increase in the number of mild reabsorption vacuoles in follicular colloid in the
thyroid of dams exposed to thiocyanate (>0.48 mg [SCN]/kg-day) during gestation. Although
these two studies identified animal effective doses lower than those in the database reported in
the PPRTV assessment for thiocyanates (U.S. EPA, 2006), they are still higher than the LOAEL
7
Thiocyanic Acid
-------
FINAL
12-10-2012
of 0.19 mg (SCN)/mg-day in humans (Banerjee et al., 1997), which served as the basis for
deriving the thiocyanate p-RfDs.
The study of Baneijee et al. (1997) evaluated a group of women exposed to an average of
0.19-mg thiocyanate (SCN)/kg-day for 5 years, relative to a matched control group. In addition
to elevated serum thiocyanate levels, a significant increase in serum TSH and a significant
decrease in serum T4 were observed in thiocyanate-exposed women. While the change in TSH
was statistically significant (p < 0.01) from the controls, the mean value of the treated group
(2.49 (j,U/mL) was within the normal range of the assay (0.2-4.0 (j,U/mL). Serum T4 was both
statistically different from controls and altered to a level outside of the normal assay range. The
0.19-mg (SCN)/kg-day exposure level is, therefore, identified as a LOAEL for changes in
thyroid endpoints.
The Dahlberg et al. (1985) study identified a lowest LOAEL of 0.018 mg (SCN)/kg-day
for decreased serum TSH, T3, and T4 in iodine-deficient subjects exposed to thiocyanate for
4 weeks. However, concerns over the design of this study, including the age of the study group
(13-17 years), the comparatively short duration (4 weeks), and the fact that the subjects were
goiterous in Stage I or II (and, therefore, already had an existing thyroid condition) prior to the
start of the study, preclude its selection as the principal study for derivation of the subchronic or
chronic p-RfD for thiocyanates. Another study by the same investigators (Dahlberg et al., 1984)
identified a NOAEL of 0.11 mg (SCN)/kg-day for effects on thyroid function in healthy
volunteers exposed for 12 weeks, but concerns regarding the comparatively short study duration
and the lack of identification of a LOAEL preclude its selection as the principal study for p-RfD
derivation for thiocyanates.
The LOAEL of 0.19 mg (SCN)/kg-day reported by Baneijee et al. (1997) is supported by
a LOAEL of 0.018 mg(SCN)/kg-day in sensitive subjects reported by Dahlberg et al. (1985),
which is approximately an order of magnitude lower than that of healthy subjects, as would be
expected from a standard UF approach. The Baneijee et al. (1997) study was, therefore, selected
as the principal study for p-RfD derivation for thiocyanates.
A subchronic p-RfD of 6 x 10"4 mg/kg-day was derived previously for thiocyanates
(U.S. EPA, 2006) based on the LOAEL of 0.19 mg/kg-day divided by a composite UF of 300
(10 to protect sensitive individuals, 10 for use of a LOAEL, and 3 for deficiencies in the
database, specifically the limited evaluations of dose response available for humans, because
effects in animals appear to occur at higher doses).
Considering thiocyanic acid would mostly dissociate and act as a thiocyanate anion in
biological conditions, a screening subchronic p-RfD for thiocyanic acid is derived based on a
molecular weight (MW) conversion from the subchronic p-RfD for thiocyanates as follows:
Screening Subchronic p-RfD = Thiocyanate Subchronic p-RfD x [MW (HSCN) ^ MW
(SCN)]
= 6 x 10"4 mg/kg-day x (59.1 g/mol 58.1 g/mol)
= 6 x 10"4 mg/kg-day
8
Thiocyanic Acid
-------
FINAL
12-10-2012
Derivation of Screening Chronic Provisional RfD (Screening Chronic p-RfD)
Similar to the Screening Subchronic p-RfD, the screening chronic p-RfD is based on the
chronic p-RfD derived previously for thiocyanates (U.S. EPA, 2006). The chronic p-RfD of
2 x 10"4 mg(SCN)/kg-day for thiocyanates was derived by applying an additional UF of 3 for
extrapolation from subchronic (in the principal study) to chronic duration. A full factor of 10
was not applied because while the Baneijee et al. (1997) study ran for less than 10% of the total
expected lifespan, the study duration of 5 years was likely sufficient to establish an equilibrium
of thiocyanate levels within the body, based on an estimated serum half-life of approximately
3 days. The composite UF for the chronic p-RfD for thiocyanates is, therefore, 1000 (3 for
extrapolation from subchronic to chronic duration, 10 to protect sensitive individuals, 10 for use
of a LOAEL, and 3 for deficiencies in the database).
A screening chronic p-RfD of 2 x 10"4 mg/kg-day for thiocyanic acid is derived based on
a MW conversion from the chronic p-RfD for thiocyanates as follows:
Screening Chronic p-RfD = Thiocyanate Chronic p-RfD x [MW (HSCN) ^ MW (SCN)]
= 2 x 10"4 mg/kg-day x (59.1g/mol 58.1 g/mol)
= 2 x 10"4 mg/kg-day
9
Thiocyanic Acid
-------
FINAL
12-10-2012
APPENDIX B. PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
THIOCYANATES
10
Thiocyanic Acid
-------
3-15-2006
Provisional Peer Reviewed Toxicity Values for
Thiocyanates
(Multiple CASRNs)
Derivation of Subchronic and Chronic Oral RfDs
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
-------
ACRONYMS AND ABBREVIATIONS
Bw body weight
cc cubic centimeters
CD Caesarean Delivered
CERCLA Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS central nervous system
cu.m cubic meter
DWEL Drinking Water Equivalent Level
FEL frank-effect level
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
g grams
GI gastrointestinal
HEC human equivalent concentration
Hgb hemoglobin
i.m. intramuscular
i.p. intraperitoneal
i.v. intravenous
IRIS Integrated Risk Information System
IUR inhalation unit risk
kg kilogram
L liter
LEL lowest-effect level
LOAEL lowest-observed-adverse-effect level
LOAEL(ADJ) LOAEL adjusted to continuous exposure duration
LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human
m meter
MCL maximum contaminant level
MCLG maximum contaminant level goal
MF modifying factor
mg milligram
mg/kg milligrams per kilogram
mg/L milligrams per liter
MRL minimal risk level
MTD maximum tolerated dose
MTL median threshold limit
1
-------
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
l^g
microgram
[j,mol
micromoles
voc
volatile organic compound
11
-------
3-15-2006
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR THIOCYANATES
(MULTIPLE CASRNs)
Derivation of Subchronic and Chronic Oral RfDs
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1. EPA's Integrated Risk Information System (IRIS).
2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3. Other (peer-reviewed) toxicity values, including:
~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~ California Environmental Protection Agency (CalEPA) values, and
~ EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program
sometimes request that a frequently used PPRTV be reassessed. Once an IRIS value for a
specific chemical becomes available for Agency review, the analogous PPRTV for that same
chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a
PPRTV cannot be derived based on inadequate data.
1
-------
3-15-2006
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Neither a subchronic nor a chronic reference dose (RfD) for thiocyanates is listed on the
Integrated Risk Information System (IRIS) (U.S. EPA, 2006), in the Health Effects Assessment
Summary Tables (HEAST) (U.S. EPA, 1997), or in the Drinking Water Standards and Health
Advisories list (U.S. EPA, 2004). The Chemical Assessments and Related Activities (CARA)
list (U.S. EPA, 1991, 1994) does not report any relevant documents for thiocyanates. The
Agency for Toxic Substances and Disease Registry (ATSDR) (2005), International Agency for
Research on Cancer (IARC) (2005), National Toxicology Program (NTP) (2005) and the World
Health Organization (WHO) (2005) have not published documents for thiocyanates. Literature
searches were conducted from 1965 to September, 2002 in TOXLINE, MEDLINE,
CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK and
EMIC/EMICBACK. Update literature searches were conducted from September, 2002 to
August, 2005 in MEDLINE, TOXLINE (NTIS), TOXCENTER (BIOSIS), TSCATS, CCRIS,
DART/ETIC, GENETOX, HSDB, RTECS and Current Contents. Searches were conducted for
the following thiocyanates: sodium thiocyanate (CASRN 540-72-7), potassium thiocyanate
(CASRN 333-20-0), calcium thiocyanate (CASRN 2092-16-2), ammonium thiocyanate (CASRN
1762-95-4) and thiocyanic acid (CASRN 463-56-9).
2
-------
3-15-2006
REVIEW OF THE PERTINENT LITERATURE
Human Studies
In the past, thiocyanate was used therapeutically to treat severe hypertension. A number
of early reports describe the efficacy of thiocyanate therapy, with 45-78% of treated patients
responding favorably to the treatment (Barker, 1936; Barker et al., 1941; Palmer et al., 1929).
Dose levels ranged from 0.09-0.3 g/day (1.3-4.3 mg/kg-day, assuming a 70 kg reference body
weight) with a general lowering of blood pressure of 20-40 mm Hg. However, the results of
thiocyanate therapy were inconsistent from clinic to clinic, and even within a single study two
patients rarely responded similarly to equivalent treatment regimens (Barker, 1936). Numerous
adverse effects were noted in treated patients, including weakness, swollen face, somnolence,
enlarged thyroid, and death (Barker, 1936; Barker et al., 1941; Palmer et al., 1929; Russel and
Stahl, 1942). These effects were unpredictable in occurrence, even when blood thiocyanate
levels were monitored to control the dose. The mechanism of the antihypertensive effects of
thiocyanate is not presently known.
Of particular note were the reports of effects of thiocyanate exposure on the thyroid.
While the reported incidence of thyroid-related effects was generally less than 10% (Barker et
al., 1941; Taylor, 1945), the studies typically noted only gross changes, with no discussion of
possible alterations in functional status. Thiocyanate has since been shown to produce a marked,
reversible depression of thyroid iodine uptake, which is exacerbated by iodine deficiency and can
be reduced or eliminated by co-exposure to iodide (Beamish et al., 1954; Thilly et al., 1980).
Later studies (Baneijee et al., 1997; Dahlberg et al., 1984, 1985; Delange et al., 1980a; Thilly et
al., 1980) have reported that elevated thiocyanate levels in serum can have effects on the
histologic structure and function of the thyroid.
Thiocyanate is believed to play a role in an endogenous antibacterial system
(lactoperoxidase/ thiocyanate/ hydrogen peroxide system) present in milk. It has been added
commercially to some milk preparations as an antibacterial agent. Dahlberg et al. (1984)
exposed 37 volunteers (9 males and 28 females) affiliated with University departments in
Uppsala (Sweden), ages 16-54, to milk containing 20 mg SCN (thiocyanate)/L as sodium
thiocyanate. The human subjects research ethics of this study were reviewed and approved by
the Human Subjects Committee of the University of Upsala, Sweden. Of the subjects, 32 were
nonsmokers and 5 were smokers; smokers and nonsmokers were analyzed separately. All
subjects had normal dietary habits, were of normal health status and had no early incidence of
goiter or thyroid dysfunction. Each subject consumed 200 mL of milk twice daily, for a total
intake of 8 mg SCN/day, for 12 weeks; assuming a reference body weight of 70 kg, the average
daily dose was 0.11 mg SCN/kg-day. Serum thiocyanate levels were significantly increased at 4,
8 and 12 weeks of exposure in nonsmokers and at 4 weeks in smokers. No changes were seen in
urinary iodine levels in either group at any evaluated time point. No significant changes were
reported in serum concentrations of thyroxine (T4), triiodothyronine (T3) or thyroid-stimulating
hormone (TSH) in either the smokers or the nonsmokers. Effects on other endpoints were not
evaluated.
Dahlberg et al. (1985) examined the effect of 4 weeks of exposure to thiocyanate on 55
iodine-deficient subjects (31 males, 24 females) between 13 and 17 years of age. The subjects
3
-------
3-15-2006
were volunteers from four different secondary schools in western Sudan, where goiter is
endemic, reportedly as a consequence of dietary iodine deficiency. The human subjects research
ethics of this study were reviewed and approved by the Human Subjects Committee of the
University of Upsala, Sweden and by the University of Kartoum, Sudan. All subjects were
goiterous in stage I and II based on the size of the thyroid gland, but otherwise had a normal
health status and were clinically euthyroid. Subjects consumed 250 mL of milk containing either
3.6 mg SCN/L (n=19) or 19 mg SCN/L (n=18) per day; an additional group received milk
containing 19 mg SCN/L together with an iodine supplement. Using an estimated mean body
weight of 50 kg for the Sudanese teenagers (which appears reasonable based on average body
weights of 53 to 65 kg for U.S. teenagers of the same ages [U.S. EPA, 2002]), average daily
doses were 0.018 mg/kg-day and 0.095 mg/kg-day for the 3.6 mg/L and 19 mg/L groups,
respectively. Day 0 readings for each group served as reference values for statistical analysis.
Serum thiocyanate levels were significantly elevated in both groups receiving 19 mg SCN/L, but
not in the 3.6 mg SCN/L group. In all groups, an increase in urinary iodine was seen following
thiocyanate exposure; the magnitude of the change was greatest in the iodine-supplemented
subjects and lowest in the unsupplemented 19 mg/L group. Thiocyanate exposure resulted in
significantly decreased serum TSH in all groups (14%, 17% and 25% decreases in the 3.6 mg/L,
19 mg/L and 19 mg/L+iodine groups, respectively), as well as decreased T3 (12.5% and 15%
decrease in the 3.6 and 19 mg/L groups, respectively) and T4 (13% and 11% decrease in the 3.6
and 19 mg/L groups, respectively) in groups without iodine supplementation. Iodine
supplementation reversed the decrease in serum T3 and T4 levels seen in the 19 mg/L group.
Other endpoints were not evaluated in this study.
Baneijee et al. (1997) evaluated the chronic effects of oral thiocyanate on women in
Calcutta. Thirty five women who had consumed -250 mL/day of a commercially-available
cow's milk containing 30-50 mg SCN/L (average level of 45 mg SCN/L) for the previous 5 years
were selected as the exposed group, while an equal number of women matched for age and
dietary habits, aside from consumption of thiocyanate-treated milk, were designated as the
control group. Review of the publication does not provide information on the human subjects
research ethics procedures undertaken in this study, but there is no evidence that the conduct of
the research was fundamentally unethical or significantly deficient. Women from both groups
had similar dietary patterns, did not use tobacco products and had no prior history of thyroid
disease. Blood was taken from each subject and analyzed for serum levels of SCN, TSH, T3, and
T4, and a urine sample was taken for iodine determination. Other endpoints were not evaluated.
Based on the average milk concentration of 45 mg SCN/L, an estimated milk consumption of
0.25 L/day, and a reference body weight for women of 60 kg, average daily consumption of
thiocyanate was 0.19 mg/kg-day. No differences in urinary iodine elimination were noted
between groups. The results of the thyroid hormone evaluations are presented in Table 1, below.
Women who consumed SCN-containing milk had significantly lower levels of serum T4 and
significantly greater levels of serum TSH than controls; serum T3 levels were elevated, but not
significantly. The decrease in serum T4 went below normal levels, as described by the assay
manufacturer. Significant correlations were found between serum thiocyanate concentrations
and serum T4 (negative correlation) and TSH levels (positive correlation) in the exposed group;
similar correlations were not found in the control group. Although the data in Table 1 suggest
that levels of serum thiocyanate in controls were above normal, the researchers noted that a
previous analysis conducted on non-smokers from the same geographic region as the current
4
-------
3-15-2006
study found serum thiocyanate levels in non-smokers for this region in the range of 80-100
|imol/L, which is consistent with results of this study.
Table 1 - Results of Banerjee et al. (1997) Evaluations of Thyroid Endpoints
Control Subjects
Thiocyanate Subjects
Normal Range
Mean
SE
Mean
SE
SCN (umol/L)
90.8
9.0
230.0a
10.0
34-69b
T4 (nmol/L)
125.4
11.5
87.8a
6.6
110-270°
T3 (nmol/L)
1.71
0.16
2.39
0.32
0.93-3.12c
TSH (nU/mL)
1.09
0.28
2.49a
0.20
0.2-4.0°
a significantly different (p<0.01) from the control group
b Pechacek et al., 1985
0 reported by the assay manufacturer
Studies of humans who consume heavy amounts of cassava, consisting of up to 80% of
the total diet in some cases (Dorea et al., 2004), have provided suggestive evidence of effects of
thiocyanate on the thyroid of both adults and the developing child. Cassava contains high levels
of cyanide, which, when consumed orally, is metabolized to thiocyanate; considerable increases
(up to 5-fold or more) in blood thiocyanate levels have been reported following exposure to
cyanide-rich cassava (Cliff et al., 1986; Delange et al., 1980b).
Delange et al. (1980b) reported that pregnant women in Zaire who regularly consumed
cassava had statistically significantly elevated blood thiocyanate levels relative to a control group
of pregnant Belgian women (0.68 mg SCN/dL in the Zairian women, relative to 0.21 mg
SCN/dL in the Belgian women), as well as significantly elevated TSH (14.0 [lU/mL in the
Zairian women and 3.9 [lU/mL in the Belgian women) and significantly decreased serum
concentrations of T4 (8.6 |ig/dL in the Zairian women and 15.3 |ig/dL in the Belgian women) and
T3 (191 ng/dL in the Zairian women and 220 ng/dL in the Belgian women). In newborns of
these women, significantly greater serum SCN levels were noted (0.62 mg/dL in the Zairian
newborns and 0.19 mg/dL in the Belgian newborns), as well as significantly increased serum
TSH (50.9 [j,U/mL in the Zairian newborns and 6.8 p,U/mL in the Belgian newborns) and T3 (106
ng/dL in the Zairian newborns and 60 ng/dL in the Belgian newborns) and significantly
decreased serum T4 (7.5 (J,g/dL in the Zairian newborns and 12.0 (J,g/dL in the Belgian
newborns). Similar results were seen in infants (aged 2 weeks to 15 months), with significantly
increased serum SCN (0.55 mg/dL in the Zairian infants and 0.38 mg/dL in the Belgian infants)
and TSH (52.6 p,U/mL in the Zairian infants and 3.5 [j,U/mL in the Belgian infants) and
significantly decreased T4 (6.9 (J,g/dL in the Zairian infants and 8.7 (J,g/dL in the Belgian infants);
serum levels of T3 were not affected in infants. Maternal serum concentrations of thiocyanate at
delivery were linearly correlated with those in the umbilical cord blood. Concentrations of
thiocyanate in the milk were not significantly different between Zairian and Belgian mothers.
5
-------
3-15-2006
Animal Studies
In an early study of the subchronic toxicity of thiocyanate, Anderson and Chen (1940)
exposed groups of 10 female rats (strain unspecified) by gavage to 100 mg sodium
thiocyanate/kg-day (-71.6 mg SCN/kg-day), 100 mg potassium thiocyanate/kg-day (-59.8 mg
SCN/kg-day) or vehicle 5 days/week for 12 weeks. Prior to study termination, four control rats,
four sodium thiocyanate rats and two potassium thiocyanate rats died due to gavage errors.
Neither thiocyanate compound resulted in growth inhibition; effects on other endpoints were not
reported. A follow-up experiment was conducted, exposing groups of 10 rats to 200 mg of
sodium or potassium thiocyanate (143 or 120 mg SCN/kg-day, respectively) 5 days/week for 8
weeks. As with the previous experiment, no changes in growth were seen as a result of
thiocyanate treatment and other endpoints were not evaluated. In the third portion of the study,
groups of dogs (n=4-5) were exposed to approximately 100 mg/kg-day of sodium (-71.6 mg
SCN/kg-day) or potassium (-59.8 mg SCN/kg-day) thiocyanate, as enterically-coated capsules, 5
days/week for up to 3 months. Repeated ingestion of 100 mg/kg-day of sodium or potassium
thiocyanate resulted in severe clinical effects, including progressive weight loss, apathy, head-
droop and ataxia; all animals but one at this exposure level died, despite discontinuation of
exposure (cause of death could not be determined). Another group of three animals, one of
which had been previously exposed to higher levels of thiocyanate, was exposed to 20-25 mg/kg-
day; these animals showed no evidence of toxicity (further details not reported). A single dog
exposed to 31 mg sodium thiocyanate/kg-day died following 7 weeks of treatment during which
the dog showed progressive body weight decrease; a precise cause of death was not determined.
Lindberg et al. (1941) exposed 12 dogs to 300 mg potassium thiocyanate/day (75 mg
SCN/kg-day, assuming a reference body weight [U.S. EPA, 1988] of 2.4 kilograms) for 3
months. Body weight and clinical signs were not evaluated. Thiocyanate exposure resulted in
an abrupt fall in blood cholesterol, followed by a slow decline over time. There was a rough
parallel between elevation of blood thiocyanate levels and decreased cholesterol level once the
initial decrease had stabilized. A similar effect was noted for total plasma protein levels.
Thiocyanate exposure resulted in a fall in erythrocyte numbers, as well as decreased hematocrit
and hemoglobin; no changes were seen in white cell numbers. Histologic sections of bone
marrow revealed an essentially acellular bone marrow in treated animals, and examination of the
livers of treated animals revealed a diffuse intracellular vacuolization with no evidence of
hyperplasia or regeneration; no changes were seen in the adrenal glands of treated animals.
Nagasawa et al. (1980) exposed groups of 18 weanling SHN female mice (a strain with a
high background mammary tumor incidence) to 0, 0.1 or 0.3% potassium thiocyanate in the
drinking water for 12 weeks. Using the allometric equations and mean body weights presented
in U.S. EPA (1988), mean thiocyanate doses were estimated at 0, 153 and 457 mg SCN/kg-day
for the 0, 0.1 and 0.3% groups, respectively. No differences between groups were noted in body
weight or body weight gain, estrous cycle pattern, pituitary or adrenal weight or ovarian
histology. Dose-related decreases in serum T3 (significant in the 0.3% group) and T4 (significant
in the 0.1 and 0.3% groups) were reported. Development of the lobulo-alveolar system of the
mammary gland was significantly inhibited in the 0.3% group. Dose-related decreases in
preneoplastic mammary hyperplastic alveolar nodules and mammary tumor incidence were
reported; these decreases attained statistical significance in the 0.3% animals.
6
-------
3-15-2006
In a second experiment, Nagasawa et al. (1980) exposed groups of 19-22 female GR/A
mice to 0, 0.1 or 0.3% potassium thiocyanate in the drinking water for 5 weeks prior to and for
10 weeks following mating; exposure was discontinued for the 3 days during which mating
occurred. Using the allometric equations and mean body weights presented in U.S. EPA (1988),
mean thiocyanate doses were estimated at 0, 155 and 470 mg SCN/kg-day for the 0, 0.1 and
0.3% groups, respectively. At the end of exposure, the animals were sacrificed and examined for
changes in reproductive parameters (number of pregnancies, litter size, pup weight, percent
stillborn pups) and the presence of pregnancy-dependent mammary tumors (PDMT). On day 4
of lactation, plasma prolactin levels were evaluated in the dams. No changes in maternal body
weight, evaluated reproductive parameters or plasma prolactin levels were noted following
thiocyanate treatment. Treatment with thiocyanate resulted in a significantly decreased number
of PDMT (16/22, 7/20, 5/19 PDMT in the 0, 0.1 and 0.3% groups, respectively). No other
endpoints were evaluated in the study.
Ermans et al. (1980) exposed groups of rats (n=9-25) to 0.1-10 mg thiocyanate/day (-0.6-
56 mg/kg-day, based on a reference body weight of 180 g) in the diet for 2-5 weeks; the diet was
intentionally iodine-deficient. Treated rats showed a dose-related depletion of thyroid iodine
content, reaching 40-50% of the control value. Exposure to 10 mg/day resulted in a significant
decrease in T4 levels, while T3 levels were not altered. Effects on organs other than the thyroid
were not reported.
Philbrick et al. (1979) exposed groups (n=10) of male rats to 0 or 2240 ppm potassium
thiocyanate (KSCN) in the diet for 11.5 months. Both iodine-supplemented and iodine-deficient
diets were provided, with appropriate controls. Using a reference body weight of 380 grams and
reference food consumption of 30 g/day (U.S. EPA, 1988), an average daily dose of 106 mg
SCN/kg-day can be estimated. At 4 and 11 months, five animals per group were evaluated for
plasma T4, T4 secretion rates and urinary thiocyanate concentrations. At terminal sacrifice,
weights of whole brain, heart, liver and thyroid were obtained. Brain, optic nerves, spinal cord
and thyroid glands were fixed for light microscopy and sections of spinal cord were prepared for
electron microscopic evaluation. No changes in body weight gain were seen as a result of KSCN
treatment and no adverse clinical effects were reported. Treatment with thiocyanate resulted in
significant decreases in plasma T4 and T4 secretion rate at 4 months and decreased thyroid
weight and plasma T4 at 11 months; T4 secretion rate was not different from controls after 11
months of thiocyanate exposure. No definitive histological changes in the thyroid gland, optic or
sciatic nerves or neural tissues were seen in animals receiving iodine supplementation along with
KSCN treatment. However, it appeared that KSCN treatment resulted in an alteration of the
vacuolization in spinal cord tissues that was seen in control animals fed an iodine-deficient diet.
This vacuolization, which was accompanied by a mild-to-moderate astrogliosis (no
quantification was provided), was seen at both the light and electron microscopic level.
Bala et al. (1996) exposed groups of 8-week old female Wistar/NIN rats to 0 or -15 mg
SCN/kg-day, as potassium thiocyanate, for varying times throughout conception and lactation.
After 8 weeks of exposure, the animals were mated with control males and monitored throughout
gestation, parturition and lactation. In one group, the effect of exposure of the offspring was also
examined, using the same dietary exposure level, with a parallel group that was exposed during
gestation and weaning but not post-weaning. Exposure to KSCN did not affect the body weight
7
-------
3-15-2006
or the ratio of brain-to-body weight of any group of dams. Animals exposed to KSCN from the
beginning of the experiment through weaning showed a significantly increased urinary excretion
of iodine, as well as increased thyroid weight and decreased levels of serum T4. In the pups of
animals exposed to SCN, a significant decrease in serum T4 levels was noted; this decrease was
present whether the dams had been exposed from the beginning of the study, were exposed from
conception through weaning or were exposed only after giving birth. Pup body weights at
weaning were decreased in animals exposed beginning at conception through weaning, but not in
those exposed throughout the experiment or those only exposed postpartum. Exposure to SCN
did not result in a significant change in the uptake of sucrose, leucine, tyrosine or 2-deoxy-D-
glucose, regardless of time of exposure. Offspring not exposed during gestation, but exposed in
the diet post-weaning showed significant decreases in serum T4 and significant increases in brain
weight, as did offspring exposed during gestation and lactation, but not exposed post-weaning.
The paper did not report on the presence or lack of malformations in the offspring of treated
dams.
In a subsequent report, Raghunath and Bala (1998) examined the offspring of Wistar/NIN
rat dams exposed either prior to mating throughout weaning, from conception through weaning
or from parturition through weaning (offspring of the dams from Bala et al., 1996) to -15 mg
SCN/kg-day in the diet, as potassium thiocyanate, for 8 weeks. At weaning (the start of the
follow-up study), the offspring in all three treated groups already had lower serum T4 levels,
relative to untreated controls. Further treatment with SCN did not result in an additional
lowering of serum T4 levels. Offspring of animals exposed continuously from weaning, through
pregnancy and lactation, showed a decreased brain uptake of 2-deoxy-D-glucose relative to
controls; this change was not noted in the offspring of animals treated from conception onward
or in those whose dams were only exposed during weaning.
In a second portion of the manuscript (Raghunath and Bala, 1998), the authors describe a
continuous 2-generation exposure to -15 mg SCN/kg-day, as potassium thiocyanate, in
Wistar/NIN rats. Fo animals were exposed from weaning (8 weeks of age) throughout gestation
and lactation. At weaning, the Fi pups were exposed to an identical diet for 8 weeks, then mated
and exposed throughout gestation, parturition and weaning. F2 pups showed no changes in body
weight at birth or weaning and brain weight was not affected. Serum levels of T4 were
significantly decreased in F2 pups; this decrease was greater than the decrease seen in their Fi
counterparts. Treated F2 rats showed a significant decrease in the brain uptake of 2-deoxy-D-
glucose, leucine and tyrosine; brain uptake of sucrose was not affected. Effects on other
endpoints were not evaluated.
Delange et al. (1980a) exposed pregnant Wistar rats to 0 or 10 mg thiocyanate/day from
the second day of pregnancy through weaning (postnatal day 16). Based on body weights
provided in the manuscript, the average daily dose was calculated to be 45-56 mg/kg-day.
Additional groups received 25 or 100 jag of potassium iodide by intraperitoneal injection 2 days
prior to delivery. Exposure to SCN had no effect on body weights of the dams at birth or at the
end of exposure. Maternal thyroid weights were increased, but not significantly. At both
delivery and weaning, hyperplasia of the thyroid was noted in SCN-exposed dams; treatment
with iodide resulted in a dose-related reduction in the severity of the hyperplastic effect. A
significant decrease in T4 was noted only at delivery and a decrease in T3 was noted only at
8
-------
3-15-2006
weaning; treatment with iodide completely reversed these effects. Weights of the pups were not
affected by exposure with the exception of the group that received 25 jag of iodide prior to
delivery (pup weights in 100 jag iodide group were not different from controls). Effects in pups
at weaning, relative to controls, were significantly increased thyroid weights, hyperplasia of the
thyroid and decreased levels of serum T4; administration of iodide prior to birth did not
ameliorate these effects.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC RfDs
FOR THIOCYANATES
The available human data clearly identify both decreased blood pressure and changes in
thyroid function as sensitive effects of oral exposure to thiocyanates. However, the effects on
blood pressure were reported at doses generally ranging from 1.3-4.3 mg/kg-day (Barker, 1936;
Barker et al., 1941; Palmer et al., 1929), while effects on the thyroid occurred at exposure levels
of 0.19 mg/kg-day in healthy subjects (Banerjee et al., 1997). Animal studies likewise indicate
that the thyroid is the most sensitive target of thiocyanate toxicity, although the effect levels are
considerably greater in animal studies (on the order of 15-100 mg/kg-day) than in the available
human studies.
The Dahlberg et al. (1985) study was considered for use as the principal study in p-RfD
derivation because it identified the lowest LOAEL in exposed humans, 0.018 mg/kg-day for
decreased serum TSH, T3 and T4 in iodine-deficient subjects exposed to thiocyanate for 4 weeks.
However, concerns over the design of this study, including the age of the study group (13-17
years), the comparatively short duration (4 weeks) and the fact that the subjects were goiterous in
stage I or II (and therefore already had an existing thyroid condition) prior to the start of the
study, preclude its selection as the principal study for derivation of the subchronic or chronic p-
RfD. Another study by the same investigators (Dahlberg et al., 1984) identified a NOAEL of
0.11 mg/kg-day for effects on thyroid function in healthy volunteers exposed for 12 weeks, but
concerns regarding the ages of the study population, the comparatively short study duration and
the lack of identification of a LOAEL preclude its selection as the principal study for p-RfD
derivation.
The study of Baneijee et al. (1997) evaluated a group of women exposed to an average of
0.19 mg thiocyanate/kg-day for 5 years, relative to a matched control group. In addition to
elevated serum thiocyanate levels, a significant increase in serum TSH and a significant decrease
in serum T4 were observed in thiocyanate-exposed women. While the change in TSH was
statistically significant (p<0.01) from the controls, the mean value of the treated group (2.49
|iU/mL) was within the normal range of the assay (0.2-4.0 |iU/mL). Serum T4 was both
statistically different from controls and altered to a level outside of the normal assay range. The
0.19 mg/kg-day exposure level is therefore identified as a LOAEL for changes in thyroid
endpoints. The LOAEL is supported by the LOAEL of 0.018 mg/kg-day in sensitive subjects
reported by Dahlberg et al. (1985), which is approximately an order of magnitude lower than that
of healthy subjects, as would be expected from a standard uncertainty factor (UF) approach. The
Baneijee et al. (1997) study was therefore selected as the principal study for p-RfD derivation.
9
-------
3-15-2006
To derive the subchronic p-RfD, the LOAEL of 0.19 mg/kg-day is divided by an UF of
300 (10 to protect sensitive individuals, 10 for use of a LOAEL and 3 for deficiencies in the
database, specifically the limited evaluations of dose-response available for humans, since
effects in animals appear to occur at considerably higher doses). The subchronic p-RfD of 6E-4
mg/kg-day is derived as follows:
Subchronic p-RfD = LOAEL + UF
= 0.19 mg/kg-day ^-300
= 0.0006 or 6E-4 mg/kg-day
To derive the chronic p-RfD, an additional UF of 3 was applied for extrapolation from
subchronic to chronic duration. A full factor of 10 was not applied because while the Banerjee et
al. (1997) study ran for less than 10% of the total expected lifespan, the study duration of 5 years
was likely sufficient to establish an equilibrium of thiocyanate levels within the body, based on
an estimated serum half-life of approximately 3 days (Schulz, 1984). The total UF for the
chronic p-RfD is therefore 1000 (3 for extrapolation from subchronic to chronic duration, 10 to
protect sensitive individuals, 10 for use of a LOAEL and 3 for deficiencies in the database,
specifically the limited evaluations of dose-response available for humans, since effects in
animals appear to occur at considerably higher doses). The chronic p-RfD of 2E-4 mg/kg-day
is derived as follows:
p-RfD = LOAEL - UF
= 0.19 mg/kg-day + 1000
= 0.0002 or 2E-4 mg/kg-day
Confidence in the principal study is low. While the study evaluated the most sensitive
known endpoints for thiocyanate exposure, it did so at only one time point, non-thyroid
endpoints were not evaluated and a NOAEL was not identified. Confidence in the database is
medium. The available human data support the choice of critical effect and considerable animal
data exist supporting thyroid effects as a sensitive endpoint of thiocyanate; however, only limited
dose-response data on the effects of oral thiocyanate in humans are available and the effects seen
in animal studies appear to occur at considerably greater levels (-100-1000-fold) than those in
humans. Low confidence in the provisional subchronic and chronic RfD values results.
REFERENCES
Anderson, R.C. and K.K. Chen. 1940. Absorption and toxicity of sodium and potassium
thiocyanates. J. Am. Pharm. Assoc. 6:152-161.
ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Internet HazDat
Toxicol ogical Profile Query. U.S. Department of Health and Human Services, Public Health
Service. Atlanta, GA. Available at http ://www.atsdr.cdc. gov/gsql/toxprof. script.
Bala, T.S., M.K. Janardanasarma and M. Raghunath. 1996. Dietary goitrogen-induced changes
in the transport of 2-deoxy-D-glucose and amino acids across the rat blood-brain barrier. Int. J.
Dev. Neurosci. 14(5):575-583.
10
-------
3-15-2006
Baneijee, K.K., P. Marimuthu, P. Bhattacharyya and M. Chatteijee. 1997. Effect of thiocyanate
ingestion through milk on thyroid hormone homeostasis in women. Brit. J. Nutr. 78(5):679-681.
Barker, M.H. 1936. The blood cyanates in the treatment of hypertension. J. Am. Med. Assoc.
106:762-767.
Barker, M.H., H. A. Lindberg and M.H. Wald. 1941. Further experiences with thiocyanates. J.
Am. Med. Assoc. 117:1591-1594.
Beamish, R.E., W.F. Perry and V.M. Storrie. 1954. Observations on thyroid function in
hypertensive patients treated with potassium thiocyanate. Am. Heart. J. 48:433-438.
Cliff, J., P. Lundquist, H. Rosling, B. Sorbo and L. Wide. 1986. Thyroid function in a cassava-
eating population affected by epidemic spastic paraparesis. Acta Endocrin. 113:523-528.
Dahlberg, P.A., A. Bergmark, L. Bjorck et al. 1984. Intake of thiocyanate by way of milk and
its possible effect on thyroid function. Am. J. Clin. Nutr. 39(3):416-420.
Dahlberg, P.A., A. Bergmark, M. Eltom et al. 1985. Effect of thiocyanate levels in milk on
thyroid function in iodine deficient subjects. Am. J. Clin. Nutr. 41(5): 1010-1014.
Delange, F., N. Van Minh, L. Vanderlinden et al. 1980a. Influence of goitrogens in pregnant
and lactating rats on thyroid function in the pups. In: Role of cassava in the etiology of endemic
goitre and cretinism. A.M. Ermans, N.M. Mbulamoko, F. Delange and A. Ahluwalia, Eds. pp.
127-134.
Delange, F., P. Bourdoux, R. Lagasse et al. 1980b. Effects of thiocyanate during pregnancy and
lactation on thyroid function in infants. In: Role of assava in the etiology of endemic goitre and
cretinism. A.M. Ermans, N.M. Mbulamoko, F. Delange and A. Ahluwalia, Eds. pp. 121-126.
Dorea, J.D. 2004. Maternal thiocyanate and thyroid status during breast-feeding. J. Am. Col.
Nutr. 23(2):97-101.
Ermans, A.M., J. Kinthaert, M. van der Velden and P. Bourdoux. 1980. Studies of the
antithyroid effects of cassava and of thiocyanate in rats. In: Role of cassava in the etiology of
endemic goitre and cretinism. A.M. Ermans, N.M. Mbulamoko, F. Delange and A. Ahluwalia,
Eds. pp. 93-110.
IARC (International Agency for Research on Cancer). 2005. IARC Agents and Summary
Evaluations. Available at http://www-cie.iarc.fr/htdieJsearch.html.
Lindberg, H.A., M.H. Wald and M.H. Barker. 1941. Observations on the pathologic effects of
thiocyanate: An experimental study. Am. Heart. J. 21:605-616.
Nagasawa, H., R. Yanai, Y. Nakajima et al. 1980. Inhibitory effects of potassium thiocyanate
on normal and neoplastic mammary development in female mice. Eur. J. Cancer. 16:473-480.
11
-------
3-15-2006
NTP (National Toxicology Program). 2005. Management Status Report. Available at
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html.
Palmer, R.S., L.S. Silver and P.D. White. 1929. Clinical use of potassium sulfocyanate in
hypertension: A preliminary report of 59 cases. New Engl. J. Med. 201:709-714.
Pechacek, T.F., A.R. Folsom, R. de Gaudermaris et al. 1985. Smoke exposure in pipe and cigar
smokers: Serum thiocyanate measures. JAMA. 254:3330-3332.
Philbrick, D.J., J.B. Hopkins, D.C. Hill et al. 1979. Effects of prolonged cyanide and
thiocyanate feeding in rats. J. Toxicol. Environ. Health. 5:579-592.
Raghunath, M. and T.S. Bala. 1998. Diverse effects of mild and potent goitrogens on blood-
brain barrier nutrient transport. Neurochem. Int. 33:173-177.
Russel, W.O. and W.C. Stahl. 1942. Fatal poisoning from potassium thiocyanate treatment of
hypertension. J. Am. Med. Assoc. 119:1177-1181.
Schulz, V. 1984. Clinical Pharmacokinetics of Nitroprusside, Cyanide, Thiosulphate and
Thiocyanate. Clin. Pharmacokinet. 9:239-251.
Taylor, R.D. 1945. Experience with potassium thiocyanate as a therapeutic agent in arterial
hypertention. Proc. Am. Federation. Clin. Res. 2:10 (Cited in Beamish et al., 1954)
Thilly, C.H., G. Roger, R. Lagasse et al. 1980. Fetomaternal relationship, fetal hypothyroidism,
and psychomotor retardation. In: Role of cassava in the etiology of endemic goitre and
cretinism. A.M. Ermans, N.M. Mbulamoko, F. Delange and A. Ahluwalia, Eds. pp. 111-120.
U.S. EPA. 1988. Recommendations for and Documentation of Biological Values for Use in
Risk Assessment. Environmental Criteria and Assessment Office, Office of Health and
Environmental Assessment, Office of Research and Development, U.S. Environmental
Protection Agency, Cincinnati, OH. EPA/600/6-87/008. NTIS PB 88-17874.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2002. Child-Specific Exposure Factors Handbook. Interim Report. Office of
Research and Development, Washington, DC. EPA/600/P-00/002B.
12
-------
3-15-2006
U.S. EPA. 2004. 2004 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA/822/R-02/038. Available at
http://www.epa.gov/waterscience/drinkine/standards/dwstandards.pdf.
U.S. EPA. 2006. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
www.epa.gov/iris
WHO (World Health Organization). 2005. Online Catalogs for the Environmental Criteria
Series. Available at http://www.inchem.org/pages/ehc.html.
13
------- |