? UNITED STATES ENVIRONMENTAL PEOTECTION AGENCY
WASHINGTON B.C. 20460
December 20, 1991
OFFICE OF
THE ADMMSTRATOR
SCIENCE .ADVISORV EOAKD
EPA-SAB-DWC-LTR-92-002
Honorable William K, Reilly
Administrator
U.S. Environmental Protection Agency
401 M Street, SW.
Washington, B.C. 20460
Subject; Science Advisory Board Review of the Office of Drinking Water
(ODW) Issue Paper on Cyanogen Chloride
Dear Mr, Reilly;
The Drinking Water Committee (DWC) of the Science Advisory Board met in
Washington, D.C. April 4-5, 1991 to review, among other topics, the Office of Drinking
Water issue paper on cyanogen chloride. The DWC was asked to comment on the
appropriateness of using hydrogen cyanide (HCN) toxicity data as a surrogate for cyanogen
chloride (C1CN) data in developing a reference dose (RfD). Cyanogen chloride is a by-
product of chloramine disinfection that is being considered for regulation (June 1993) in
drinking water under the disinfection by-product rule. Currently there are no definitive
studies of C1CN for chronic or subchronic toxicity, mutagenicity, teiatogenitity, reproductive
or carcinogenic effects. Also, no environmental occurrence data on C1CN are available.
The Committee was charged with evaluating whether it is scientifically valid to use
HCN toxicity data to quantify C1CN toxicity or is it necessary to conduct research on the
toxicity of ingested C1CN to establish the basis for a risk assessment in the drinking water
guidelines.
The Committee recommends that the option of conducting research on the toxicity of
ingested C1CN be implemented. This recommendation is based primarily on the need to
ascertain that there are no adverse lexicological effects from C1CN at levels below the effects
exhibited by HCN before the Agency can confidently employ safe criteria based on HCN
requirements. Since such direct experimental evidence has not been acquired, it is premature
to adopt criteria based on HCN,
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The following factors were addressed by the Committee in its discussion of the two
options presented:
1. Due to the fact that there is a paucity of lexicological data on which to make
an informed judgment, there is no a priori basis for concluding that any one
chemical reaction of cyanogen chloride will have a greater or lesser influence
on the compounds toxicity than any other. It depends on whether the
compound has sufficient stability to reach critical macroniolecular targets and
whether binding to such sites will have adverse biological consequences* The
basic difference between C1CN and HCN is the generation of a chloride
radical. Therefore, experiments should be conducted to determine if reactions
subsequent to formation of the radical have any toxicological significance.
Such reactions occur as C1CN is converted to cyanide, therefore, this question
cannot be addressed entirely by metabolic balance studies* It might be
addressed by examining the mutagenic activity of the compounds (C1CN &
HCN) in in vitro experiments, (e.g. do they form DMA adducts that lead to
mutation). The extent to which C1CN produces localised irritation of the
gastrointestinal tract in relationship to equimolar neutralized solutions of
potassium cyanide should be examined.
2. One of the first questions to be addressed in dealing with whether HCN data
should be a surrogate for C1CN data is to examine whether or not the body
really encounters C1CN as such. Pharmacokinetic studies following oral
administration are needed. These should address uptake, distribution,
metaboEsm and excretion. C1CN administered orally may undergo different
reactions then those seen with inhalation studies. The Committee recommends
that appropriate disposition studies be performed using dose-related
experiments following both Cl and CN radiolsbelled compounds taking care to
document the extent to which labelled chlorine exchanges with the body's
chloride pool. This would help answer this question. Since C1CN is stable at
low pH's (e.g. at the stomach's pH) it's reaction rate with glutathione (GSM)
may be partially inhibited by HC1, thus allowing for other nucleophilic
reactions to predominate.
3, Fourteen day oral administration studies as done by EPA for other chemicals
would be appropriate as weE as longer-term studies if, indeed, there is a
substantial amount of C1CN actually absorbed.
4. Although it may not be so important from the regulatory standpoint, from the
scientific standpoint it is important to really know if serum does detoxify, and
if this is related to albumin binding. This study could be incorporated into the
pharmacokinetic studies.
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5, Normally, it would be predicted from the literature related to CN reactivity
with rhodanese, that the major disposition of CN is through conversion of CN
to SCN'(CN"+ S2O4=-*SCN'+ SO4"). The limitation appears to be S204=
availability in a species. At low levels of C1CN, studies should be performed
to determine whether other reactions such as GSH interaction takes precedence
over the rhodanese reaction.
6. The Committee recommends that C1CN be administrated in life-time animal
experiments at several doses that are sublethal with respect to HCN (by-
product to GSH reaction) to allow any non HCN toxicological effects to be
expressed,
We appreciate having been given the opportunity to conduct this particular review.
We request that the Agency provide us with a formal response to this Advisory effort.
Sincerely,
RaymondC.fSihr, Chairman
Executive Commit
Verne A. Ray, Chairman^
Drinking Water Commi
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f
i
ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
DRINKING WATER COMMITTEE
CHAIRMAN
Dr. Verne lay, Medical Research Laboratory, Pfizer Inc., Groton, CT
Dr. William Glaze, University of North Carolina, Chapel Hill, NC, was Chairman during the
early part of FY91, but subsequently resigned his position due to the press of other
professional duties. Dr. Ray was appointed Chairman on October 1, 1991,
Dr. Richard Bull, College of Pharmacy, Washington State University, Pullman, WA
Dr. Gary Carton, Department of Pharmacology and Toxicology, School of Pharmacy, Purdue
University, West Lafayette, IN
* Dr. Keith E. Cams, East Bay Municipal Utility District, Oakland, CA
Dr. David Kaufman, Department of Pathology, University of North Carolina, Chapel Hill, NC
Dr. Nancy Kim, New York State Department of Health, Albany, NY
Dr. Ellen O'Flaherty, University of Cincinnati, Institute of Environmental Health, Concinnati,
OH
Dr. Edo D. PeUizzari, Research Triangle Institute, Research Triangle Park, NC
* Dr. Vern Snoeyink, Department of Civil Engineering, University of Illinois, Urbana, EL
* Dr. MarkD. Sobsey, Department of Environmental Sciences and Engineering, School of Public
Health, University of North Carolina, Chapel Hill, NC
* Dr. James Symons, Department of Civil and Environmental Engineering, University of
Houston, Houston, TX
Dr. Thomas TepMy, Department of Pharmacology, University of Iowa, Iowa City, IA
* Did not attend meeting.
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SCIENCE ADVISORY BOARD STAFF
Mr. A. Robert Flaak, Assistant Staff Director and Acting Designated Federal Official, Science
Advisory Board (A-101F), U.S. EPA, 401 M Street, SW, Washington, DC 20460
Dr. C, Richard Cothera, Designated Federal Official (during the review), Science Advisory Board
(A-101F), U.S. EPA, 401 M Street, SW, Washington, DC 20460
Mrs. Frances Dolby, Staff Secretary, Science Advisory Board (A-10IF), U.S. EPA, 401 M
Street, SW, Washington, DC 20460
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