[Federal Register Volume 81, Number 49 (Monday, March 14, 2016)]
[Notices]
[Pages 13361-13362]
[FR Doc No: 2016-05652]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. ER16-1033-000]

Windrose Power and Gas LLC; Supplemental Notice That Initial
Market-Based Rate Filing Includes Request for Blanket Section 204
Authorization

    This is a supplemental notice in the above-referenced proceeding of
Windrose Power and Gas LLC's application for market-based rate
authority, with an accompanying rate tariff, noting that such
application includes a request for blanket authorization, under 18 CFR
part 34, of future issuances of securities and assumptions of
liability.
    Any person desiring to intervene or to protest should file with the
Federal Energy Regulatory Commission, 888 First Street NE., Washington,
DC 20426, in accordance with Rules 211 and 214 of the Commission's
Rules of Practice and Procedure (18 CFR 385.211 and 385.214). Anyone
filing a motion to intervene or protest must serve a copy of that
document on the Applicant.
    Notice is hereby given that the deadline for filing protests with
regard to the applicant's request for blanket authorization, under 18
CFR part 34, of future issuances of securities and assumptions of
liability, is March 28, 2016.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper, using the FERC Online links at http://www.ferc.gov. To facilitate electronic service, persons with Internet
access who will eFile a document and/or be listed as a contact for an
intervenor must create and validate an eRegistration account using the
eRegistration link. Select the eFiling link to log on and submit the
intervention or protests.
    Persons unable to file electronically should submit an original and
5 copies

of the intervention or protest to the Federal Energy Regulatory
Commission, 888 First Street NE., Washington, DC 20426.
    The filings in the above-referenced proceeding are accessible in
the Commission's eLibrary system by clicking on the appropriate link in
the above list. They are also available for electronic review in the
Commission's Public Reference Room in Washington, DC. There is an
eSubscription link on the Web site that enables subscribers to receive
email notification when a document is added to a subscribed docket(s).
For assistance with any FERC Online service, please email
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For
TTY, call<PHONE_NUMBER>.

    Dated: March 8, 2016.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2016-05652 Filed 3-11-16; 8:45 am]
 BILLING CODE 6717-01-P


[Federal Register Volume 76, Number 167 (Monday, August 29, 2011)]
[Notices]
[Pages 53707-53708]
[FR Doc No: 2011-22047]

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DEPARTMENT OF TRANSPORTATION

Federal Motor Carrier Safety Administration

[FMCSA Docket No. FMCSA-2011-0145]

Qualification of Drivers; Exemption Applications; Diabetes
Mellitus

AGENCY: Federal Motor Carrier Safety Administration (FMCSA), DOT.

ACTION: Notice of final disposition.

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SUMMARY: FMCSA announces its decision to exempt twenty-two individuals
from its rule prohibiting persons with insulin-treated diabetes
mellitus (ITDM) from operating commercial motor vehicles (CMVs) in
interstate commerce. The exemptions will enable these individuals to
operate CMVs in interstate commerce.

DATES: The exemptions are effective August 29, 2011. The exemptions
expire on August 29, 2013.

FOR FURTHER INFORMATION CONTACT: Elaine M. Papp, Chief, Medical
Programs,<PHONE_NUMBER><EMAIL_ADDRESS>FMCSA, Room W64-224,
Department of Transportation, 1200 New Jersey Avenue, SE., Washington,
DC 20590-0001. Office hours are from 8:30 a.m. to 5 p.m., Monday
through Friday, except Federal holidays.

SUPPLEMENTARY INFORMATION:

Electronic Access

    You may see all the comments online through the Federal Document
Management System (FDMS) at: http://www.regulations.gov.
    Docket: For access to the docket to read background documents or
comments, go to http://www.regulations.gov and/or Room W12-140 on the
ground level of the West Building, 1200 New Jersey Avenue, SE.,
Washington, DC, between 9 a.m. and 5 p.m., Monday through Friday,
except Federal holidays.
    Privacy Act: Anyone may search the electronic form of all comments
received into any of DOT's dockets by the name of the individual
submitting the comment (or of the person signing the comment, if
submitted on behalf of an association, business, labor union, or other
entity). You may review DOT's Privacy Act Statement for the Federal
Docket Management System (FDMS) published in the Federal Register on
January 17, 2008, (73 FR 3316), or you may visit http://edocket.access.gpo.gov/2008/pdf/E8-785.pdf.

Background

    On July 8, 2011, FMCSA published a notice of receipt of Federal
diabetes

exemption applications from twenty-two individuals and requested
comments from the public (76 FR 40439). The public comment period
closed on August 8, 2011, and no comments were received.
    FMCSA has evaluated the eligibility of the twenty-two applicants
and determined that granting the exemptions to these individuals would
achieve a level of safety equivalent to or greater than the level that
would be achieved by complying with the current regulation 49 CFR
391.41(b)(3).

Diabetes Mellitus and Driving Experience of the Applicants

    The Agency established the current standard for diabetes in 1970
because several risk studies indicated that drivers with diabetes had a
higher rate of crash involvement than the general population. The
diabetes rule provides that ``A person is physically qualified to drive
a commercial motor vehicle if that person has no established medical
history or clinical diagnosis of diabetes mellitus currently requiring
insulin for control'' (49 CFR 391.41(b)(3)).
    FMCSA established its diabetes exemption program, based on the
Agency's July 2000 study entitled ``A Report to Congress on the
Feasibility of a Program to Qualify Individuals with Insulin-Treated
Diabetes Mellitus to Operate in Interstate Commerce as Directed by the
Transportation Act for the 21st Century''. The report concluded that a
safe and practicable protocol to allow some drivers with ITDM to
operate CMVs is feasible.
    The September 3, 2003 (68 FR 52441), Federal Register notice in
conjunction with the November 8, 2005 (70 FR 67777), Federal Register
notice provides the current protocol for allowing such drivers to
operate CMVs in interstate commerce.
    These twenty-two applicants have had ITDM over a range of 1 to 27
years. These applicants report no severe hypoglycemic reactions
resulting in loss of consciousness or seizure, requiring the assistance
of another person, or resulting in impaired cognitive function that
occurred without warning symptoms, in the past 12 months and no
recurrent (2 or more) severe hypoglycemic episodes in the past 5 years.
In each case, an endocrinologist verified that the driver has
demonstrated a willingness to properly monitor and manage his/her
diabetes mellitus, received education related to diabetes management,
and is on a stable insulin regimen. These drivers report no other
disqualifying conditions, including diabetes-related complications.
Each meets the vision standard at 49 CFR 391.41(b)(10).
    The qualifications and medical condition of each applicant were
stated and discussed in detail in the July 8, 2011, Federal Register
notice and they will not be repeated in this notice.

Discussion of Comment

    FMCSA did not receive any comments in this proceeding.

Basis for Exemption Determination

    Under 49 U.S.C. 31136(e) and 31315, FMCSA may grant an exemption
from the diabetes standard in 49 CFR 391.41(b)(3) if the exemption is
likely to achieve an equivalent or greater level of safety than would
be achieved without the exemption. The exemption allows the applicants
to operate CMVs in interstate commerce.
    To evaluate the effect of these exemptions on safety, FMCSA
considered medical reports about the applicants' ITDM and vision, and
reviewed the treating endocrinologists' medical opinion related to the
ability of the driver to safely operate a CMV while using insulin.
    Consequently, FMCSA finds that in each case exempting these
applicants from the diabetes standard in 49 CFR 391.41(b)(3) is likely
to achieve a level of safety equal to that existing without the
exemption.

Conditions and Requirements

    The terms and conditions of the exemption will be provided to the
applicants in the exemption document and they include the following:
(1) That each individual submit a quarterly monitoring checklist
completed by the treating endocrinologist as well as an annual
checklist with a comprehensive medical evaluation; (2) that each
individual reports within 2 business days of occurrence, all episodes
of severe hypoglycemia, significant complications, or inability to
manage diabetes; also, any involvement in an accident or any other
adverse event in a CMV or personal vehicle, whether or not it is
related to an episode of hypoglycemia; (3) that each individual provide
a copy of the ophthalmologist's or optometrist's report to the medical
examiner at the time of the annual medical examination; and (4) that
each individual provide a copy of the annual medical certification to
the employer for retention in the driver's qualification file, or keep
a copy in his/her driver's qualification file if he/she is self-
employed. The driver must also have a copy of the certification when
driving, for presentation to a duly authorized Federal, State, or local
enforcement official.

Conclusion

    Based upon its evaluation of the twenty-two exemption applications,
FMCSA exempts Bryan K. Aaron, Michael A. Anderson, Donald M. Bergman,
Ronald J. Boehm, Ernest E. Bogan, Eric B. Bratanich, Jerry A. Campbell,
Paul Dessesow, Vernon W. Elmore, Michael J. Gilbert, William D. Hanam,
Steven S. Hanna, Michael M. Harms, Johnathan R. Hartman, Devon K.
Johnson, Andrew W. Richey, Rob T. Romans, Thomas M. Shafer, Allen D.
Stevenson, Oleg Tarasov, Richard H. Willis, and Harvey N. Woody from
the ITDM standard in 49 CFR 391.41(b)(3), subject to the conditions
listed under ``Conditions and Requirements'' above.
    In accordance with 49 U.S.C. 31136(e) and 31315 each exemption will
be valid for two years unless revoked earlier by FMCSA. The exemption
will be revoked if: (1) The person fails to comply with the terms and
conditions of the exemption; (2) the exemption has resulted in a lower
level of safety than was maintained before it was granted; or (3)
continuation of the exemption would not be consistent with the goals
and objectives of 49 U.S.C. 31136(e) and 31315. If the exemption is
still effective at the end of the 2-year period, the person may apply
to FMCSA for a renewal under procedures in effect at that time.

    Issued on: August 19, 2011.
 Larry W. Minor,
Associate Administrator Office of Policy.
[FR Doc. 2011-22047 Filed 8-26-11; 8:45 am]
BILLING CODE 4910-EX-P


Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 1 Chapter IX. Risk Characterization Summary A. Hazard Characterization and Mode of Action Implications The data on health effects of cyanogen chloride are very limited, and so there is significant uncertainty in the cyanogen chloride hazard characterization. The available studies on cyanogen chloride are useful primarily for hazard identification, but are not sufficiently quantitative or of an appropriate design to be useful for dose response assessment. A single study of the health effects of occupational exposure to cyanogen chloride reported dizziness, nausea, and prostration lasting several hours after high exposure incidents ( Reed, 1920). Chronic symptoms included weakness,

and eye, nose and throat irritation. Other studies of short term exposure of humans reported rapid paralysis of nerve centers, as well as eye, throat, and lung irritation ( Prentiss, 1937; Flury and Zernik, 1931). Except for the irritative effects, which may be due to the parent compound,

the observed symptoms are consistent with those seen following cyanide exposure. The animal data on cyanogen chloride are limited to acute studies of rats, cats, and dogs exposed by either inhalation or injection before the advent of modern toxicology methods ( Flury and Zernik, 1931;

Reed, 1920; Aldridge and Evans, 1946; Haymaker et al., 1952). These studies are unsuitable for risk assessment because key information about doses and study design were not reported.

However, the studies do help to identify the potential health effects of cyanogen chloride, which include neurotoxicity ( depressed reflexes, muscular tremors, rigidity and weakness of limbs,

convulsions, brain necrosis), weight loss, cardiac irregularities, and pulmonary congestion and Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 2 edema. The animal and human data also indicate that cyanogen chloride irritates the respiratory passages and eyes. Based on the human and animal data, high short term exposure to cyanogen chloride vapor, and longer term exposure to unknown levels, causes neurological effects, and respiratory and ocular irritation. The minimum exposure levels causing either short term or longterm effects are unknown. With the exception of the irritative effects from inhalation of cyanogen chloride, the limited data on cyanogen chloride toxicity are consistent with the toxic effects of its known primary metabolites, cyanide and thiocyanate.

Due to this lack of toxicity data on cyanogen chloride, surrogates were considered as the basis for the cyanogen chloride assessment. Toxicokinetics data ( Aldridge and Evans, 1946;

Aldridge, 1951) show that cyanogen chloride is rapidly metabolized to cyanide ( CN), and thiocyanate ( SCN), two chemicals for which much more toxicity information is available.

Metabolism to either of these compounds would also result in production of HCl, although HCl production has not been directly evaluated. The reduction of cyanogen chloride to cyanide appears to occur via reaction with the  SH group of glutathione, hemoglobin, or other proteins.

Since cyanide is metabolized to thiocyanate, it is unknown whether the thiocyanate seen after cyanogen chloride exposure is formed directly from cyanogen chloride, or as a metabolite of cyanide. Water chemistry data also suggest that cyanogen chloride can react to form cyanate ( OCN) or cyanamide ( CH 2 N 2), and can react with other nucleophiles, although these other reactions have not been confirmed in animals dosed with cyanogen chloride, or even in in vitro studies of metabolism. Since cyanogen chloride is metabolized almost immediately, it is likely that Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 3 the systemic toxicity of cyanogen chloride is due to the activity of metabolites rather than the parent compound. Unfortunately, no mass balance toxicokinetic studies of cyanogen chloride have been conducted, so no quantitative identification of metabolites is possible. The irritative properties of cyanogen chloride indicate that ingestion of high concentrations may directly affect the gastrointestinal tract, but such effects are unlikely at environmental exposure levels. Because cyanogen chloride is rapidly metabolized in the blood, and reacts directly with glutathione, which is present in the liver at high concentrations, first pass metabolism may lead to marked differences between the toxicokinetics of inhaled and ingested cyanogen chloride. Based on these considerations, the following text focuses on the known metabolites of cyanogen chloride.

The toxicity of thiocyanate is generally well known. Animal ( Nagasawa et al., 1980;

Pyska, 1977; Philbrick et al., 1979; Kanno et al., 1990) and human ( Dahlberg et al., 1984;

Banerjee et al., 1997) data show that the primary target of thiocyanate is the thyroid, although no toxicity studies have thoroughly evaluated other organs and tissues, so toxicity to other targets cannot be ruled out. Human data on thiocyanate exposures leading to changes in thyroid hormone levels ( Dahlberg et al., 1984; Banerjee et al., 1997) form the basis for the thiocyanate RfD. These studies are supported by another human study ( Beamish et al., 1954), which reported effects at a similar concentration of thiocyanate in the plasma, but did not provide any information on dose levels. The ionic size of thiocyanate is similar to that of iodine, and thiocyanate acts by blocking the active transport of iodine into the thyroid gland, and by causing iodine already accumulated in the thyroid to be discharged ( Wolff, 1998). Although no standard multigeneration Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 4 reproduction or developmental toxicity studies of thiocyanate were located,

reproductive/ developmental toxicity studies that focused on the thyroid have found effects such as increased thyroid weight and changes in the levels of thyroid hormones ( Raghunath and Bala,

1998; Bala et al., 1996; Kreutler et al., 1978; Pyska, 1977).

Potential neurodevelopmental toxicity is a key unresolved issue for both thiocyanate and cyanide ( and, by implication, for cyanogen chloride), due to the potential for these chemicals to induce hypothyroidism in fetuses and neonates. While hypothyroidism, defined by increased serum levels of TSH and decreased levels of T3 and T4, causes goiter in adults, the effects of hypothyroidism in infants ( stunted growth and mental development) are more severe. In humans,

congenital hypothyroidism, or cretinism, is characterized by long term effects on behavior,

locomotor ability, speech, hearing and cognition ( Chan and Kilby, 2000). The LOAELs for decreased thyroid hormone levels in animal developmental toxicity studies ( Raghunath and Bala,

1998; Bala et al., 1996) are more than an order of magnitude higher than the NOAEL/ LOAEL boundary for changes in thyroid hormone levels in humans ( Dahlberg et al., 1984; Banerjee et al.,

1997) that forms the basis for the thiocyanate RfD. It is not clear, however, if there is a direct correlation between serum T3 levels and brain T3 levels. The brain changes in congenital hypothyroidism appear to be mediated by circulating T4, which is converted in the astrocytes to T3; it is the brain T3 levels that appear to be key for determining neurodevelopmental effects ( Koibuchi and Chin, 2000). The degree of decrease in serum T4 that results in neurodevelopmental effects has not been determined. In addition, thyroid hormones are Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 5 controlled by a negative feedback loop, and rats rapidly up regulate serum thyroid hormone levels. Because of this rapid feedback, the peak degree of change in hormone levels in the developmental toxicity studies could have been much larger at earlier time points. Since developmental toxicity depends on exposure during a critical developmental window, a large, but brief, change in thyroid hormone levels might result in marked neurodevelopmental effects. This means that the ratio between the free standing LOAELs identified for changes in thyroid hormone levels in rat pups and the short term NOAEL ( in the same species) for this effect may be more than an a factor of ten. Because a short term decrease in T4 levels ( of sufficient magnitude) can affect neurodevelopment if the change occurs during the window of sensitivity, even short term deviations are of concern. Based on these considerations, a neurodevelopmental toxicity study would be important in determining whether the brain is affected at doses below those observed to affect serum hormone levels in rat pups. If neurodevelopmental toxicity occurs at these lower doses, fetuses and children would constitute a sensitive population.

People with hypothyroid disorders, and protein or iodine deficiency may also be more sensitive to the thyroid effects of thiocyanate ( Kreutler et al., 1978). Protein deficiency is rare in Western populations ( U. S. FDA, 1999), but the percentage of the U. S. population that may be at risk for hypothyroidism resulting from iodine deficiency may be as much as a few percent ( Hollowell et al., 1998). Studies in human populations that eat cyanide containing foods, such as cassava, also suggest that an increased susceptibility to thyroid effects may be associated with deficiencies of protein, iodine, vitamin B 12, or other vitamins, although an etiological agent other Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 6 than cyanide has also been proposed as the cause of the tropical neuropathies ( reviewed in ATSDR, 1997).

The central nervous system is the primary target of acute exposure to cyanide, with symptoms including depression, convulsions, coma and death. Cyanide appears to exert its acute toxic effects by binding with cytochrome c oxidase, which then becomes unable to catalyze the reactions that transfer electrons from reduced cytochrome c to oxygen. These effects have been reported in animals and humans following high level exposures.

CNS effects are also observed following longer term exposure to cyanide, with myelin degeneration of the spinal cord observed in rats exposed in food for 1 year ( Philbrick et al., 1979).

Long term exposure to cyanide also causes thyroid effects due to the cyanide metabolite thiocyanate. Philbrick et al. ( 1979) reported decreased T4 levels and increased thyroid weights,

but no histopathology changes in the thyroid. A recent subchronic study conducted up to slightly lower doses ( NTP, 1993) did not report histopathology in the nervous system or thyroid, but did observe male reproductive effects ( decreased epididymal weight, testis weight, and sperm count).

Thyroid hormone levels were not measured in this study. No data were located that describe the mechanism of cyanide's toxicity on the male reproductive system, although NTP ( 1993)

suggested that the effects may be related to perturbations in hormonal balance. The male reproductive effects observed by NTP ( 1993) are the critical effects for the development of the cyanide RfD. Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 7 The database for cyanide includes subchronic studies in rats, mice, and dogs ( Philbrick et al., 1979; Kamalu, 1993; NTP, 1993), and a chronic study that did not evaluate the thyroid ( Howard and Hanzal, 1955). No study on the effects of cyanide on reproductive function in males have been located, and no standard developmental toxicity studies of cyanide are available.

The absence of a study evaluating reproductive function and of a developmental toxicity study are of particular concern, in light of the histopathological changes to the male reproductive organs ( NTP, 1993). Since exposure to low levels of cyanide may potentially cause thyroid hormone changes, and agents that affect thyroid hormone levels may affect neurological development, the potential neurodevelopmental toxicity of cyanide is an important data gap. If neurodevelopmental toxicity occurs at these lower doses, fetuses and children would constitute a sensitive population.

As for thiocyanate, people with hypothyroid disorders, or deficiencies in protein, iodine, vitamin B 12, or other vitamins may also be more sensitive to the thyroid effects of cyanide.

A further uncertainty for cyanide is whether the observed lesions progress with increasing exposure duration. Although no data are available on progression of testicular effects, it does not appear that liver effects progress with increasing exposure to cyanide. Based on the increased liver weight in rats exposed to 12 mg CN/ kg day for 21 days ( Palmer and Olson, 1979) and the absence of an effect on liver weight at the same dose in male rats exposed for 13 weeks ( NTP,

1993), also via drinking water, there was no progression in liver effects ( actually, a regression)

with increased exposure duration. Similarly, progression would not be expected for the thyroid effects, because the thyroid responds rapidly to iodine like ions, and thiocyanate does not Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 8 accumulate in the body. Together, these data suggest that cyanide's effects on the male reproductive tract may also not progress, but no data directly addressing that issue are available.

In light of the paucity of data on cyanogen chloride, there are a number of data gaps for this assessment. A primary issue is the quantitative identification of metabolites to address whether metabolites in addition to cyanide and thiocyanate are produced. Ideally, these data would be collected from an in vivo metabolism study in which all metabolites are tracked and quantified, although an in vitro study using cell extracts that investigates and quantifies all metabolites would help to address these issues. A related issue is determining the relative amounts of cyanide and thiocyanate produced from dosing with cyanogen chloride, particularly since thiocyanate can be converted back to cyanide in the body. In the absence of any toxicity data on cyanogen chloride collected according to modern toxicology methods, a subchronic oraltoxicity study that meets EPA test guidelines is needed to meet the minimal database requirement for development of a cyanogen chloride RfD from cyanogen chloride data. Based on information from cyanide, thiocyanate, and the putative metabolites, particular attention in such a study should be paid to the nervous system ( e. g., histopathology that could detect demyelination), thyroid,

male reproductive tract, and liver; a developmental toxicity study ( particular neurodevelopmental toxicity) would also be useful. In the absence of such a high quality subchronic study of cyanogen chloride, a short term study that includes a thorough histopathology analysis could at least confirm key targets of cyanogen chloride, and aid in the determination of the appropriate surrogate( s). Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 9 B. Dose Response Characterization and Implications in Risk Assessment In the absence of adequate data on cyanogen chloride, data on surrogates were used to develop the cyanogen chloride RfD. The data are insufficient for the derivation of an RfC for cyanogen chloride, particularly since cyanogen chloride appears to cause portal of entry effects that may be due to the parent compound. In the development of the RfD, data on cyanide and thiocyanate were emphasized, because these are the only metabolites that have been identified.

In the absence of adequate human or animal data on cyanogen chloride, the cyanogen chloride RfD was derived from the RfD for free cyanide, taking into account the molecular weights of cyanogen chloride and free cyanide ( CN). Using the NOAEL/ LOAEL approach, a cyanide RfD of 0.005 mg CN/ kg day was calculated, corresponding to a cyanogen chloride RfD of 0.01 mg/ kg day. Using the benchmark dose approach, a cyanide RfD of 0.0008 mg CN/ kg day was calculated, corresponding to a cyanogen chloride RfD of 0.002 mg/ kg day. The updated cyanide RfD was based on male reproductive effects ( decreased epididymal weight, testis weight,

and sperm count) in a subchronic drinking water study in rats ( NTP, 1993). There is some uncertainty in the identification of the NOAEL, since decreases in left cauda epididymis weight and sperm motility were observed at the NOAEL of 4.5 mg CN/ kg day, and at the next lower dose of 1.4 mg CN/ kg day. NTP ( 1993) did not consider the effects on sperm motility to be adverse because they were small and well within the range of historical controls. Similarly, the decrease in left cauda epididymus weight was small at 1.4 and 4.5 mg/ kg day, and there was little Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 10 evidence of a dose response at these doses. The uncertainty in the identification of the NOAEL is reflected in the fact that the study BMDL of 0.79 mg/ kg day ( for decreased left epididymis weight) is much lower than the study NOAEL. This BMDL was considered appropriate as an alternative basis for the RfD, because the effect is biologically significant and an adequate fit to the data was obtained. In addition, this BMDL is supported by a BMDL of 1.3 mg/ kg day obtained in the same study for two different measures of decreased spermatid count.

Based on these RfDs, a Lifetime HA for cyanogen chloride of 0.08 mg/ kg day ( based on the cyanide NOAEL) or 0.01 mg/ kg day ( based on the cyanide BMDL) was calculated.

A total uncertainty factor of 1000 was used to derive the cyanide RfD. Full factors of 10 were used to account for extrapolation from animals and for human variability. A factor of 10 was used to account for both subchronic to chronic extrapolation and for deficiencies in the database ( combined). No standard multigeneration or developmental toxicity studies of cyanide are available. As noted above, the absence of a study evaluating reproductive function and of a developmental toxicity study ( particularly a neurodevelopmental study) are of particular concern,

since the current critical effect is histopathological changes to the male reproductive organs ( NTP,

1993) and agents that affect thyroid hormone levels may also affect neurological development.

The combined uncertainty factor was based on an endpoint by endpoint evaluation of the potential for progression with increased dose duration, and the implications for database deficiencies. Factors considered included: ( 1) the rapid response of the thyroid to the cyanide Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 11 metabolite thiocyanate and the lack of progression of thyroid related effects from subchronic to chronic exposure; ( 2) the general absence of progression seen in studies of cyanide toxicity; ( 3)

the uncertainty as to whether the effects on the male reproductive tract are caused by cyanide or thiocyanate; and ( 4) the absence of information specifically on progression of reproductive effects from cyanide toxicity.

There is medium confidence in the principal study for the cyanide RfD. The study ( NTP,

1993) was generally well conducted, using an appropriate number of animals for that study duration ( 20/ sex/ dose), and examined a range of endpoints, but it did not evaluate thyroid hormone levels, the likely critical effect. The database includes systemic toxicity studies in several species, but does not include any standard reproductive or developmental toxicity studies, or any evaluations of effects on neurodevelopment. Accordingly, there is medium confidence in the cyanide database, and in the overall cyanide RfD.

For the cyanogen chloride RfD, the same medium confidence principal study was used.

Confidence in the database is low, however, since extrapolation from a surrogate was needed.

The resulting confidence in the cyanogen chloride RfD is low. Indeed, in light of the lack of data for cyanogen chloride, the database for cyanogen chloride is far less complete than the minimal database in order to derive a " low confidence" RfD. Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 12 Derivation of the cyanogen chloride RfD from the thiocyanate RfD was also considered.

The thiocyanate RfD of 0.001 mg/ kg day was calculated based on two human studies defining a NOAEL/ LOAEL boundary for effects on the thyroid. Dahlberg et al. ( 1984) observed no effects on serum T3, T4, TSH, or the T3: T4 ratio in 37 volunteers administered 8 mg/ day thiocyanate in milk ( 0.11 mg SCN/ kg day) for 12 weeks, and Banerjee et al. ( 1997) observed decreased serum T4 and increased TSH compared to matched controls in 35 women in India who ingested thiocyanate in milk for at least 5 years. There is considerable uncertainty in the doses in these studies, since subject body weights were not reported. Dahlberg et al. ( 1984) was conducted in Sweden with men and women, while Banerjee et al. ( 1997) was conducted in India with women only; average body weights of both of these populations are likely to be rather different from those in the United States. [ For this assessment, the usual default average body weight of 70 kg was assumed for the Swedish cohort, based on the assumption that this cohort would be comparable to the U. S. population. An average body weight of 60 kg was used for the Indian cohort, because it included only women, and because Indian women tend to be smaller than the average American woman, for whom the default average body weight is 65.4 kg ( U. S. EPA,

1997b)]. In addition, there was inter subject variability in dose within a study, since body weight varied and all of the subjects received the same dose in mg/ day. It is also unknown whether the Indian population had a borderline protein intake, which would mean that they constitute a sensitive population. Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 13 A total uncertainty factor of 100 was used to derive the thiocyanate RfD. A default uncertainty factor of 10 was applied to protect sensitive subpopulations. A factor of 10 was applied for database deficiencies, because a developmental NOAEL for effects on the thyroid has not been identified. This is of particular concern because neurodevelopmental effects are known to result from decreased T4 levels, and no neurological effects were evaluated in pups exposed to thiocyanate during gestation.

There are several uncertainties in using a surrogate for the estimation of the cyanogen chloride RfD and DWEL. A primary uncertainty is for the estimation of the cyanogen chloride RfD is the choice of a surrogate. Cyanide was selected as the surrogate for cyanogen chloride based on the fact that it is a known metabolite that represents a major part of the cyanogen chloride dose. Although the cyanide RfD is not the lowest RfD of the known or potential metabolites, the toxicokinetics of ingested cyanide and cyanogen chloride are likely to be sufficiently similar that cyanide is a reasonable surrogate. In contrast, the toxicokinetics of thiocyanate formation from cyanogen chloride are unknown. Given that a portion of an ingested cyanide dose would react or be excreted prior to metabolism to thiocyanate, the derivation of a thiocyanate RfD that is lower than the cyanide RfD is not inconsistent with the fact that cyanide is metabolized to thiocyanate. As discussed in Chapter 8, it is appropriate to use cyanide as a surrogate instead of thiocyanate, even though some cyanogen chloride may be metabolized directly to thiocyanate and the thiocyanate RfD is lower than the cyanide RfD. This is because ( 1)

there would be considerable uncertainty in using thiocyanate as a surrogate, since there is Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 14 inadequate quantitative information on the degree of cyanogen chloride metabolism directly to thiocyanate, although a rough estimate is possible by comparison with the amount of cyanogen chloride metabolized to cyanide; ( 2) a relatively small amount of thiocyanate (< 20% of the cyanogen chloride dose) would be formed directly from cyanogen chloride at environmental exposure levels; and ( 3) the conservatism lost by not using thiocyanate is well within the uncertainty of the method. Less than complete conversion of cyanogen chloride to cyanide and thiocyanate, such as by reaction with stomach contents or formation of other metabolites, would reduce the tissue dose of cyanide and thiocyanate, adding additional conservatism to the assessment. Cyanate and cyanamide have not been identified after in vivo or in vitro metabolism of cyanogen chloride, and would account for a relatively small portion ( if any) of the ingested cyanogen chloride dose, so they are less appropriate surrogates than cyanide. An additional uncertainty is that the critical effect for cyanide, male reproductive toxicity, was not evaluated in the limited studies on cyanogen chloride. However, it is plausible that male reproductive toxicity could be observed following long term exposure to cyanogen chloride, since cyanide is a major metabolite.

A second uncertainty is how to extrapolate quantitatively from the cyanide RfD to cyanogen chloride. For this assessment, a simple adjustment was made based on molecular weight. However, the degree of conversion of cyanogen chloride to cyanide at environmentally relevant doses is unknown, and it is not known whether cyanide and thiocyanate together account for all of the cyanogen chloride metabolism. Cyanide accounts for approximately 30 40% of the Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 15 cyanogen chloride dose at high doses, and at least 60 80% at lower doses ( Aldridge and Evans,

1946; Midwest Research Institute, 1997).

The data on the toxicity, kinetics, and dynamics of cyanide are sufficient to support the development of an RfD from the available experimental animal data. Standard assumptions were used in their development, and include:

1. the use of experimental animal data as a surrogate for humans;

2. the use of reproductive effects in rats as meaningful for extrapolating to human disease;

3. the use of factors based on a logarithmic scale ( 10, 3 or 1) that address additional scientific uncertainties in the overall database; and 4. the use of only 1 digit of arithmetic precision for the RfD, because our understanding of the underlying biology is unlikely to be more precise than this.

The use of these and similar assumptions is common practice in conducting dose response assessments by other environmental and health agencies throughout the world.

The Health Advisories for cyanogen chloride were also based on extrapolation from cyanide. In the absence of suitable studies on cyanogen chloride or a surrogate for a one day HA,

the Ten day HA for cyanide is used as a default. The Ten day HA for cyanogen chloride was 0.3 mg/ L, based on the molecular weight extrapolation from cyanide. The Ten day HA for cyanide was 0.1 mg/ L, based on increased liver weight in rats provided cyanide in drinking water for 21 Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 16 days ( Palmer and Olson, 1979), and using the default uncertainty factors of 10 for extrapolation from animals to humans, for human variability, and for extrapolation from a LOAEL The longer term HA for cyanide is based on the same study and endpoint as the cyanide RfD. For the cyanogen chloride values based on the cyanide NOAEL, the longer term HA for the child was 0.1 mg/ L, and the longer term HA for the adult was 0.4 mg/ L. These values were based on the longer term cyanide HA values of 0.05 and 0.2 mg/ L for the child and adult,

respectively. For the cyanogen chloride values based on the cyanide BMDL, the longer term HA for the child was 0.02 mg/ L, and the longer term HA for the adult was 0.07 mg/ L. These values were based on the longer term cyanide HA values of 0.008 and 0.03 mg/ L for the child and adult,

respectively. The critical effect was male reproductive toxicity. A composite uncertainty factor of 1000 was used, based on full factors of 10 each for extrapolation from animals to humans,

human variability, and database deficiencies. Except for the issue of progression of effects with increasing exposure duration, the uncertainties discussed above in the context of the RfD apply.

The potential for neurodevelopmental effects is of particular concern. Using an RSC of 20%, a Lifetime HA of 0.08 mg/ L was calculated for cyanogen chloride, based on the NOAEL based cyanide Lifetime HA of 0.03 mg/ L. Using the same RSC of 20%, an alternative Lifetime HA of 0.01 mg/ L was calculated for cyanogen chloride, based on the BMDL based cyanide Lifetime HA of 0.006 mg/ L. Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 17 C. Weight of Evidence and Implications in Risk Conclusions There are no cancer bioassays and no data on the potential genotoxicity of cyanogen chloride, although a QSTR analysis predicted that cyanogen chloride was negative for carcinogenicity in rats and mice ( Moudgal et al., 2000). Therefore, surrogates were used to evaluate the carcinogenic potential of cyanogen chloride. There are no cancer bioassays of cyanide and no well conducted standard cancer bioassays of thiocyanate. Two oral carcinogenicity studies in rats were conducted in the same laboratory ( Lijinsky and Reuber, 1982;

Lijinsky and Kovatch, 1989). The only effect in the first study was an increase in liver tumors,

and this was not confirmed at the higher dose tested in the second study, although a nonstatistically significant increase in thyroid tumors was observed. However, these studies suffer from a number of limitations. Only a single dose was tested in each study, only 20/ group were tested, and the assay continued until all of the animals died ( increasing the background incidence of age related tumors).

The overall data on the genotoxicity of cyanide, thiocyanate, and the putative metabolites of cyanogen chloride suggest that none of the metabolites are genotoxic, although the data are limited. Cyanide has generally been negative in bacterial mutagenicity assays ( De Flora, 1981, De Flora et al., 1984; NTP, 1993) and assays of DNA damage and repair ( De Flora et al., 1984;

Painter and Howard, 1982), although a positive result was obtained in one strain of Salmonella with and without S9 activation ( Kushi et al., 1983). No assays of mammalian gene mutation or Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 18 chromosome aberration are available. Genotoxicity data on thiocyanate are limited to marginal results in a S. typhimurium mutagenicity assay ( Kier, 1988, as reported by Rosenkranz and Klopman, 1990). Potassium thiocyanate does not have any structural alerts for genotoxicity ( Rosenkranz and Klopman, 1990). The limited genotoxicity results available on the putative metabolites cyanate and cyanamide were also generally limited.

Based on these considerations, cyanogen chloride, cyanide, and thiocyanate are classified as Group D, Not Classifiable as to Human Carcinogenicity, using the U. S. EPA ( 1986) guidelines.

Using the U. S. EPA ( 1999) Draft Guidelines for Cancer Risk Assessment, the data are inadequate for an assessment of the human carcinogenic potential of cyanogen chloride, cyanide,

and thiocyanate. The primary data gap is the absence of standard carcinogenicity bioassays for cyanogen chloride, or appropriate surrogates ( cyanide, thiocyanate). There are also gaps in the standard battery of genotoxicity testing for the surrogates. For example, no mammalian gene mutation or chromosome aberration assays are available for cyanide, and the only study of the standard battery available for thiocyanate is the bacterial mutagenicity assay.

D. Exposure Characterization and Implication in Relative Source Contribution Since cyanide is the primary metabolite of cyanogen chloride and the surrogate used for the dose response assessment, this section includes exposure characterization for both cyanogen chloride and cyanide. This characterization could be enhanced by including thiocyanate, since Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 19 cyanide is metabolized to thiocyanate, and thiocyanate accounts for at least some of the toxic effects of cyanide exposure. Exposure to cyanate and cyanamide are of less concern, since they represent a small portion of the cyanogen chloride dose, and they are not metabolized through the cyanide/ thiocyanate pathway.

Cyanogen chloride. There are very limited quantitative data on the presence of cyanogen chloride in the environment and on cyanogen chloride exposure. There is no information in the available literature on the concentration of cyanogen chloride in the air and no quantitative data on dietary levels. One investigator found that cyanogen chloride may be produced from the reaction of instant tea with water containing chloramine residual. In addition, there is no information in the available literature on dermal exposure to cyanogen chloride or on cyanogen chloride body burden. The National Occupational Exposure Survey ( NOES) conducted by the National Institute for Occupational Safety and Health from 1980  1983 estimated that 1393 workers were exposed to HCN. However, no information on exposure levels was provided. The only quantitative data available are drinking water concentrations.

Based on information in the ICR database ( U. S. EPA, 2000b), the mean concentrations of cyanogen chloride in distribution system surface water and groundwater were 3.02 and 1.63

g/ L,

respectively. Since cyanogen chloride is formed primarily from the reaction of chlorine with organic material in the presence of ammonia, only drinking water plants that used chloramine as a primary or secondary disinfectant were required to monitor for cyanogen chloride. The mean Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 20 concentration of cyanogen chloride in surface water was statistically greater ( at p = 0.05) than the mean cyanogen chloride concentration in groundwater. Therefore, a mean concentration of 3.02

g/ L was selected for later calculations, as a conservative estimate of the exposure for people served by water treatment plants that use chloramine. The ICR database reported that 35% of water treatment plants using surface water, and 23% of the plants using groundwater used chloramine as a primary or secondary disinfectant and reported cyanogen chloride observations.

Therefore, if the type of plants sampled in the ICR survey are representative of those throughout the U. S., and if the plants using chloramine are similar in size and numbers of population served to plants using different treatment methods, it could be argued that 23% to 35% of the population would be exposed to cyanogen chloride drinking water concentrations of approximately 3.02

g/ L. However, according to the WHO Environmental Health Criteria Monograph on Disinfectants and Disinfectant Byproducts ( WHO, 2000), cyanogen chloride may be formed during disinfection with other disinfectants when ammonia is present in the source waters.

Therefore the percentage of plants for which the treated drinking water contains cyanogen chloride may be under represented in the ICR database. In addition, the ICR database includes only those very large surface and ground water systems serving at least 100,000 persons. The smaller systems, serving less than 100,000 persons, are not represented. However, examination of the NCOD cyanide data using the Student's t test indicates that there was no statistically significant difference between the cyanide concentrations in the different size systems. Therefore,

if cyanogen chloride concentrations follow a similar pattern, the size of the system may not make much difference. Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 21 There is, however, considerable variability in the cyanogen chloride concentrations to which an individual may be exposed. As shown in Chapter 4, the 10th percentile for cyanogen chloride concentrations in distribution system surface water was 0

g/ L, while the 90th percentile of cyanogen chloride concentrations was 8.0

g/ L.

At a mean concentration of 3.02

g/ L cyanogen chloride, a 70 kg adult ingesting 2 L/ day drinking water would consume 0.09

g/ kg day ([ 3.02

g/ L * 2 L/ day]/ 70 kg) cyanogen chloride.

For a 10 kg child ingesting 1 L/ day, a concentration of 3.02

g/ L cyanogen chloride would result in a daily dose of 0.3

g/ kg day ([ 3.02

g/ L * 1 L/ day]/ 10 kg). An adult and child ingesting 8.0

g/ L ( the 90th percentile concentration) would receive a dose of 0.23 and 0.8

g/ kg day,

respectively.

The relative source contribution ( RSC) for cyanogen chloride is derived by application of the Exposure Decision Tree approach published in EPA's Methodology for Deriving Ambient Water Quality Criteria for the Protection of Human Health ( U. S. EPA, 2000d). An RSC of 20%

accounts for the likelihood of exposure to cyanogen chloride or cyanide from sources other than tap water, such as ambient air and food, in the absence of adequate data. This value also takes into account the potential for exposure to cyanide ( a key cyanogen chloride metabolite) via food,

air, and smoking, as described in the next paragraphs. The data are not adequate enough to quantify the contributions of each source for an overall assessment of exposure. Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 22 Cyanide. Compared to cyanogen chloride, there are more data on the presence of cyanide in the environment and cyanide exposure.

The ICR database does not include information on cyanide levels. However, information on cyanide levels in drinking water for the year 2000 were available from the NCOD survey. As discussed in Chapter 4, average cyanide concentrations in treated surface water and groundwater of systems that detected cyanide were reported as 2844

g/ L and 2194

g/ L, respectively; these numbers are not statistically significantly different. However, cyanide was detected infrequently,

in 7% of the plants using surface water as a source, and in 3% of the plants using groundwater as a source. In addition, in most water system size groupings, there were several orders of magnitude separating the minimum and maximum detected levels, and only a few analyses with detects (< 3% samples in surface water, < 2% samples in groundwater). This means that the calculated averages for these populations may be highly influenced by one or two systems with high cyanide levels, and that the calculated averages do not accurately reflect the cyanide concentrations to which these populations are exposed. Medians were not available from the NCOD survey. Despite these caveats, a conservative mean concentration of 2844

g/ L was selected as representative of the concentration of cyanide in drinking water, in the absence of more representative data. This is because, if the type of plants sampled in the NCOD survey are representative of those throughout the U. S., and if the plants detecting cyanide are similar to plants not detecting the presence of cyanide in the size and numbers of people served, it could be Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 23 argued that approximately 3% to 7% of the population would be exposed to cyanide concentrations of 2844

g/ L ( on average) in drinking water.

At a conservative average concentration of 2844

g/ L HCN, a 70 kg adult ingesting 2 L/ day drinking water would consume 81

g/ kg day ([ 2844

g/ L * 2 L/ day]/ 70 kg) HCN.

Although the 10th and 90th percentiles were not provided in the NCOD database, there is considerable variability in the cyanide concentrations, ranging from a minimum value of 0

g/ L to a maximum value of 32,700

g/ L. The number of samples at the high end is, however, unknown.

Ambient air concentrations of HCN in the northern hemisphere's non urban troposphere ranged from 160 to 166 ppt ( 177 ng/ m3 to 184 ng/ m3). Although ambient air monitoring data of HCN near source areas ( e. g., HCN manufacturing industries, coke production industries,

wastedisposal sites) could not be located in the available literature, HCN concentrations in these areas are expected to be higher than the non urban tropospheric concentrations. Based on an atmospheric concentration of 170 ppt ( 188 ng/ m3) and a daily average inhalation rate of 20 m3,

the ATSDR ( 1997) Toxicological Profile for Cyanide estimated an inhalation exposure to the general U. S. non urban, nonsmoking population of 3.8

g HCN/ day. This would be equivalent to a daily dose to a 70 kg adult of approximately 54 ng/ kg day HCN ([ 3.8

g HCN/ day]/ 70 kg).

Children, with a higher inhalation rate to body weight ratio, would receive a higher dose on a body weight basis. Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 24 Smokers and those exposed to secondary tobacco smoke make up a subset of the general population that may be exposed to elevated levels of HCN. Smokers could be exposed to 10 to 400

g HCN per cigarette, whereas nonsmokers exposed to sidestream smoke could be exposed to 0.06 to 108

g HCN/ cigarette. Depending on the amount smoked per day, the HCN exposure from cigarette smoke could be substantial.

Based on information presented in the ATSDR ( 1997) Toxicological Profile for Cyanide,

between 1981 to 1983, 4005 workers were potentially exposed to HCN. NIOSH found HCN in the workplace air at concentrations ranging from 0.001 to 4.3 mg/ m3. Although the ATSDR document provided no information on the amount of time and frequency that these workers were exposed to these concentrations of HCN, these levels were below the NIOSH recommended 15

min short term exposure limit ( STEL) of 5 mg/ m3 for HCN.

HCN is also a metabolite of a number of industrial chemicals ( acetonitrile, propionitrile,

acrylonitrile, n butyronitrile, maleonitrile, and succinonitrile). As a result, occupational or environmental exposure to these chemicals could contribute to the background levels of HCN in biological fluids. HCN is also a metabolite of pharmaceuticals such as Laetrile and a drug used to reduce high blood pressure, and clinical use of these compounds could increase internal exposure to HCN. Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 25 Although concentrations of HCN in foods are expected to be low, one author ( Fiksel et al., 1981) estimated that HCN intake from inhalation of air and ingestion of drinking water would be less than the intake from food. The ATSDR document ( ATSDR, 1997) did not provide information on the cyanide concentrations in air and water that Fiksel et al. ( 1981) used to come to this conclusion. In addition, estimates of the HCN concentration in the total diet were not located in the available literature. Therefore, no independent estimate of daily HCN intake from food could be made, nor could any comparison with HCN intake from other sources be made.

Although there is more information on HCN than on cyanogen chloride, the data are not adequate to quantify the contributions of each source for an overall assessment of exposure. The data do indicate, however, that there is potential for exposure to cyanide via food, air, and smoking. Using the Exposure Decision Tree approach published in EPA's Methodology for Deriving Ambient Water Quality Criteria for the Protection of Human Health ( U. S. EPA,

2000d), an RSC of 20% is used to account for the likelihood of exposure to cyanide from sources other than tap water.

E. Risk Characterization for Drinking Water Exposure Segments of the population with an elevated exposure to cyanogen chloride have not been identified. However, there are a number of groups that would have elevated exposure to cyanide from sources other than drinking water. A major source of potential cyanide exposure is in Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 26 cigarette smoke and through passive smoking. Smokers may be exposed to 10 to 400

g HCN per cigarette, and passive exposure of nonsmokers to sidestream smoke ranges from 0.06 to 108

g HCN/ cigarette. The actual dose would depend on the number of cigarettes smoked per day.

The dose from sidestream smoke could be higher for children than adults on a body weight basis,

because of the child's higher inhalation rate to body weight ratio. Occupational exposure to nitriles ( e. g., acetonitrile, propionitrile, acrylonitrile) would also increase the internal dose of cyanide, since these compounds are metabolized to cyanide. The cyanide dose resulting from inhalation exposure of the general U. S. non urban, nonsmoking population is approximately 54 ng/ kg day HCN, based on an average atmospheric concentration of 170 ppt ( 188 ng/ m3) and a daily average inhalation rate of 20 m3. As noted above for passive smoking, the dose to children on a body weight basis would be higher. People living or working near source areas ( e. g.,

HCNmanufacturing industries, coke production industries, waste disposal sites) would be exposed to higher atmospheric concentrations of HCN. Finally, some pharmaceuticals, such as Laetrile and a drug used to reduce high blood pressure, also result in exposure to cyanide. The available information is insufficient to quantify the variability resulting from these sources of higher exposure.

Although concentrations of cyanide in foods are expected to be low and quantitative data on the cyanide concentration in foods is sparse, the cyanide intake from food ingestion is expected to exceed HCN intake from inhalation of air and ingestion of drinking water. People eating large amounts of food containing large amounts of cyanogenic glycosides would have Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 27 elevated exposure to cyanide, particularly if these foods are not prepared in a way that removes the cyanogenic compounds. In particular, people eating large amounts of cassava root, such as immigrants from Africa or some South American countries, may have elevated exposure. People eating large amounts of canned fruits with pits could also have elevated exposure.

Cyanogen chloride was measured only in systems using chloramine as a primary or secondary disinfectant ( 35% of the surface water plants and 23% of the groundwater plants).

Even among the plants using chloramine, cyanogen chloride was not detectable at the distribution system maximum for 22% of the systems using surface water and 39% of the systems using groundwater. On the other hand, WHO ( 2000) and Richardson ( 1998) reported that ammonial compounds in the source water can react with chlorine and form cyanogen chloride in the absence of chloramination. Therefore, the number of plants where cyanogen chloride may be present may be under represented in the ICR database. Subject to this uncertainty regarding the conditions under which cyanogen chloride is formed, it appears that approximately 23% to 35% of the population would be exposed to cyanogen chloride in drinking water. This estimate also assumes that the population distribution in the systems using chloramine is representative of all public drinking water systems in the U. S. A conservative average concentration of 3.02

g/ L can be obtained from the ICR. This concentration is approximately two orders of magnitude lower than the 10 day cyanogen chloride HA of 0.3 mg/ L ( 300

g/ L). Using the health advisories based on the NOAEL for comparison, the average cyanogen chloride concentration of 3.02

g/ L is at least a factor of 30 lower than the Longer term child HA of 0.1 mg/ L ( 100

g/ L) and the Longer term Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 28 adult HA of 0.4 mg/ L ( 400

g/ L). It is also more than one order of magnitude lower than the Lifetime HA of 0.07 mg/ L ( 70

g/ L). Using the more conservative health advisories based on the BMDL for comparison, the average cyanogen chloride concentration of 3.02

g/ L is at least a factor of 6 lower than the Longer term child HA of 0.02 mg/ L ( 20

g/ L ) and more than an order of magnitude lower than the Longer term adult HA of 0.07 mg/ L ( 70

g/ L). It is also approximately a factor of 3 lower than the Lifetime HA of 0.01 mg/ L ( 10

g/ L). Thus, even using the more conservative approach of basing the health advisories on the cyanide BMDL,

average drinking water concentrations are below the relevant health advisories.

Cyanide was detected in 7% of the public water supplies using surface water as a source,

and in only 3% of the public water supplies using groundwater as a source. Therefore, exposure to cyanide in drinking water for most of the population is minimal. However, at least some of this small percentage of the population has exposures well above advisory levels. For example, of the systems with detectable levels of cyanide, the overall average concentration of cyanide in surfacewater systems of all sizes was 2844

g/ L ( 2.8 mg/ L). However, as discussed above, this average may represent only a few water systems, in light of the large difference between the minimum and maximum detected levels and the few analyses with detects. Additional information on typical exposure levels could be provided by consideration of median concentrations, but medians were not available from the NCOD survey. In the absence of more representative information about typical exposure levels, the average concentration for this small percentage of the population was compared to the cyanide health advisories. The average of 2844

g/ L is more than an order of Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 29 magnitude above the Ten day HA of 0.1 mg/ L. Using the health advisories based on the NOAEL,

this concentration is also more than an order of magnitude above the Longer term child HA of 0.05 mg/ L, almost two orders of magnitude above the Lifetime HA of 0.03 mg/ L, and approximately five times the Longer term adult HA of 0.5 mg/ L. Using the health advisories based on the BMDL, the drinking water concentration is approximately two orders of magnitude above the corresponding health advisories. These comparisons suggest that populations with elevated cyanide levels in their drinking water may be at risk. Based on the wide variability in exposure and the large numbers of nondetects, it appears that relatively few systems would have such elevated levels, but no definitive statement regarding the size of the population at risk is possible in the absence of NCOD data on median concentrations. In addition, it should be noted that the RfD is an estimate " within an order of magnitude.... that is likely to be without an appreciable risk of deleterious effects during a lifetime." Thus, a small subset of the population that lives at the same residence ( served by the same, unchanged water treatment facility) for their entire lifetime (~ 70 years), may be at risk. However, the average number of years that a person in the United States remains in their current residence was determined to be 9 years ( 50th percentile value). The upper 90th percentile estimate of residence time was 33 years ( U. S. EPA, 1997b).

Less than one percent of the population in the United States lives at the same residence for more than 55 years ( U. S. EPA, 1997b).

As discussed in greater detail in Chapter 7, males may be a sensitive population for the effects of cyanide and cyanogen chloride, because the critical effect occurs in male reproductive Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 30 organs. However, it is unclear if this is the true critical effect for cyanide exposure, in the absence of measures of thyroid hormone levels, and in the absence of neurodevelopmental toxicity testing. Children are also a potential target of concern, due to the potential for neurodevelopmental effects resulting from the effects on thyroid hormones of the cyanide metabolite thiocyanate.

F. Comparison With Other Standards The World Health Organization ( WHO) does not have a drinking water guideline for cyanogen chloride, but WHO did establish a drinking water guideline of 0.07 mg/ L for cyanide as total cyanogenic compounds ( WHO, 1996). This value was based on a LOAEL of 1.2 mg/ kg day for effects on behavioral patterns and serum biochemistry in a drinking water study in pigs ( Jackson, 1988). Uncertainty factors of 10 each were used for inter and intraspecies variation;

no additional factor for a LOAEL was considered necessary because of doubts regarding the biological significance of the observed changes. A guideline value of 0.07 mg/ L is calculated from this TDI ( similar to an RfD) using a 20% allocation of the total daily intake to drinking water, a 60 kg body weight, and daily intake of 2 L/ day. The NTP ( 1993) study was apparently not available for the WHO assessment, which was largely completed by 1993.

Health Canada has established a maximum allowable concentration of cyanide in drinking water of 0.2 mg/ L ( Health Canada, 2001), based on the study by Howard and Hanzal ( 1955). Drinking Water Criteria Document for Cyanogen Chloride and Potential Metabolites EPA/ OW/ OST/ HECD Final draft IX 31 The documentation for this value was developed in 1991, prior to the publication of the NTP ( 1993) subchronic study that was the basis for the cyanide RfD presented here. Health Canada does not have a drinking water standard for cyanogen chloride.