., we FINAL DRAFT
Umted States
2C
V
Environmental Protection
Agency August, 1988
PA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CYANOHYDR1NS
Prepared for
OFFICE OF SOLID HASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and A
Office of Health and Enviroi
U.S. Environmental Protect!
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR C
EP 530
88-518
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Its technical accuracy and policy Implications. i
-------
DISCLAIMER
This report 1s an external draft for review purposes only and does not M
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for 1n this document
and the dates searched are 'Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial Hfei.me RfD, 1s an estimate of an
exposure level that would not be expected
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EXECUTIVE SUMMARY
CyanohydMns are a class of compounds that contain both a cyanide and a
hydroxy group 1n the aliphatic structure of a molecule. They are usually
colorless to straw yellow liquids that have an objectionable odor similar to
hydrogen cyanide. With the exception of benzaldehyde cyanohydrln, the
cyanohydMns discussed 1n this document are soluble In water; all five
cyanohydrlns are soluble 1n ethanol and a variety of other organic solvents
(Cholod, 1979). Generally, the cyanohydrlns decompose at high basic pH, but
are stable under acidic pH conditions (Sunde'-man and K1nca1d, 1953; Fomunyam
et al.f 1985). One of the Important processes for the production of the
cyanohydrlns Is the reaction of hydrogen cyanide with the appropriate
aldehyde or ketone In the presence of an add or an alkali as a catalyst.
Of the five cyanohydrlns, acetone cyanohydrln Is produced 1n the largest
amount 1n the United States. Currently, four companies manufacture 1082
million pounds of acetone cyanohydrln 1n the United States per year. Only
one company manufactures lactonHMle 1n the United States; the amount 1s
unknown. The manufacturers' names and the annual production volumes for the
other cyanohydrlns are not known (SRI, 1987; USITC, 1987). Cyanohydrlns are
used primarily as Intermediates In the manufacture of other chemicals. Some
of the products manufactured from cyanohydrlns are methyl methacrylate,
Insecticides and Pharmaceuticals. They are also used In metal refining, as
a solvent In fiber-spinning and as antiknock agents 1n fuel oil (Cholod,
1979).
The limited data available 1n the literature are not sufficient to
assess the fate and transport of cyanohydrlns In any medium with certainty.
1v
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In the atmosphere, cyanohydrlns may undergo direct photolysis, as photolysis
was found to occur 1n aqueous solutions (Shlrane, 1982). The estimated
half-life for the reaction of vapor-phase acetone cyanohydMn with photo-
chemical ly-generated HO radical Is >13 days (Singh et al., 1984). There-
fore, this reaction may not be significant In the removal of acetone cyano-
hydrln from the atmosphere. The high water solubility for many of the
cyanohydrlns Indicates that wet deposition would be a major removal pathway
for atmospheric cyanohydrlns. Since most rain waters have pH values <7, the
washed cyanohydrlns may be stable toward hydrolysis. In basic waters.
hydrolysis may be an Important pathway for the removal of cyanohydrlns
(Fomunyam et al., 1985). Loss of cyanohydrlns through blodegradatlon may be
an Important process 1n water, although no half-life value resulting from
this process can be assigned (Ludzack et al., 1958, 1959a,b, 1961; Dow
Chemical Co., 1986). The Importance of photolysis In the degradation of
aquatic cyanohydrlns remains unclear (Shlrane, 1982). Significant loss of
cyanohydrlns from evaporation may be unlikely. The «-cyanohydr1ns may
hydrolyze In basic soils, and blodegradatlon In soils may be an Important
process. Because of their expected low K , these compounds may have high
mobility In soil and may Infiltrate groundwaters.
There 1s a paucity of data on the levels of cyanohydrlns 1n any environ-
mental medium. Ethylene cyanohydrln has been detected qualitatively 1n the
expired air of predlabetlc patients, and Us origin has been speculated to
be metabolic (Krotoszynskl and O'Neill, 1982). Storage of crude essential
oil of bitter almonds has been shown to produce benzaldehyde cyanohydrln, in
situ, through a reaction of benzaldehyde and hydrogen cyanide naturally
present 1n the oil (Garnero, 1947). Two kinds of brandy and liqueur
manufactured from two varieties of sour cherries contained 0.0112 and 0.010X
-------
benzaldehyde cyanohydrln, and the source of the compound was traced to the
pits of fruit (KobHc, 1952). Similarly, foods produced by the hydrolysis
of cassava, used 1n South America and Africa, will contain acetone and
benzaldehyde cyanohydrlns (Fomunyam et al., 1985).
The acute toxldty of acetone cyanohydrln to all fish as demonstrated by
the 96-hour LC,-- ranged from 0.22 mg/SL for rainbow trout (EG&G
Bionomics, 1981a) to 1.37 -mg/l for gupples (Henderson et al., 1961).
Water hardness did not Influence the acute toxic effects of acetone cyano-
hydrln to fathead minnows (Henderson et al., 1961). Exposure of fathead
minnows to acetone cyanohydrln 1n a flowthrough study produced a lower
-»
LC5Q (0.71 mg/l) than that 1n a static test (0.9 mg/l) (Henderson et-
al., 1961). Toxlclty thresholds were reached relatively quickly (-24-48
hours) In acute studies exposing fish to acetone cyanohydrln. Toxldty of
acetone cyanohydrln to an Invertebrate, D. maqna. (48-hour LC5Q = 0.13,
95% confidence limit = 0.088-0.19 mg/l) was comparable to the toxldty of
acetone cyanohydrln to, rainbow trout (48-hour LC5Q = 0.22, 95% confidence
limit = 0.13-0.36 mg/l; EG&G Bionomics, 1981a,c).
Limited specific Information Is available regarding the pharmacoklnetlcs
of the a-hydroxyl cyanohydrlns. The a-hydroxyl cyanohydrlns appear to
be absorbed readily by all routes of exposure and converted extensively to
hydrogen cyanide and the corresponding ketone or aldehyde. Cyanide Is
converted primarily to thlocyanate and eliminated through the urine. It has
been demonstrated that acetone cyanohydrln behaves like Us molar equivalent
1n free cyanide in vitro and in vivo (W1llh1te and Smith, 1981).
Ethylene cyanohydrln, a B-hydroxyl cyanohydrln, was absorbed extensively
(~85X) by rats following oral exposure, but conversion to cyanide was low
(Sauerhoff et al., 1976).
v1
-------
Information 1s available regarding the subchronlc Inhalation toxlclty of
acetone cyanohydrln. Rats exposed to approximate concentrations of 10, 30
or 60 ppm for 6 hours/day, 5 days/week for -14 weeks showed no treatment-
related signs of toxldty or hematologlcal, serum biochemical or gross or
hlstologlcal effects (Blank and Thake, 1984). Signs of toxlclty were
observed at >30 ppm 1n a 4-week study of essentially Identical design (Blank
and Rlbelln, 1985; Roloff et al., 1985). The reason for the Inconsistency
In the results of the two studies 1s not apparent, and clinical observations
1n fertility studies (K1er et al., 1985a,b) conducted at the same concentra-
tions support the findings of the 14-week study. Pathologic lesions of the
lungs, kidney and liver were observed 1n rat exposed to acetone cyanohydrln
by Inhalation In a study with Inadequately reported exposure Information
(Motoc et al., 1971).
Inadequately reported subchronlc oral toxldty studies have been
conducted with two a-hydroxylated cyanohydrlns, acetone cyanohydrln and
formaldehyde cyanohydrln. In the study with acetone cyanohydrln (Motoc et
al., 1971), 5 mg doses were administered to rats by an unspecified* method
twice a week for 3, 5 or 8 months. Treatment-related effects Included
various serum enzyme and protein alterations and lesions of the stomach,
liver and kidneys. In the study with formaldehyde cyanohydrln (Wolfsle,
1960), "111 effects" were not observed 1n rats maintained on diets that
provided doses of 62 mg/kg/day (males) or 92 mg/kg/day (females) for 13
weeks (Wolfsle, 1960); toxlclty endpolnts were not reported.
Ethylene cyanohydrln, a B-hydroxyl cyanohydrln, was administered to rats
of both sexes In drinking water that provided doses of 0, 10, 30, 90 or 270
mg/kg/day for 90 days (Sauerhoff et al., 1976). There were no treatment-
related alterations 1n body weight or hematology or urlnalysls Indices.
-------
Gross and hlstologlcal examinations were unremarkable, but brain and heart
weights were slightly but significantly lowered 1n the 90 and 270 mg/kg/day
females. Dietary administration of ethylene cyanohydrln to growing rats at
a dose of 1.31 g/day for 52-56 days did not produce skeletal deformities or
femoral flbrosls (Bachhuber et al., 1955).
Chronic tox1c1ty/carc1nogen1dty data are available only for ethylene
cyanohydrln. Ethylene cyanohydrln was administered to male rats In the diet
In concentrations of 0, 100, 1000 or 3000 ppm for 78 weeks (Hlrose et al.,
1980). Groups of male mice were similarly exposed to 100, 1000 or 3000 ppm
ethylene cyanohydrln for 78 weeks and maintained for an additional 7 weeks
wtthout treatment. Slightly decreased final weight, slightly Increased
relative liver weight and slightly decreased ount, UBC count, hemato-
crlt and hemoglobin occurred at >100 ppm In th; is; there were no treat-
ment-related gross or hlstologlcal effects. Mean final body weights were
slightly decreased 1n mice at >1000 ppm; hematology and blood biochemistry
evaluations were not conducted 1n the mice, but organ weight and gross and
hlstologlcal examinations were unremarkable.
Acetone cyanohydrln did not produce reverse mutations In S. typhlmurlum.
forward mutations 1n CHO cells in vitro or chromosome aberrations In rat
bone marrow cells following oral administration (see Table 6-2). Genotoxlc-
Hy studies of the other cyanohydrlns were not located.
Acetone cyanohydrln was not teratogenlc or fetotoxlc 1n rats treated
with doses of 1, 3 or 10 mg/kg by gavage on days 6-15 of gestation (IRDC,
1984). There were no effects on fertility In male or female rats exposed to
acetone cyanohydrln by Inhalation at nominal concentrations of 10, 30 or 60
ppm for 6 hours/day, 5 days/week for 48 (male) or 21 (female) exposure days
(Kler et al., 1985a,b).
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A NOAEL from the 14-week Inhalation study of Blank and Thake (1984) was
used to calculate a subchronlc Inhalation RfD of 3 mg/day for acetone cyano-
hydrln; this RfD was adopted as the chronic Inhalation RfD for acetone
cyanohydrln. A chronic oral RfD of 5 mg/day for acetone cyanohydrln was
calculated based on analogy to cyanide; this RfD was adopted as the sub-
chronic oral RfD for acetone cyanohydrln. A NOAEL from the 90-day oral
study of Sauerhoff et al. (1976) was used to calculate a subchronlc oral RfD
of 21 mg/day for ethylene cyanohydrln; this RfD was adopted as the chronic
oral RfD for ethylene cyanohydrln. A chronic toxldty-based RQ of 1000 was
calculated for ethylene cyanohydrln.
1x
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TABLE 0 NTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER . . 1
1.2. PHYSICAL AND CHEMICAL PROPER 1
1.3. PRODUCTION DATA 3
1.4. USE DATA 6
1.5. SUMMARY 6
2. ENVIRONMENTAL FATE AND TRANSPORT. . . 8
2.1. AIR 8
2.2. WATER 9
2.3. SOIL 10
2.4. SUMMARY 11
3. EXPOSURE 13
4. AQUATIC TOXICITY 14"
4.1. ACUTE TOXICITY 14
4.2. CHRONIC EFFECTS 16
4.3. PLANT EFFECTS 16
4.4. SUMMARY 16
5. PHARMACOKINETCS 18
5.1. ABSORPTION 18
5.2. DISTRIBUTION 18
5.3. METABOLISM 19
5.4. EXCRETION 21
5.5. SUMMARY 21
6. EFFECTS 23
6.1. SYSTEMIC TOXICITY 23
6.1.1. Inhalation Exposure 23
6.1.2. Oral Exposure 25
6.1.3. Other Relevant Information 28
6.2. CARCINOGENICITY 31
6.2.1. Inhalation 31
6.2.2. Oral 31
6.2.3. Other Relevant Information 32
6.3. MUTAGENICITY 32
6.4. TERATOGENICITY 32
6.5. OTHER REPRODUCTIVE EFFECTS 34
6.6. SUMMARY ' 36
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TABLE OF CONTENTS (cont.)
Page
7. EXISTING GUIDELINES AND STANDARDS 39
7.1. HUMAN 39
7.2. AQUATIC 39
8. RISK ASSESSMENT 40
8.1. CARCINOGENICITY 40
8.1.1. Inhalation 40
8.1.2. Oral 40
8.1.3. Other Routes 40
8.1.4. Weight of Evidence 40
8.1.5. Quantitative Risk Estimates 41
8.2. SYSTEMIC TOXICITY 41
8.2.1. Inhalation Exposure 41
8.2.2. Oral Exposure 44
9. REPORTABLE QUANTITIES 51
9.1. BASED ON SYSTEMIC TOXICITY 51
9.2. BASED ON CARCINOGENICITY 54
10. REFERENCES 58
APPENDIX A: LITERATURE SEARCHED 69
APPENDIX B: SUMMARY TABLE FOR CYANOHYDRINS 72
x1
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LIST OF TABLES
No. Title Page
1-1 Identities of Five Cyanohydrlns 2
1-2 A Few Physical Properties of the Selected Cyanohydrlns. ... 4
1-3 1977 Production Volume for a Few Cyanohydrlns 5
6-1 Acute Oral and Inhalation Lethality of Cyanohydrlns 29
6-2 Genotoxldty Studies of Acetone Cyanohydrln 33
9-1 Toxlclty Summary for Cyanohydrlns 52
9-2 Oral Composite Scores for Ethylene Cyanohydrln 55
9-3 Ethylene Cyanohydrln: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 56
9-4 Formaldehyde Cyanohydrln, Lactonltrlle, Benzaldehyde
Cyanohydrln and Acetone Cyanohydrln: Minimum Effective
Dose (MED) and Reportable Quantity (RQ) 57
-------
LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
CAS Chemical Abstract Service
CHO Chinese hamster ovary
CNS Central nervous system
CS Composite score
BOD Biochemical oxygen demand
Koc Soil sorptlon coefficient
Concentration lethal to 50% of recipients
Concentration lethal to 100% of recipients
1050 Dose lethal to 50% of recipients
MED Minimum effective dose
MTL Med'lan tolerance limit
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RBC Red blood cell
RfD Reference dose
RQ Reportable quantity
RVd Dose-rated value
RVe Effect-rated value
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc-pyruvlc transamlnase
TLm Median tolerance limit
UV Ultraviolet
NBC White blood cell
-------
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Cyanohydrlns are a class of compounds that contain both a cyanide and a
hydroxy group on the same or a different aliphatic carbon structure of a
molecule. The cyanohydMns may also be called hydroxy nltrlles. Chemi-
cally, there are two Important types of cyanohydrlns: a-cyanohydr1ns and
non-a-cyanohydrlns. In a-cyanohydr1ns, both the cyanide and hydroxy
group substitution 1s on the same aliphatic carbon atom. In non-a-cyano-
hydrlns, the cyanide and hydroxy substitution are on different carbon atoms.
For example, when the hydroxy substitution Is on the second carbon atom 1n
relation to cyanide group of the molecule, It Is called a B-cyanohydrlru
Ethylene cyanohydrln 1s an example of 8-hydroxy nltrlle or 8-cyanohydr1n
(Cholod, 1979). Of the several cyanohydrlns available, this document will
discuss only five commercially Important compounds. The synonyms, struc-
tures, molecular formulas, molecular weights and CAS Registry numbers of the
five selected cyanohydrlns are given 1n Table 1-1.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Cyanohydrlns are usually colorless to straw yellow liquids that have
objectionable odors similar to hydrogen cyanide. With the exception of
benzaldehyde cyanohydrln, the other four cyanohydrlns are soluble In water
and all of the five cyanohydrlns are soluble in a variety of organic
solvents. Chemically, the cyanohydrlns are reactive either at the nltrlle
or at the hydroxy group of the molecule. Cyanohydrlns undergo hydrolysis
under add catalysis to the amides and finally to the corresponding
carboxyllc adds under addle or basic conditions (Cholod, 1979). The
a-cyanohydr1ns decompose to their corresponding carbonyl compounds and
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hydrogen cyanide under moderate temperature conditions and particularly
under basic pH conditions. The B-cyanohydrlns are fairly stable under these
conditions (Sunderman and K1nca1d, 1953; Fomunyam et al., 1985). The
hydroxy group of cyanohydrlns can undergo displacement reactions with other
electronegative groups (Cholod, 1979). Selected physical properties of the
five cyanohydrlns are given 1n Table 1-2.
1.3. PRODUCTION DATA
Generally, a-cyanohydr1ns are produced by the following methods:
1) the reaction of hydrogen cyanide with the appropriate aldehyde or ketone
In the presence of an acid or an alkali; 2) the reaction of 1on1c cyanide
with the bisulfite addition compounds of an aldehyde or a ketone; and 3) the
reaction of a ketone cyanohydrln with an aldehyde to produce the more stable
aldehyde cyanohydrlns (Cholod, 1979). The S-cyanohydr1n, ethylene cyano-
hydrln, 1s produced by either of the following methods: 1) Interaction of
ethylene chlorohydrln with an alkali cyanide; or 2) the reaction of ethylene
oxide with hydrogen cyanide 1n the presence of a base (Cholod, 1979;
Vhndholz, 1983). The total production volumes of these chemicals manufac-
tured 1n the United States In 1977 are given In Table 1-3.
Currently, CYRO Industries, New Orleans, LA; DuPont Co, Memphis, TN;
Rohm and Haas Co, Deer Park, TX; and Sterling Chemical Co, Texas City, TX
(SRI, 1987) manufacture 1082 million pounds of acetone cyanohydrln In the
United States (USITC, 1987). In addition, Monsanto Co., Texas City, TX,
produces an unknown amount of lactonltrlle In the United States (USITC,
1987). The names of current producers and their annual production volumes/
capacities for the other cyanohydrlns are not available.
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TABLE 1-3
1977 Production Volume for a Few CyanohydMns*
Compound
Manufacturers
Total Production Volume
(million pounds/year)
Formaldehyde
cyanohydMne
LactonltMle
Acetone
cyanohydMn
Benzaldehyde
cyanohydrln
Ethylene
cyanohydrln
Dow Chem.Co., Freeport, TX
Kay-Fries Chem., Stony Pt., NY
Technlc Inc., Cranston, RI
Monsanto Co, Texas City, TX
Technlc Inc., Cranston, RI
Eastman Kodak, Rochester, NY
DuPont Co., Belle, MV and
Memphis, TN
Rohm and Haas, Deer Park, TX
CYRO Indus., Westwego, LA
confidential
confidential
Haven Chem, Philadelphia, PA
Monsanto Co., Decatur, AL
Thlokol Chem., Calvert City. KY
NR
1-10
300-1500
0.2-2
*Source: U.S. EPA, 1977
NR = Not reported
0115d
-5-
05/10/88
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1.4. USE DATA
CyanohydMns are used primarily as Intermediates In the manufacture of
other chemicals. The manufacture of methyl methacrylate from acetone cyano-
hydrln 1s the most commercially Important usage of this compound. Acetone
cyanohydrln 1s also used as a raw material for the manufacture of certain
Insecticides and Pharmaceuticals, as a chelatlng agent 1n metal refining and
as a stereoselectlve hydrocyanatlng reagent 1n other organic reactions.
CyanohydMns are used as solvents 1n applications Including fiber-spinning,
and their derivatives act as antiknock agents 1n fuel oil (Cholod, 1979).
1.5. SUMMARY
Cyanohydrlns are a class of compounds that contain both a cyanide and a
hydroxy group 1n the aliphatic structure of a molecule. They are usually
colorless to straw yellow liquids that have an objectionable odor similar to
hydrogen cyanide. With the exception of benzaldehyde cyanohydrln, the
cyanohydrlns discussed In this document are soluble In water; all five
cyanohydrlns are soluble 1n ethanol and a variety of other organic solvents
(Cholod, 1979). Generally, the cyanohydrlns decompose at high basic pH, but
are stable under acidic pH conditions (Sunderman and Klncald, 1953; Fomunyam
et al., 1985). One of the Important processes for the production of the
cyanohydrlns Is the reaction of hydrogen cyanide with the appropriate
aldehyde or ketone In the presence of an add or an alkali as a catalyst.
Of the five cyanohydrlns, acetone cyanohydrln 1s produced In the largest
amount In the United States. Currently, four companies manufacture 1082
million pounds of acetone cyanohydrln In the United States per year. Only
one company manufactures lactonltMle 1n the United States; the amount Is
unknown. The manufacturers' names and the annual production volumes for the
0115d -6- * 05/31/88
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other cyanohydrlns are not known (SRI, 1987; USITC, 1987). Cyanohydrlns are
used primarily as Intermediates 1n the manufacture of other chemicals. Some
of the products manufactured from cyanohydrlns are methyl methacrylate,
Insecticides and Pharmaceuticals. They are also used In metal refining, as
a solvent 1n fiber-spinning and as antiknock agents 1n fuel oil (Cholod,
1979).
0115d -7- 05/31/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
The sources of cyanohydMns In the environment are both natural and
anthropogenic. Industrial processes Involving the production and use of the
cyanohydrlns will result 1n the emissions of these compounds (Panova et al.,
1977). Benzaldehyde cyanohydMn Is a component of the natural glycoslde
amygdalln found In the leaves and seeds of plums, peaches and apricots
(Cholod, 1979). Both acetone and benzaldehyde cyanohydrlns are components
of cassava glycosldes and are formed during the hydrolysis of the glycosldes
(Fomunyam et al., 1985).
2.1. AIR
Because the vapor pressures of the cyanohydrlns at ambient temperatures
are >10~4 mm Hg (see Table 1-2), these chemicals are expected to be
present predominantly In the vapor phase In the atmosphere (Elsenrelch et
al., 1981). No experimental data regarding the reactivity of these com-
pounds In the vapor phase with respect to their reactions with ozone,
sunlight or other oxldants are available 1n the literature (Singh et al.,
1984). Therefore, It 1s difficult to assess the atmospheric stability of
these chemicals. The rate constant for the reaction of vapor-phase acetone
cyanohydrln with HO radical has been estimated to be 6xlO~13 cmVmole-
cule-sec (Singh et al., 1984). If this value 1s combined with a value of
10* radicals/cm3 as the concentration of atmospheric HO radical, the
half-life of this reaction can be estimated to be 13.4 days. Based on this
half-life value, acetone cyanohydrln will probably be reasonably stable In
air and may undergo 1ntramed1a transport. The high water solubility of the
cyanohydrlns (with the exception of benzaldehyde cyanohydrln) would Indicate
that wet deposition may be the major removal mechanism for the majority of
OllSd -8- * 05/10/88
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atmospheric vapor phase cyanohydrlns. Since most rain waters have pH values
<7, the washed cyanohydrlns may be stable toward hydrolysis (see below).
2.2. WATER
There 1s a paucity of data on the abiotic fate of cyanohydrlns In water.
It Is well known that cyanohydrlns are unstable at high pH, but stable under
acidic pH conditions (Cholod, 1979). For example, the decomposition of
acetone cyanohydrln In water at pH 10 Is too fast to measure. The decompo-
sition of the same compound, to acetone and hydrogen cyanide In neutral and
acidic solutions Is slow (Sunderman and Klncald, 1953). Other Investigators
have reported that the hydrolysis of benzaldehyde cyanohydrln was very low
(10-20%) at pH 4-5, but was high (55-80%) at higher pH. Similarly, the
hydrolysis of acetone cyanohydrln was very low (5-15X) at pH 3-7 and was
high at pH >9 (Fomunyam et al., 1985). No kinetic data regarding the
pH-dependent hydrolysis of these compounds were found 1n the literature.
TJie Irradiation of acetone cyanohydrln In water by UV light easily decom-
posed acetone cyanohydrln Into acetone and hydro.gen cyanide (Shlrane, 1982).
The author Indicated that the decomposition will occur with UV light avail-
able In natural sunlight. Again, no kinetic data were available to assess
the half-life of cyanohydrlns 1n this reaction. The rate of oxldatlve
removal of acetone cyanohydrln from water and wastewater with ozone at
different pH values was reported by Ish1zak1 et al. (1978).
The fate of cyanohydrlns with respect to blodegradatlon has been well
studied. One Isolate from heterotrophlc soil bacteria was shown to act as a
nitrifying microorganism to Iacton1tr1le (Doxtader and Alexander, 1966);
however, lactonHMle was found to Inhibit the growth of a Nocardla rhodo-
chrous sp. (Llnton and Knowles, 1986). The blodegradabllUy of cyanohydrlns
by mixed microorganisms was also studied. Sasaki (1978) reported that
0115d -9- "' 05/10/88
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ethylene cyanohydrln was biodegradable (oxygen consumption >30% of theoreti-
cal demand) when Incubated with activated sludge for a period of 14 days.
With acclimated activated sludge as the mlcroblal Inoculum, 87-98% BOO
removal was obtained for lactonltrlle during an Incubation period of 4 weeks
(Ludzack et al., 1959a, 1961). When acclimated aged sewage was used as
mlcroblal Inoculum, 60% theoretical BOO removal was observed 1n 5 days at an
Initial lactonltrlle concentration range of 0.4-15 mg/i (Ludzack et al.,
1958, 1959b). These authors also observed 70% of theoretical BOD removal
for lactonltrlle (Initial .concentration range 0.4-15 mg/i) In 5 days with
Ohio River water as the mlcroblal Inoculum. Acetone cyanohydrln was only
partially biodegradable with activated sludge by the standard bottle
dilution technique (Slave et al., 1974). The results of a Dow Chemical Co.
(1986) Investigation showed that acetone cyanohydrln removal from wastewater
was equivalent to 0% of theoretical BOO by the standard BOD technique for an
Incubation period of 10 days. When the Incubation period was Increased to
20 days, 41% of theoretical BOD removal occurred.
Limited quantitative data are available on the processes that may lead
to the loss of cyanohydMns from water. From a value of 3.32x10* mg/l
for the water solubility and a vapor pressure value of 0.8 mm Hg (see Table
1-2), the Henry's Law constant (H) can be estimated (H = p/S) to be
3.2xlO~7 atm mVmol. Such a value for H Indicates that this compound
will be essentially nonvolatile from water (Lyman et al., 1982).
2.3. SOIL
Data regarding the fate of cyanohydrlns 1n soil are extremely limited;
however, based on their fate In water (see Section 2.2.), some predictions
about their fate 1n soil can be made. The a-cyanohydr1ns are expected to
hydrolyze In basic soil and the rate of hydrolysis would Increase with the
0115d -10- * 05/10/88
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Increase of pH. Blodegradatlon 1n soil may also be an Important degradatlve
fate of these compounds. Loss of these compounds as a result of volatiliza-
tion from soil may not be Important. Based on their generally high water
solubilities, these compounds are expected to have low K values, leading
to high mobility 1n soils. If the blodegradatlon rates are slower than the
Infiltration rates, these compounds could Infiltrate groundwater from addle
soils.
2.4. SUMMARY
The limited data available In the literature are not sufficient to
assess the fate and transport of cyanohydrlns 1n any medium with certainty.
In the atmosphere, cyanohydrlns may undergo direct photolysis, as photolysis
was found to occur 1n aqueous solutions (Shlrane, 1982). The estimated
half-life for the reaction of vapor-phase acetone cyanohydrln with photo-
chemical ly-generated HO radical Is >13 days (Singh et al., 1984).
Therefore, this reaction may not be significant 1n the removal of acetone
cyanohydrln from the atmosphere. The high water solubility for many of the
cyanohydrlns Indicates that wet deposition would be a major removal pathway
for atmospheric cyanohydrlns. Since most rain waters have pH values <7, the
washed cyanohydrlns may be stable toward hydrolysis. In basic waters,
hydrolysis may be an Important pathway for the removal of cyanohydrlns
(Fomunyam et al., 1985). Loss of cyanohydrlns through blodegradatlon may be
an Important process 1n water, although no half-life value resulting from
this process can be assigned (Ludzack et al., 1958, 1959a,b, 1961; Dow
Chemical Co., 1986). The Importance of photolysis 1n the degradation of
aquatic cyanohydrlns remains unclear (Shlrane, 1982). Significant loss of
cyanohydrlns from evaporation may be unlikely. The a-cyanohydr1ns may
0115d -11- » 05/10/88
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hydrolyze 1n basic soils, and blodegradatlon 1n soils may be an Important
process. Because of their expected low K , these compounds may have high
mobility 1n soil and may Infiltrate groundwaters.
0115d -12- > 05/10/88
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3. EXPOSURE
There 1s a paucity of data on the levels of cyanohydrlns In any environ-
mental medium. Ethylene cyanohydrln has been detected qualitatively In the
expired air of predlabetlc patients, and Us origin has been speculated to
be metabolic (Krotoszynskl and O'Neill, 1982). Storage of crude essential
oil of bitter almonds has been shown to produce benzaldehyde cyanohydrln, jm
situ, through a reaction of benzaldehyde and hydrogen cyanide naturally
present In the oil (Garnero, 1947). Two kinds of brandy and liqueur manu-
factured from two varieties of sour cherries contained 0.0112 and 0.010X
benzaldehyde cyanohydrln, and the source of the compound was traced to the
pits of fruit (KobHc, 1952). Similarly, foods produced by the hydrolysis
of cassava, used 1n South America and Africa, will contain acetone and
benzaldehyde cyanohydrlns (Fomunyam et al., 1985).
0115d -13- * 05/10/88
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The acute toxlclty of acetone cyanohydrln was assessed In several
studies with various species of fish and an aquatic Invertebrate. Henderson
et al. (1961) reported that the 24- to 96-hour TL was 0.9 mg/l 1n
static tests conducted In either hard or soft water with fathead minnows,
Plmephales promelas. and 1n static tests conducted 1n soft water with blue-
gill sunflsh, Lepomls macrochlrus. The TL for gupples, Leblstes retlcu-
111
latus. exposed to acetone cyanohydrln 1n soft water was 1.37 mg/l for
exposure durations of 24-96 hours. Alkalinity and hardness of soft dilution
water was 16 and 20 ppm, respectively. Alkalinity and hardness of hard
dilution water was 320 and 380 ppm, respectively. All tests were conducted
at 25°C. Acetone cyanohydrln was 1-3 orders of magnitude more acutely toxic
than five other organic n1tr1les tested 1n conjunction with acetone cyano-
hydrln by Henderson et al. (1961). These Investigators also exposed fathead
minnows to acetone cyanohydrln for up to 20 days 1n a flowthrough test at
25°C. They reported average 1-, 2-, 3-, 4-, 5-, 10-, 15- and 20-day TL
values from duplicate experiments of 0.75, 0.73, 0.73, 0.71, 0.69, 0.69,
0.69 and 0.69 mg/l, respectively.
Dawson et al. (1977) reported a 96-hour LC5Q of 0.57 mg/l for
blueglll sunflsh, L_. macrochlrus. exposed to acetone cyanohydrln. F1sh were
exposed to acetone cyanohydrln In well water at a temperature of 23°C. They
also reported a 96-hour LC5Q for the marine tidewater sllverslde, Henldla
berylUna. of 0.50 mg/l. Well water was used as a base to prepare a
synthetic saltwater for the test dilution water. Sllversldes were exposed
to acetone cyanohydrln at a temperature of 20°C. The authors reported that
test solutions with sllversldes were constantly aerated during the test to
0115d -14- * 05/10/88
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maintain an acceptable dissolved oxygen concentration, whereas acetone
cyanohydMn solutions with sunflsh were only Intermittently aerated.
The acute toxldty of acetone cyanohydrln to the golden orfe, Leuclscus
Idus melanotus. was reported by Juhnke and Ludemann (1978). A pair of
48-hour tests 1n separate laboratories produced LC5Qs of 1.7 and 0.9
mg/l. No mortalities were observed at 0.1 and 0.8 mg/l, respectively,
while the LC for both tests was 1.9 and 1.1 mg/l, respectively.
Exposure of rainbow trout, Salmo qa1rdner1. to acetone cyanohydrln In
.static acute toxldty tests produced nominal 24- and 48- to 96-hour LC5Q
estimates and 95% confidence limits of 0.28 (0.22-0.36) and 0.22 (0.13-0.36)
mg/l, respectively (EG&G Bionomics, 1981a). No mortalities were observed
at 0.078 mg/l acetone cyanohydrln after 96 hours, but fish were lethargic
and respiring rapidly In 0.13 mg/l acetone cyanohydrln after 72 and 96
hours. The test was conducted 1n reconstituted water at 12°C.
Exposure of blueglll sunflsh, L_. macrochlrus. to acetone cyanohydrln In
static acute toxldty tests produced nominal 24- to 72-hour and 96-hour
LC5Q estimates and 95% confidence limits of 0.46 (0.36-0.60) and 0.42
(0.32-0.58) mg/l, respectively (EG&G Bionomics, 1981b). No effects were
observed at 0.079 mg/l acetone cyanohydrln, and no mortalities were
observed at 0.21 mg/l after 96 hours. The test was conducted 1n recon-
stituted water at 21-22°C.
Exposure of Daphnla maqna to acetone cyanohydrln 1n static acute toxlc-
1ty tests produced nominal 24- and 48-hour LC estimates and 95% confi-
dence limits of 0.27 (0.19-0.38) and 0.13 (0.088-0.19) mg/l, respectively
(EG&G Bionomics, 1981c). The Investigators also reported a NOEL of 0.076
mg/l acetone cyanohydrln after 48 hours. The test was conducted 1n
reconstituted water at a temperature of 22-23°C.
0115d -15- ' 05/10/88
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In an oral dosing study, Loeb and Kelly (1963) force-fed acetone cyano-
hydrln to carp, Cyprlnus carplo. at 79, 89 and 125 mg/kg. F1sh were
collected with an electric boat shocker In the field and ranged 1n size from
1-10 pounds (average ~3 pounds). Acetone cyanohydrln was force-fed to at
least three fish 1n gelatinous capsules that disintegrated after -1 hour.
Fish were held at 65°F and observed for up to 94 hours after feeding. Test
fish at the lowest dose showed no effects from the treatment after 94 hours
of observation. Test fish dosed with 125 mg/kg acetone cyanohydrln experi-
enced sickness after only 4 hours and death at 5 hours. The authors con-
cluded that the results of this study and of those for 1495 other chemicals
could not be explained adequately because of the lack of any trends 1n the
results.
4.2. CHRONIC EFFECTS
Pertinent data regarding the effects of chronic exposure of aquatic
organisms to acetone cyanohydrln were not located 1n the available litera-
ture cited 1n Appendix A.
4.3. PLANT EFFECTS
Pertinent data regarding the effects of exposure of aquatic plants to
acetone cyanohydrln were not located 1n the available literature cited In
Appendix A.
4.4. SUMMARY
The acute toxlclty of acetone cyanohydrln to all fish as demonstrated by
the 96-hour LC5Q ranged from 0.22 mg/l for rainbow trout (EG&G
Bionomics, 1981a) to 1.37 mg/l for gupples (Henderson et al., 1961).
Water hardness did not Influence the acute toxic effects of acetone cyano-
hydrln to fathead minnows (Henderson et al., 1961). Exposure of fathead
minnows to acetone cyanohydrln 1n a flowthrough study produced a lower
0115d -16- * 05/31/88
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LC5Q (0.71 mg/8.) than that 1n a static test (0.9 mg/l) (Henderson et
al., 1961). Toxlclty thresholds were reached relatively quickly (~24-48
hours) In acute studies exposing fish to acetone cyanohydrln. Toxlclty of
acetone cyanohydrln to an Invertebrate, D. magna. (48-hour LC5Q = 0.13,
95% confidence limit = 0.088-0.19 mg/l) was comparable with the toxlclty
of acetone cyanohydrln to rainbow trout (48-hour LC = 0.22, 95%
confidence limit = 0.13-0.36 mg/l; EG&G Bionomics, 1981a,c).
0115d -17- 05/31/88
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5. PHARMACOKINETICS
5.1. ABSORPTION
Quantitative Information regarding absorption of the a-hydroxyl cyano-
hydrlns (I.e., those other than ethylene cyanohydrln) was not located In the
literature cited 1n Appendix A. Acute toxldty data for animals and humans
(case reports of occupational exposure), available primarily for acetone
cyanohydrln and formaldehyde cyanohydrln, Indicate that the a-hydroxyl
cyanohydrlns are absorbed rapidly by all routes of exposure (NIOSH, 1978;
Hartung, 1982). In general, nltrlles are absorbed readily following 1nges-
tlon, inhalation and skin contact.
14C-Ethylene cyanohydrln, labeled at the n1tr1le carbon, was adminis-
tered to six Sprague-Dawley rats (three/sex) by gavage at a dose of 20 mg/kg
(Sauerhoff et al., 1976). Determination of radioactivity 1n the plasma
1-116 hours following treatment showed that absorption of 14C was a first-
order process with a rate constant of 1.0 hour'1, corresponding to a half-
time of 0.69 hour. Peak plasma levels were attained at 4 hours. During the
120 hours following dosing, >85% of the administered radioactivity was
recovered 1n the urine and expired air, Indicating extensive absorption.
5.2. DISTRIBUTION
Information regarding distribution of the a-hydroxyl cyanohydrlns
following absorption by natural routes of exposure was not located In the
literature cited 1n Appendix A. W1llh.1te and Smith (1981) found that
cyanide was distributed to the liver and brain of mice 5 minutes after an
Intraperltoneal Injection of acetone cyanohydrln. Following uptake by
blood, cyanide accumulates within erythro.cytes, where It combines with
Fe*** of methemoglobln and the heme moiety of hemoglobin (U.S. EPA,
1985a). Relatively high levels of cyanide have been found In the spleen,
0115d -18- * 05/10/88
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"liver and brain at autopsies of humans fatally poisoned with cyanide, but
cyanide does not accumulate In blood and tissues following chronic exposure
(U.S. EPA, 1985a).
Clearance of radioactivity from the plasma of rats following oral admin-
istration of 20 mg/kg 14C-ethylene cyanohydMn was determined to be
blphaslc (Sauerhoff et al., 1976). The rate constants and half-times for
plasma clearance were 0.157 hour"1 and 4.4 hours for the first phase, and
0.013 hour"1 and 53.3 hours for the second phase. The authors Interpreted
that the second phase reflects the Incorporation of 14C Into the
one-carbon metabolic pool and subsequent elimination as CO. throughout the
experiment, Indicating that ethylene cyanohydrln would not accumulate In the
body with repeated administration.
5.3. METABOLISM
a-Hydroxyl cyanohydrlns are hydrolyzed readily Iji vivo to yield
hydrogen cyanide and the corresponding ketone or aldehyde (Sunderman and
Klncald, 1953; NIOSH, 1978; Hartung, 1982). Cyanide liberation from acetone
cyanohydrln (WHlhlte and Smith, 1981), formaldehyde cyanohydrln (Freeman
and Hayes, 1987) and benzaldehyde cyanohydrln (Strugala et al., 1986) has
been demonstrated In ^n vitro and jji v1vo studies with rats and mice. Other
evidence Indicates that a-hydroxyl cyanohydrlns are Intermediates 1n the
metabolism of aliphatic nltrlles to cyanide (Wlllhlte and Smith, 1981;
Silver et al., 1982; KaplUa and Smith, 1986). Cyanide 1s primarily con-
verted to thlocyanate by the enzymatic action of rhodanese, which transfers
sulfur from thlosulfate (U.S. EPA, 1985a). Thlocyanate may be reconverted
partially to cyanide by thlocyanate oxldase If 1t 1s not excreted rapidly 1n
the urine. Minor metabolic pathways for cyanide Include conjugation with
0115d -19- 05/10/88
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cystelne to form 2-1m1no-4-th1azol1d1necarboxyl1c add and reaction with
hydroxycobalamln (vitamin B^) to form cyanocobalamlne. Some free HCN 1s
eliminated unchanged In the breath, saliva, sweat and urine.
Experiments with acetone cyanohydrln and sodium cyanide demonstrated
that acetone cyanohydrln behaved qualitatively and quantitatively like Us
molar equivalent In cyanide (Wlllhlte and Smith, 1981). These experiments,
conducted in vitro and in vivo with mice, Included determinations of cyto-
chrome c oxldase activity Inhibition, toxlclty (toxic signs, times to death
and LDj.Qs), liver and brain cyanide concentrations, and effectiveness of
cyanide antagonists (sodium nitrite and sodium thlosulfate). It was also
demonstrated that acetone cyanohydrln, unlike other aliphatic nltrlles, was
not metabolized to cyanide by mouse mlcrosomal liver enzymes i£ vitro. The
results of this study demonstrated that acetone cyanohydrln degraded rapidly
and completely Into Us molar equivalent 1n free cyanide under physiological
conditions.
The hydroxyl group of ethylene cyanohydrln Is 1n the 8 position relative
to the nUMle group. Because of this configuration, ethylene cyanohydrln
Is hydrolyzed less readily to cyanide in vivo than the a-hydroxyl cyano-
hydrlns (Sunderman and Klncald, 1953; Hartung, 1982). The relatively low
toxlclty of ethylene cyanohydrln compared with the a-hydroxyl cyanohydMns
(Section 6.1.) appears to be attributable to the dissimilarity 1n chemical
structure.
Single 20 mg/kg oral doses of 14C-ethylene cyanohydrln were adminis-
tered to rats (Sauerhoff et al., 1976). Approximately 25.6, 0.4, 47, 6 and
2% of the administered radioactivity appeared as CO- 1n expired air, HCN
In expired air, an undetermined hydrolyzable conjugate(s) of ethylene cyano-
hydrln In the urine, unmetabollzed ethylene thlocyanohydrln In the urine and
0115d -20- * 05/31/88
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thlocyanate In the urine, respectively, during 32-120 hours following
dosing. Cyanoacetlc add was Identified as a urinary metabolite of ethylene
cyanohydrln 1n rats following IntraperHoneal Injection of -100 mg/kg
(Merkow et al., 1959).
5.4. EXCRETION
Specific Information regarding elimination of the a-hydroxyl cyano-
hydrlns was not located It the literature dted 1n Appendix A. Thlocyanate
derived from cyanide 1s eliminated primarily 1n the urine (U.S. EPA, 1985a).
Single 20 mg/kg oral doses of [CN-14C]ethylene cyanohydrln were adm1nr
Istered to rats (Sauerhoff et al., 1976). The percentages of administered
radioactivity recovered In the urine, feces, COp In expired air and HCN In
expired air during the following 120 hours were 53.2, 7.39, 25.6 and 0.44,
respectively. Elimination of radioactivity 1n the urine and C0_ appeared
to be blphaslc, with first phase half-lives of 4.0 and 3.3 hours, respec-
tively, and second phase half-lives of 36.5 and 38.5 hours, respectively.
The net elimination of [14C]HCN In the expired air appeared to follow
first-order kinetics over the first 40 hours following administration of the
dose; the half-life was calculated to be 6.1 hours. Excretion of thlocyanate
In the urine reached peak levels after 8 and 16 hours and declined
relatively slowly, persisting long after the HCN In the expired air was
undetectable (throughout the 120-hour duration of the study); the half-life
was not calculated.
5.5. SUMMARY
Limited specific Information 1s available regarding the pharmacoklnetlcs
of the a-hydroxyl cyanohydMns. The a-hydroxyl cyanohydrlns appear to
be absorbed readily by all routes of exposure and converted extensively to
hydrogen cyanide and the corresponding ketone or aldehyde. Cyanide 1s
0115d -21- ' 05/10/88
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converted primarily to thlocyanate and eliminated 1n the urine. It has been
demonstrated that acetone cyanohydMn behaves like Its molar equivalent 1n
free cyanide In vitro and in vivo (WHlhUe and Smith, 1981).
Ethylene cyanohydrln, a 0-hydroxyl cyanohydrln, was absorbed extensively
(~85%) by rats following oral exposure, but conversion to cyanide was low
(Sauerhoff et al., 1976).
0115d -22- * 05/10/88
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6. EFFECTS
6.1. SYSTEHIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC Groups of 15 Sprague-Dawley rats of each sex
were exposed to mean measured concentrations of 0, 10.1, 28.6 or 57.7 ppm
acetone cyanohydMn for 6 hours/day, 5 days/week (except holidays) for -14
weeks (minimum 69 exposure days) 1n a study conducted by Monsanto Company
(Blank and Thake, 1984). Five rats/sex/group were randomly selected for
each of three terminal sacrifice days; the rats not selected for the first
sacrifice were exposed until the day before sacrifice. All rats were
observed for gross signs of toxldty on each exposure day and weighed weekly.
throughout the study. Serum chemistry, hematology, urine volume and urine
and serum thlocyanate concentrations were evaluated before the terminal
sacrifices. Organ weight determinations and gross pathological examinations
were conducted on all rats. H1stolog1cal evaluation (comprehensive) of
tissues were performed on rats from the control and high concentration
groups. No rats died during the course of the study, and there were no
treatment-related effects. Metabolism of absorbed compound was Indicated by
Increased levels of thlocyanate In the urine and serum. Urine thlocyanate
levels were Increased In both sexes 1n an exposure-related manner, but the
Increase was significant (p<0.01) only 1n the 28.6 and 57.7 ppm groups.
Serum thlocyanate levels were Increased significantly 1n the 10.1 and 28.6
ppm female groups (p<0.01) and 10.1 ppm male group (p<0.05).
Groups of 10 Sprague-Dawley rats of each sex were exposed to mean
measured concentrations of 0, 9.2, 29.9 or 59.6 ppm acetone cyanohydrln for
6 hours/day, 5 days/week (except holidays) for ~4 weeks (minimum 19 exposure
days) (Blank and Rlbelln, 1985; Roloff et al., 1985). Gross toxldty, serum
0115d -23- 05/31/88
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chemistry, hematology, urine and pathology determinations were similar to
those 1n the 14-week study (Blank and Thake, 1984). Compound-related signs
of tox1c1ty were observed 1n both sexes, Including Irritation of the eyes
and nose and breathing difficulties at >29.9 ppm, and hypoactlvHy at 59.6
ppm. Signs associated with anoxla/hypoxla (e.g., respiratory distress),
tremors and convulsions, foaming at the mouth, and prostrate posture were
observed In 4/10 high-exposure males following the first exposure; three of
these rats subsequently died. Mean body weight was reduced In the males
exposed to 59.6 ppm; this reduction was not statistically significant but
was considered to be compound-related by the Investigators. Thlocyanate
levels In the urine and serum were Increased 1n all exposure groups. The
Increases 1n urine thlocyanate were significant at p<0.01 In the 29.9 and
59.6 ppm groups 1n both sexes, and the Increases 1n serum thlocyanate were
significant at p<0.01 at 9.2 ppm In both sexes, at p<0.01 at 29.9 ppm In the
males and at p<0.05 at 29.9 ppm 1n the females.
The approximate saturation concentration for acetone cyanohydrln Is 0.3
mi/84 i {1026 ppm) air. However, acetone cyanohydrln was administered
to a group of 50 albino rats by Inhalation at a reported concentration of 1
ml/84 l of air for 18 sessions In 3 months, 40 sessions In 5 months or
65 sessions In 8 months (Hotoc et al., 1971). Effects of exposure Included
pathologic alterations of the lung (Including desquamatlon of the bronchial
epithelium and superficial ulceratlons associated with Inflammatory Infil-
trates), kidney (unspecified Irreversible lesions affecting the entire
nephron) and liver (unspecified Irreversible lesions similar to those
associated with oral exposure 1n the same study) (Section 6.1.2.1.).
Additional Information regarding the design or results of this study (e.g.,
duration of exposure sessions) were not reported.
OllSd -24- * 08/02/88
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6.1.1.2. CHRONIC Pertinent data regarding the chronic Inhalation
toxldty of the cyanohydrlns were not located In the literature dted 1n
Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC Motoc et al. (1971) orally administered 5 mg
acetone cyanohydrln to 50 white rats twice a week for 3, 5 or 8 months;
however, this study was Inadequately reported. The method of oral adminis-
tration, vehicle, and number of animals treated for each duration were not
specified, and an unspecified number of rats served as controls. Serum
chemistry and protein evaluations, and gross and hlstologlc examinations of
the liver, kidney and stomach were conducted. Effects attributed to-
treatment Included decreased serum total proteins (-15X) and albumin/
globulin ratio, and Increased gamma-globulin, transamlnase, aldolase and
leuclnamlnopeptldase levels. Levels of serum glycoprotelns reportedly
Increased by 3 months, decreased by 5 months and Increased gradually by 8
months without returning to normal. B-Glucuron1dase activity Increased
Initially but decreased by the end of the study. Activities of hepatic
leuclnamlnopeptldase, SGOT and SGPT were Increased, and there were
unspecified alterations In hepatic protein metabolism. The pathologic
examinations revealed Increased gastric gland secretions and stomach
ulceratlons that Increased In severity with Increased duration of exposure,
and reversible and Irreversible dystrophlc alterations 1n the liver cells,
Including karyopyknosls, anlsokaryosls, abnormal fat deposits, cytoplasmlc
thinning and lack of cytoplasmlc granules. Unspecified kidney lesions that
were not as severe as the liver lesions were also observed. More specific
Information regarding the results of this study was not available.
OllSd -25- * 05/31/88
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Formaldehyde cyanohydrln was administered to unspecified numbers of
albino rats In diet at doses of 62 mg/kg/day (males) and 92 mg/kg/day
(females) for 13 weeks (Wolfsle. 1960). No "111 effects" were observed 1n
the study. A dose-related Increase 1n serum thlocyanate was reported, but
Increased serum cyanide "generally" was not observed. Additional Informa-
tion regarding the design or results of this study was not reported.
Groups of 10 Sprague-Oawley rats (6-7 weeks old) of each sex were
administered drinking water that provided ethylene cyanohydrln (>99% pure)
at doses of 0, 10, 30, 90 or 270 mg/kg/day for 90 days (Sauerhoff et a!.,
1976). Constant doses were provided by weekly adjustments of the water
concentrations of the chemical to correct for changes In water consumption
and body weight. Weights were measured Initially and weekly thereafter,
food consumption was determined weekly and hematologlc evaluations and
urlnalyses were conducted on five rats/sex from the 0 and 270 mg/kg groups
on day 85. Serum urea nitrogen levels, alkaline phosphatase activities and
glutamlc pyruvlc transamlnase activities were determined In five rats/sex
from each dose group at terminal sacrifice (days 91 or 92). Comprehensive
gross examinations and brain, heart, liver, kidney and testes weight deter-
minations were performed on all rats. Hlstologlc examinations that Included
the brain were completed on five rats/sex from the 0 and 270 mg/kg/day
groups. There were no changes 1n physical appearance or demeanor In any of
the rats, and no deaths. There were no treatment-related alterations In
food or water consumption, body weight gain or clinical evaluations. Brain
and heart weights were slightly but significantly (p<0.05) decreased In the
90 and 270 mg/kg/day females; 1t was not Indicated whether the decreases
were dose-related. The pathologic examinations were unremarkable.
OllSd -26- * 05/10/88
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Administration of ethylene cyanohydrln In the diet to six growing rats
(-0.04 kg at start) at a dose of 1.31 g/day for 52-56 days did not produce
skeletal deformities or femoral flbrosls (Bachhuber et a!., 1955). Bone
developmental abnormalities were produced by substitution of the hydroxy
group with an amlno group (I.e., with B-am1nopropr1on1tr1le).
6.1.2.2. CHRONIC Ethylene cyanohydrln was administered to groups
of 43 male Wlstar rats (7 weeks old) 1n diet In concentrations of 100, 1000
or 3000 ppm for 78 weeks (Hlrose et al., 1980); 31 male rats served as
controls. Groups of 50 male ICR mice were similarly exposed to 100, 1000 or
3000 ppm ethylene cyanohydrln for 78 weeks and maintained for an additional
7 weeks without treatment; 30 male mice served as controls. Hematologlcal
and blood biochemical analyses were conducted on all rats, but not mice,
after 78 weeks. Gross and hlstologlcal examinations were conducted on all
rats and mice that died, were moribund during the study or were sacrificed
at termination of the study. Initial and final body weights and liver,
kidney and spleen weights were determined 1n the rats and mice. Survival
data for rats after 60 and 78 weeks and mice after 62 weeks (mouse 78-week
data not reported) Indicated no treatment-related effects In either species.
Slightly decreased final body weight, slightly Increased relative liver
weight and slightly decreased RBC count, WBC count, hematocrlt and hemo-
globin occurred at >100 ppm In the rats. These effects were dose-related
but are difficult to evaluate because statistical significance was not
reported; statistical evaluation by SRC 1s precluded because group mean
values are the only data reported. Interpretation of these effects 1s also
complicated by lack of food consumption data. There were no treatment-
related pathologic effects 1n the rats. Mean final body weights were
decreased slightly at >1000 ppm In the mice, but the organ weight and
0115d -27- *' 05/10/88
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pathologic evaluations were unremarkable. Interpretation of the decreased
body weight 1n mice 1s also complicated for the reasons discussed for the
rat data.
6.1.3. Other Relevant Information. Acetone cyanohydrln was administered
to 44 albino rats and 16 rabbits at dally doses of 0.00005, 0.0005, 0.005 or
1.33 mg/kg/day for 6 months (Shkodlch, 1966). The route of administration
and additional Information regarding dosing were not provided. Effects
(p<0.01) 1n the rats Included Increased erythrocytes, retlculocytes and
hemoglobin, Increased vitamin C 1n the liver and adrenals, decreased -SH
group content 1n the brain, and decreased activities of serum catalase and
chollnesterase at 1.33 mg/kg/day. Functional changes In nervous system.
activity, described as "attenuation of the processes of Internal Inhibition
and certain Intensification of the excitatory process," were observed In
rats at 0.0005 and 1.33 mg/kg; 1t 1s not clear whether these changes also
occurred at 0.005 mg/kg/day. Unspecified changes 1n blood morphology, serum
catalase and chollnesterase activities, and vitamin C content occurred 1n
rats at 0.0005 mg/kg/day. Rabbits showed a disturbed glycogenlc function In
the liver at 1.33 mg/kg/day, as Indicated by reduced galactose utilization
(p<0.05) and decreased serum content of -SH groups. There were no effects
1n the rabbits at <0.005 mg/kg/day.
Acute oral and Inhalation toxldty data for various cyanohydrlns are
summarized 1n Table 6-1. These data are of limited quality; there Is a
relative paucity of data for compounds other than acetone cyanohydrln and
ethylene cyanohydrln. The available oral data Indicate that ethylene cyano-
hydrln Is substantially less toxic (LD5Qs 1800-10,000 mg/kg) than the
a-hydroxylated cyanohydrlns (LD50s 9-116 mg/kg).
0115d -28- 05/31/88
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Cyanohydrlns, particularly a-hydroxyl cyanohydrlns, display acute
toxic effects that appear to be related to cyanide toxldty (NIOSH, 1978;
Hartung, 1982). Human case reports, for example, have described character-
istic signs and symptoms of cyanide poisoning following occupational dermal
exposure to acetone cyanohydrln and formaldehyde cyanohydrln (NIOSH, 1978).
These Include headache, nausea, vomiting, respiratory distress, tonlc-clonlc
convulsions, loss of consciousness, and death. Although cyanohydrlns
exhibit characteristic signs of acute cyanide toxldty, quantitative differ-
ences are evident that are related to differences 1n cyanide release.
Cyanide exerts Us toxic effects by reacting with ferric 1on (Fef**)
In cytochrome oxldase, the enzyme that catalyzes the terminal step 1n th«
respiratory electron transport chain, thereby preventing utilization of
oxygen by cells (U.S. EPA, 1985a). The CNS and heart are particularly
sensitive to hlstotoxlc hypoxla.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenldty of
Inhaled cyanohydrlns were not located In the available literature dted In
Appendix A.
6.2.2. Oral. Ethylene cyanohydrln was administered to groups of 43 male
Wlstar rats (7 weeks old) 1n diet 1n concentrations of 100, 1000 and 3000
ppm for 78 weeks (Hlrose et a!., 1980); 31 male rats served as controls.
Groups of 50 male ICR mice were similarly exposed to 100, 1000 or 3000 ppm
ethylene cyanohydrln for 78 weeks and maintained for an additional 7 weeks
without treatment; 30 male mice served as controls. Gross and hlstologlcal
examinations were conducted on all rats and mice that died, were moribund
during the study or were sacrificed at termination of the study. Survival
In the 0, 100, 1000 and 3000 ppm groups was 15/31, 22/43, 29/43 and 20/43,
0115d -31- 05/31/88
-------
respectively, In rats after 60 weeks; 13/31, 20/43, 24/43 and 19/43, respec-
tively, 1n rats after 78 weeks; and 18/30, 30/50, 24/50 and 33/50. respec-
tively, 1n mice after 62 weeks. Additional survival data were not reported.
H1stopatholog1cal examination of unspecified organs did not show signifi-
cantly Increased Incidences of tumors or preneoplastlc lesions 1n either
species.
6.2.3. Other Relevant Information. The cyanohydrlns that are the subject
of this report have not been scheduled for carclnogenlclty testing by the
NTP (1988).
6.3. MUTAGENICITY
Acetone cyanohydrln did not produce reverse mutations 1n various strains
of Salmonella typhlmuMum (Hazleton Laboratories American, Inc., 1983),
forward mutations 1n CHO cells \n vitro. (Pharmakon Research International
Inc., 1984) or chromosome aberrations 1n rat bone marrow cells following
oral administration (Hazleton Laboratories American, Inc., 1984) (Table
6-2). Genotoxlclty studies of the other cyanohydrlns that are the subject
of this report were not located 1n the available literature cited In
Appendix A.
6.4. TERATOGENICITY
A study was conducted by the International Research and Development
Corporation for Monsanto Company to determine dosage levels of acetone
cyanohydrln to be used 1n a teratology study (IROC, 1983). In this range-
finding study, groups of five Charles River COBS CD rats were administered
single doses of 0 (vehicle control), 1.0, 2.5, 5.0, 7.5 or 10.0 mg/kg In
water by gavage on days 6-15 of gestation. The animals were sacrificed on
day 20 of gestation for gross examinations of the uterus, ovaries and abdom-
inal and thoracic organs, but teratologlcal evaluations were not conducted.
0115d -32- *' 05/10/88
-------
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No rats died during the study, and there were no treatment-related clinical
signs, alterations In mean body weight or gross pathologic alterations 1n
the maternal rats. The uterine examinations revealed no treatment-related
alterations In viable fetuses/dam, postlmplantatlon loss/dam, total
Implantations/dam or corpora lutea/dam. Group mean prelmplantatlon and
postlmplantatlon losses were not Increased.
The teratology study of acetone cyanohydrln based on the range-finding
study (IRDC, 1983) was also conducted by International Research and
Development Corporation (IROC, 1984). Groups of 25 Charles River COBS CO
rats were administered single doses of 0 (vehicle control), 1, 3 or 10 mg/kg
1n water by gavage on days 6-15 of gestation. The rats were sacrificed on-
day 20 of gestation for teratologlc evaluation; -50% of the fetuses were
examined for soft tissue abnormalities, and the remaining fetuses were
examined for skeletal abnormalities. No rats died during the study, and
there were no treatment-related clinical signs or gross pathologic altera-
tions In the abdominal or thoracic cavities 1n the maternal rats. Maternal
body weight gain In the 3 and 10 mg/kg/day dosage groups was slightly lower
than In the control group during the overall treatment (days 0-20) and
gestation (days 6-15) periods (statlslcal evaluation of data not provided).
There were no treatment-related effects on numbers or location of viable or
nonvlable fetuses, numbers of early or late resorptlons, numbers of total
Implantations or corpora lutea, fetal body weights or external, visceral or
skeletal fetal malformations. Conclusions as to teratogenlc potential are
limited since the highest dose level employed did not produce frank maternal
effects.
6.5. OTHER REPRODUCTIVE EFFECTS
The fertility of female Sprague-Oawley rats exposed to acetone cyano-
hydrln (98.5% pure) by Inhalation was evaluated In a study conducted by
0115d -34- * 08/02/88
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Monsanto Company (K1er et al., 1985a). Groups of 24 virgin females were
exposed at nominal concentrations of 0, 10, 30 or 60 ppm for 6 hours/day, 5
days/week for 21 exposure days and mated to untreated males. The average
mean analytical exposure concentrations for all exposure days were 10.7
(range 9.8-11.6), 30.4 (26.0-34.4) and 58.6 (51.8-62.0) ppm. The females
were sacrificed on gestation day 13 or on the nearest working day after
gestation day 13 (up to gestation day 15). Upon sacrifice, tissues and
organs of the abdominal and thoracic cavities were examined for gross
lesions and fertility was evaluated. There were no deaths or treatment-
related body weight alterations or gross lesions In the maternal rats 1n any
of the groups. The only frequently observed clinical sign was postexposure.
red nasal discharge or encrustation; this effect appeared to be related to
exposure at 58.6 ppm during the third week but was not judged to be a
significant toxic response. There were no treatment-related effects on
fertility as evaluated by mating efficiency, pregnancy rates, numbers of
live Implants and pre- and postlmplantatlon losses.
In another study conducted by Monsanto Company, fertility was evaluated
1n male Sprague-Dawley rats exposed to acetone cyanohydrln (98.5X pure) by
Inhalation (Kler et al., 1985b). Groups of 15 rats were exposed to nominal
concentrations of 0, 10, 30 or 60 ppm for 6 hours/day, 5 days/week for 48
exposure days (study duration 69 days) and mated to untreated virgin
females. The average mean analytical exposure concentrations for all expo-
sure days were 10.0 (range 7.2-11.3), 28.5 (23.4-31.6) and 57.2 (47.4-61.2)
ppm. The males were sacrificed at the end of the exposure period for gross
examination of the thoracic, abdominal and scrotal cavities. The females
were sacrificed on gestation days 13-15 for gross necropsy and determination
of number of Implantations and pre- and postlmplantatlon loss. None of the
male rats died, and there were no treatment-related clinical signs, body
0115d -35- '' 08/02/88
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weight alterations or gross pathologic lesions. There also were no
treatment-related effects on fertility as evaluated by mating efficiency,
pregnancy rates, numbers of live Implants and pre- and postlmplantatlon
losses.
6.6. SUMMARY
Information 1s available regarding the subchronlc Inhalation toxldty of
acetone cyanohydMn. Rats exposed to approximate concentrations of 10, 30
or 60 ppm for 6 hours/day, 5 days/week for -14 weeks showed no treatment-
related signs of toxlclty or hematologlcal, serum biochemical or gross or
hlstologlcal effects (Blank and Thake, 1984). Signs of toxldty were
observed at >30 ppm In a 4-week study of essentially Identical design (Blank
and R1bel1n, 1985; Roloff et a!., 1985). The reason for the Inconsistency
In the results of the two studies 1s not apparent, and clinical observations
1n fertility studies (K1er et al., 1985a,b) conducted at the same concentra-
tions support the findings of the 14-week study. Pathologic lesions of the
lungs, kidney and liver were observed 1n rats exposed to acetone cyanohydrln
by Inhalation (Motoc et al., 1971); exposure Information 1n this study was
Inadequately reported.
Inadequately reported subchronlc oral toxldty studies have been
conducted with two a-hydroxylated cyanohydrlns, acetone cyanohydrln and
formaldehyde cyanohydrln. In the study with acetone cyanohydrln (Motoc et
al., 1971), 5 mg doses were administered to rats by an unspecified method
twice a week for 3, 5 or 8 months. Treatment-related effects Included
various serum enzyme and protein alterations and lesions of the stomach,
liver and kidneys. In the study with formaldehyde cyanohydrln (Wolfsle,
1960), "111 effects" were not observed 1n rats maintained on diets that
provided doses of 62 mg/kg/day (males) or 92 mg/kg/day (females) for 13
weeks (Holfsle, 1960); toxldty endpolnts were not reported.
0115d -36- *' 05/31/88
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Ethylene cyanohydMn, a B-hydroxyl cyanohydrln, was administered to rats
of both sexes In drinking water that provided doses of 0, 10, 30, 90 or 270
mg/kg/day for 90 days (Sauerhoff et al., 1976). There were no treatment-
related alterations 1n body weight or hematology or urlnalysls Indices.
Gross and hlstologlcal examinations were unremarkable, but brain and heart
weights were slightly but significantly lowered In the females dosed at 90
and 270 mg/kg/day. Dietary administration of ethylene cyanohydrln to
growing rats at a dose of 1.31 g/day for 52-56 days did not produce skeletal
deformities or femoral flbrosls (Bachhuber et al., 1955).
Chronic tox1c1ty/cardnogen1c1ty data are available only for ethylene
cyanohydrln. Ethylene cyanohydrln was administered to male rats In diet io
concentrations of 0, 100, 1000 or 3000 ppm for 78 weeks (Hlrose et al.,
1980). Groups of male mice were similarly exposed to 100, 1000 or 3000 ppm
ethylene cyanohydrln for 78 weeks and maintained for an additional 7 weeks
without treatment. Slightly decreased final body weight, slightly Increased
relative liver weight and slightly decreased RBC count, WBC count, hemato-
crH and hemoglobin occurred at >100 ppm In the rats; there were no treat-
ment-related gross or hlstologlcal effects. Mean final body weights were
slightly decreased 1n mice at >1000 ppm; hematology and blood biochemistry
evaluations were not conducted In the mice, but organ weight and gross and
hlstologlcal examinations were unremarkable.
Acetone cyanohydrln did not produce reverse mutations In S. typhlmurlum.
forward mutations In CHO cells jji vitro or chromosome aberrations In rat
bone marrow cells following oral administration (see Table 6-2). Genotoxlc-
Uy studies of the other cyanohydMns were not located.
0115d -37- 05/31/88
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Acetone cyanohydrln was not teratogenlc or fetotoxlc In rats treated
with doses of 1, 3 or 10 mg/kg by gavage on days 6-15 of gestation (IRDC,
1984). There were no effects on fertility 1n male or female rats exposed to
acetone cyanohydrln by Inhalation at nominal concentrations of 10, 30 or 60
ppm for 6 hours/day, 5 days/week for 48 (male) or 21 (female) exposure days
(K1er et al., 1985a,b).
OllSd -38- > 05/10/88
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
An oral ADI of 4.9 mg/day was derived for acetone cyanohydrln by analogy
to cyanide (U.S. EPA, 1985b) (Section 8.2.2.2.).
An RQ of 10 Is listed for acetone cyanohydrln (U.S. EPA, 1987).
NIOSH (1978) recommended a celling concentration limit of 1 ppm for any
!5-m1nute period for occupational exposure to acetone cyanohydrln. This
recommendation 1s based on data Indicating that acetone cyanohydrln Is 18.3
times as toxic as acetonltHle by Inhalation, and on the apparent ability of
a-hydroxyl cyanohydrlns to readily release hydrogen cyanide.
NIOSH (1978) recommended a celling concentration limit of 2 ppm for any
15-mlnute period for occupational exposure to formaldehyde cyanohydrln
(GlycolonltrUe). This recommendation 1s based on data Indicating that
formaldehyde cyanohydrln 1s -11 times as toxic to rats as acetonltMle and
that the onset of toxic action Is expected to be rapid.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to cyanohydrlns were not located In the available literature cited
In Appendix A.
0115d -39- 05/31/88
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled cyanohydrlns were not located 1n the available literature cited 1n
Appendix A.
8.1.2. Oral. Pertinent data regarding the oral cardnogenldty of the
a-hydroxyl cyanohydrlns were not located 1n the available literature cited
1n Appendix A.
Ethylene cyanohydrln was administered to groups of 43 male Wlstar rats
(7 weeks old) 1n diet 1n concentrations of 100, 1000 and 3000 ppm for 78
weeks (Hlrose et al., 1980); 31 male rats served as controls. Groups of 50
male ICR mice were similarly exposed to 100, 1000 or 3000 ppm ethylene
cyanohydrln for 78 weeks and maintained for an additional 7 weeks without
treatment; 30 male mice served as controls. Gross and hlstologlcal examina-
tions conducted on all rats and mice did not show significantly Increased
Incidences of tumors or preneoplastlc lesions.
8.1.3. Other Routes. Pertinent data regarding cyanohydrln cardno-
genldty by routes other than oral or Inhalation were not located In the
available literature dted 1n Appendix A.
8.1.4. Weight of Evidence. Pertinent data regarding the cardnogenldty
of the a-hydroxyl cyanohydrlns are not available. Acetone cyanohydrln did
not produce mutations 1n S. typhlmurlum or CHO cells, or chromosome aberra-
tions In rat bone marrow cells In vivo (see Section 6.3.). Using the EPA
ranking system (U.S. EPA, 1986b), the a-hydroxyl cyanohydrlns that are the
subject of this report are categorized 1n EPA Group D (not classifiable as
to human carclnogenlclty).
0115d -40- * 05/10/88
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Ethylene cyanohydrln was not carcinogenic In rats or mice 1n an
adequately designed 78-week feeding study (Hlrose et al., 1980).
8.1.5. Quantitative Risk Estimates. Quantitative estimation of carcino-
genic risk Is precluded by the lack of appropriate data.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- Two similarly
designed subchronlc Inhalation studies of acetone cyanohydrln have been
conducted by Monsanto Company. In one study, groups of 15 Sprague-Dawley
rats of each sex were exposed to mean measured concentrations of 0, 10.1,
28.6 or 57.7 ppm for 6 hours/day, 5 days/week (except holidays) for -H
weeks (minimum 69 exposure days) (Blank and Thake, 1984). In the other
study, groups of 10 Sprague-Dawley rats of each sex were exposed to mean
measured concentrations of 0, 9.2, 29.9 or 59.6 ppm for 6 hours/day, 5
days/week (except holidays) for -4 weeks (minimum 19 exposure days) (Blank
and R1bel1n, 1985; Roloff et al., 1985). Evaluations 1n both studies
Included observations for gross signs of toxlclty on each exposure day,
weekly weight measurements throughout the study, serum chemistry, hematology
and urine volume determinations prior to terminal sacrifices, organ weight
determinations and gross pathological examinations 1n all animals from all
exposure groups. Hlstologlcal examinations were performed only on rats from
the control and high concentration groups. Absorption of compound was
Indicated by Increased thlocyanate concentrations 1n the serum and urine at
all exposure levels 1n both studies. Deaths or treatment-related effects of
any type were not observed In the 14-week study. In contrast, compound-
related signs of toxlclty were observed In both sexes 1n the 4-week study;
these Included Irritation of the eyes and nose, and breathing difficulties
0115d -41- 08/02/88
-------
at >29.9 ppm, and hypoactlvlty at 59.6 ppm. Additionally, signs associated
with anoxla/hypoxla (e.g., respiratory distress), tremors and convulsions,
foaming at the mouth and prostrate posture were observed In 4/10 high-
concentration males following the first exposure; three of these rats
subsequently died. Another effect 1n the high concentration males was
reduced mean body weight; this reduction was not statistically significant
but was considered to be compound-related by the Investigators. Also, signs
of toxUHy were not observed 1n rats exposed to acetone cyanohydrln by
Inhalation at the same nominal concentrations (10, 30 or 60 ppm) for 6
hours/day, 5 days/week for 48 (males) or 21 (females) exposure days In
fertility studies (Kler et al., 1985a,b).
Acetone cyanohydrln was administered to a group of 50 albino rats by
Inhalation at a reported concentration of 1 ml/84 i of air for 18
sessions 1n 3 months, 40 sessions 1n 5 months or 65 sessions 1n 8 months
(Motoc et al., 1971). The duration of the sessions was not reported.
Effects of exposure Included pathologic alterations of the lung and unspeci-
fied Irreversible lesions of the kidney and liver (see Section 6.1.1.1.).
Additional Information regarding the design or results of this study were
not available. The approximate saturation concentration for acetone cyano-
hydrln Is 0.3 ml/84 l (1026 ppm) air.
The 14-week study (Blank and Thake, 1984) Is the most appropriate basis
for a subchronlc Inhalation RfD for acetone cyanohydrln. Reporting Inade-
quacies, particularly the lack of detail regarding exposure duration and
uncertainty regarding actual exposure concentration, preclude assessment of
the Motoc et al. (1971) study. Evaluation of the 14-week study (Blank and
Thake, 1984) Is complicated by Inconsistencies with the results of the
essentially Identical 4-week study (Blank and Rlbelln, 1985). As Indicated,
0115d -42- * 08/02/88
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signs of toxldty were observed at the middle and high concentration levels
1n the 4-week but not 1n the 14-week study or the fertility studies. These
effects represent acute responses consistent with cyanide Intoxication, and
the more severe effects (tremors, convulsions and death following the first
exposure) only occurred at the high concentration (59.6 ppm) 1n the males.
Although there 1s no obvious explanation for the absence of signs of toxlc-
Hy 1n the 14-week and fertility studies, H could be due to Intrastraln
differences, exposure concentration fluctuations or other relevant vari-
ables, and cannot be d-lscounted. Also, Smyth et al. (1962) found that
exposure to 62.5 ppm for 4 hours caused death 1n 2/6 rats (see Table 6-1).
Therefore, the 10.1 ppm (35.2 mg/m3) NOEL from the 14-week study will be
used as the basis for a subchronlc Inhalation RfD for acetone cyanohydrln.
If 35.2 mg/ma 1s multiplied by 6/24 hours and 5/7 days to adjust for
partial dally and weekly exposure, multiplied by the reference rat
respiratory volume of 0.223 mVday and divided by the reference rat body
weight of 0.35 kg, the NOEL dose Is 4.0 mg/kg/day. Dividing this dose by an
uncertainty factor of 100 (10 for Interspecles extrapolation and 10 to
protect most sensitive Individuals) yields a subchronlc Inhalation RfD of
0.04 mg/kg/day or 3 mg/day for a 70 kg human for acetone cyanohydrln. If It
1s assumed that human respiratory volume 1s 20 ma/day, the air concentra-
tion corresponding to the RfD Is 0.15 mg/m3. Confidence In the RfD Is
medium because of the uncertainties regarding the appropriateness of the
NOEL.
Pertinent data regarding subchronlc Inhalation toxldty of the other
cyanohydrlns were not located 1n the available literature cited In
Appendix A.
0115d -43- 05/31/88
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8.2.1.2. CHRONIC EXPOSURES Pertinent data regarding chronic
Inhalation toxldty of the subject cyanohydrlns were not located 1n the
available literature cited In Appendix A. It 1s appropriate to adopt the
subchronlc Inhalation RfD for acetone cyanohydrln (3 mg/day, 0.15 mg/m3)
as the chronic Inhalation RfD for this compound, because acetone cyanohydrln
exhibits effects similar to Us molar equivalent 1n free cyanide under
physiological conditions (WlllhUe and Smith, 1981) (see Section 5.3.).
Also, there Is little difference 1n short-term and long-term toxldty of
cyanide because of Us mechanism of toxldty and lack of bloaccumulatlon
(U.S. EPA, 1985a). Confidence 1n the RfD Is medium because of uncertainty
regarding the appropriateness of the subchronlc NOEL.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) Inadequately
reported subchronlc oral toxldty studies have been conducted with two
a-hydroxyl cyanohydrlns, acetone cyanohydrln and formaldehyde cyanohydrln.
In the study with acetone cyanohydrln (Motoc et'al., 1971), 5 mg doses were
administered to 50 white rats by an unspecified method twice a week for 3, 5
or 8 months; the number of rats exposed for each duration was not specified.
Biochemical effects were attributed to treatment. Including decreased serum
total proteins and albumin/globulin ratio, Increased serum gamma-globulin,
transamlnase, aldolase and Ieuc1nam1nopept1dase levels, altered levels of
serum glycoprotelns (Increased by 3 months, decreased by 5 months and
Increased gradually by 8 months without returning to normal), altered
B-glucuronldase activity (Increased Initially but decreased by the end of
the study), Increased activities of hepatic leudnamlnopeptldase, SGOT and
SGPT, and unspecified alterations 1n hepatic protein metabolism. Hlsto-
pathologlc examinations of the stomach, liver and kidney revealed Increased
OllSd -44- ' 05/31/88
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gastric gland secretions and stomach ulceratlons, reversible and Irrevers-
ible dystrophlc alterations In the liver cells and unspecified kidney
lesions. Limitations of this study Include Inadequate control data, use of
a single dose level and Intermittent bolus exposure (5 mg/rat, 2 days/week),
which does not adequately represent steady-state exposure. Additionally,
there 1s uncertainty regarding actual dosage. If It Is assumed that the
average body weight of the rats was 0.35 kg (U.S. EPA, 1986c), then the
dosage was -14 mg/kg, which 1s 1n the range of the single dose oral LD_
for rats determined by Smyth" et al. (1962) (17 mg/kg} (see Table 6-1).
Evaluation of this study 1s precluded by the Inadequate reporting, particu-
larly with respect to the unspecified method of oral administration and the
lack of Information regarding signs of toxlclty and survival.
In the study with formaldehyde cyanohydrln (Wolfsle, 1960), diets that
provided doses of 62 mg/kg/day (males) and 92 mg/kg/day (females) were
administered to unspecified numbers of albino rats for 13 weeks. No "111
effects" were observed In the study. A dose-related Increase In serum
thlocyanate was reported, but additional Information was not provided.
Interpretation of these results 1s precluded by the Inadequate Information
regarding experimental design and results, particularly, unspecified
toxlclty endpolnts.
It Is Inappropriate to use the above studies as bases for derivations of
subchronlc oral RfDs for acetone cyanohydrln and formaldehyde cyanohydrln
because of the Inadequacies Indicated above. It 1s appropriate, however, to
adopt the chronic oral RfD for acetone cyanohydrln as the subchronlc RfD for
this compound, as there 1s little difference 1n the short-term and long-term
toxldty of cyanide because of Us mechanism of toxldty and lack of
0115d -45- 09/19/88
-------
bloaccumulatlon (U.S. EPA, 1985a). As discussed 1n Section 8.2.2.2., the
chronic oral RfD for acetone cyanohydMn (0.07 mg/kg/day or 5 mg/day) Is
based on analogy to cyanide.
In a study with ethylene cyanohydMn, groups of 10 Sprague-Dawley rats
(6-7 weeks old) of each sex were administered drinking water that provided
doses of 0, 10, 30, 90 or 270 mg/kg/day for 90 days (Sauerhoff et al.,
1976). Hematologlc evaluations and urlnalyses were conducted on five
rats/sex from the 0 and 270 mg/kg groups on day 85, and serum urea nitrogen
levels, alkaline phosphatase activities and glutamlc pyruvlc transamlnase
activities were determined 1n five rats/sex from each dose group at terminal
sacrifice (day 91 or 92). Comprehensive gross pathologic examinations and
organ (brain, heart, liver, kidney, testls) weight determinations were
performed on all rats, and hlstologlc examinations were performed on five
rats/sex from the 0 and 270 mg/kg/day groups. There were no changes In
physical appearance or demeanor In any of the rats, and no deaths. There
were no treatment-related alterations In food or water consumption, body
weight gain or clinical evaluations. The pathology examinations were
unremarkable, but brain and heart weights were slightly but significantly
(p<0.05) decreased In the 90 and 270 mg/kg/day females.
In another study, dietary administration of ethylene cyanohydHn to six
growing rats at a dose of 1.31 g/day for 52-56 days did not produce skeletal
deformities or femoral flbrosls (Bachhuber et al., 1955). Other relevant
endpolnts were not examined.
Since toxlclty was evaluated Inadequately In the Bachhuber et al. (1955)
study, the findings of Sauerhoff et al. (1976) can be used to derive a
subchronlc oral RfD for ethylene cyanohydrln. Slight but significantly
decreased lowered brain and heart weights 1n female rats at 90 and 270 mg/kg
were the only treatment-related effects. These effects did not occur In
0115d -46- * 05/31/88
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males, and H cannot be determined whether the unremarkable hlstologlcal
evaluations, which were not conducted on all rats, were conducted on the
same rats that had the lowered brain and heart weights. Although these
limitations complicate Interpretation of the significance of the decreased
brain and heart weights, these organs are not normally the most likely to
respond to stress by a significant weight change and are usually cited as
being the target organs f6r acute cyanide toxldty. Therefore, 1t 1s
appropriate to conclude that the decreased brain and heart weights are
toxlcologlcally significant effects and regard 90 and 270 mg/kg as LOAELs.
Division of the highest NOEL (30 mg/kg/day) by an uncertainty factor of 100
(10 for Interspedes extrapolation and 10 to protect the most sensitive-
Individuals) yields a subchronlc oral RfO of 0.3 mg/kg/day, or 21 mg/day for
a 70 kg human, for ethylene cyanohydrln.
8.2.2.2. CHRONIC EXPOSURES Chronic toxldty studies of the
a-hydroxylated cyanohydrlns were not located 1n the available literature
dted 1n Appendix A. Because of the lack of adequate oral subchronlc
studies, an oral ADI for acetone cyanohydrln was derived by analogy to
cyanide (U.S. EPA, 1985b). This approach was used because evidence was
available Indicating that acetone cyanohydrln exhibits effects similar to
Its molar equivalent 1n free cyanide (Hlllhlte and Smith, 1981) (see Section
5.3.). The ADI for acetone cyanohydrln, 0.07 mg/kg/day or 5 mg/day for a 70
kg human (U.S. EPA, 1985b), 1s the molar equivalent of the ADI for cyanide
(0.02 mg CN~/kg/day) (U.S. EPA, 1985a). This ADI 1s adopted as the
chronic oral RfD for acetone cyanohydrln. The ADI for acetone cyanohydrln
based on analogy to cyanide Is tenable only 1f the rate constants for
absorption, distribution, binding to cytochrome oxldase, detoxification and
excretion of cyanide following exposure to cyanide and acetone cyanohydrln
are Identical, or 1f the breakdown of acetone cyanohydrln to cyanide Is
0115d -47- '' 05/31/88
-------
Instantaneous. Because data regarding these rate constants are Insuffi-
cient, there Is low confidence In the ADI and chronic oral RfD and they are
regarded as provisional.
Qualitative evidence Indicates that the other a-hydroxyl cyanohydMns
are also hydrolyzed rapidly to free cyanide under physiologic conditions
(see Section 5.3.). Since data showing that these cyanohydrlns exhibit
effects similar to their molar equivalent In free cyanide or acetone cyano-
hydrln are not available, It Is Inappropriate to base RfDs by analogy to
cyanide.
Ethylene cyanohydrln was administered to groups of 43 male Wlstar rats
(7 weeks old) 1n diet In concentrations of 100, 1000 or 3000 ppm for 78-
weeks (Hlrose et al., 1980); 31 male rats served as controls. Groups of 50
male ICR mice were similarly exposed to 100, 1000 or 3000 ppm ethylene
cyanohydrln for 78 weeks and maintained for an additional 7 weeks without
treatment; 30 male mice served as controls. Females of either species were
not tested. Data for rats after 60 and 78 weeks and mice after 62 weeks
Indicate that there were no treatment-related effects on survival In either
species. Slightly decreased mean final body weight, slightly Increased mean
relative liver weight, and slightly decreased mean RBC count, WBC count,
hematocrlt and hemoglobin occurred at >100 ppm 1n the rats. These effects
were dose-related but are difficult to evaluate because statistical signifi-
cances and food consumption data were not reported; limitations of the
reported data precluded statistical evaluation by SRC. There were no treat-
ment-related effects on liver, kidney or spleen organ weights, or gross or
hlstologlcal alterations, 1n the rats. Mean final body weights were reduced
slightly 1n mice at >1000 ppm, but Interpretation of these data 1s also com-
plicated for the reasons discussed for the rat data. Hematology and blood
0115d -48- * 05/31/88
-------
biochemistry evaluations were not conducted 1n the mice, but organ weight
measurements and gross and hlstologlcal examinations were unremarkable.
The results of the Hlrose et al. (1980) dietary study Indicate that
final body weight was decreased slightly, relative liver weight was
Increased slightly and several hematology Indices were decreased slightly 1n
the rats at >100 ppm, and that final body weight was decreased slightly 1n
the mice at >1000 ppm. Interpretation of these results 1s complicated by
the lack of body weight measurements during the study, lack of food consump-
tion data and lack of statistical evaluation of data. Since the effects
were slight and nonspecific, however, and because comprehensive gross and
hlstologlcal evaluations, conducted on all rats and mice, did not reveal
treatment-related alterations, H 1s appropriate to regard >100 ppm In the
rats and mice as NOAELs. Alternatively, H may be appropriate to consider
3000 ppm 1n rats as a LOAEL since It appears that the body weight and
hematologlcal alterations at this concentration differed from control values
by >10%. If 1t Is assumed that rats and mice consume 5 and 13%, respec-
tively, of their body weights In food dally (U.S. EPA, 1986c), the highest
NOAELs provided doses of 50 or 150 mg/kg/day In the rats and 390 mg/kg/day
1n the mice.
Decreased brain and heart weight occurred 1n female rats at doses of 90
and 270 mg/kg/day, but not 30 mg/kg/day. In the Sauerhoff et al. (1976)
90-day drinking water study. These effects are considered to be toxlcologl-
cally significant, Indicating that 90 and 270 mg/kg/day represent LOAELs
(see Section 8.2.2.1.); 30 mg/kg Is a NOAEL that Is used as the basis for
the subchronlc oral RfD. Since female rats were not tested and hear' and
brain weights were not measured 1n the Hlrose et al. (1980) chronic study,
confidence In the 50 mg/kg/day chronic NOAEL (the only chronic NOAEL below
0115d -49- . 09/19/88
-------
the lowest subchronlc LOAEL) Is low. The 30 mg/kg/day subchronlc NOAEL
therefore appears to be the most appropriate basis for the chronic RfD.
Since there Is little difference In the short-term and long-term toxUHy of
cyanide, H 1s recommended that the subchronlc oral RfD (0.3 mg/kg/day, or
21 mg/day for a 70 kg human) be used as the chronic oral RfD. Confidence In
the RfD Is low because of the lack of adequate chronic toxldty data.
OllSd -50- * 05/31/88
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxldty of the cyanohydrlns was discussed 1n Chapter 6. Studies
potentially useful for derivation of chronic toxlclty-based RQs are avail-
able for acetone cyanohydMn and ethylene cyanohydrln; these are summarized
1n Table 9-1.
The data for acetone cyanohydrln are Inadequate for RQ derivation. In
the Motoc et al. (1971) oral- study, rats were dosed only 2 days/week with a
bolus, which does not represent chronic steady-state exposure. Also, only
one dose level was tested; since a threshold for effects cannot be defined,
this dose may not represent an appropriate MED. The rat Inhalation study of
Motoc et al. (1971) Is Inadequate because the exposure schedule was not
provided, precluding calculation of a dose; also, only a single exposure
level was used. Blank and R1be11n (1985) observed signs of toxldty In rats
exposed to transformed doses of >11.9 mg/kg/day during a 4-week study.
These effects are an Inappropriate basis for RQ derivation because the study
duration Is short, the effects represent acute responses and effects were
not observed 1n H-week (Blank and Thake, 1984) and 21- or 48-day fertility
studies (Kler et al., 1985a,b) of essentially Identical design.
Subchronlc (Sauerhoff et al., 1976) and chronic (Hlrose et al., 1980)
toxldty data are available for ethylene cyanohydrln. The subchronlc study
Is not considered for RQ derivation because the chronic study Is more
appropriate with respect to duration and numbers of animals evaluated. As
detailed 1n Table 9-1, slight effects occurred In rats (decreased body
weight, Increased relative Itver weight, decreased RBC, WBC, hematocrit and
hemoglobin) and mice (decreased body weight) In the chronic study at equiva-
lent human doses of 0.9 and 9.8 mg/kg/day, respectively. Since the effects
OllSd -51- * 05/10/88
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In both species were slight, nonspecific and not accompanied by hlstologlcal
alterations, they are consistent with an RV of 2. CSs are calculated to
C
be 5.6 from the rat data and 2.4 from the mouse data (Table 9-2). The
higher CS corresponds to an RQ of 1000 and Is selected as the basis for the
RQ for ethylene cyanohydrln (Table 9-3). Insufficient data are available
for derivation of RQs for formaldehyde, lactonHMle, benzaldehyde and
acetone cyanohydrln (Table 9-4).
9.2. BASED ON CARCINOGENICITY
Ethylene cyanohydrln was not tumoMgenie when administered to male rats
or mice 1n the diet In concentrations of 100, 1000 and 3000 ppm for 78 weeks
(Hlrose et al., 1980). Cardnogenlclty of the other cyanohydrlns that ace
the subject of this report has not been evaluated. The lack of appropriate
data precludes derivation of carc1nogen1dty-based RQs.
0115d -54- 05/31/88
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-55-
05/10/88
-------
TABLE 9-3
Ethylene Cyanohydrln
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 60 rag/day
Effect: decreased body weight, RBC, UBC, hematocrlt and
hemoglobin; Increased liver weight
Reference: Hlrose et al., 1980
RVd: 2.8
RVe: 2
Composite Score: 5.6
RQ: 1000
*Equ1valent human dose
OllSd -56- * 05/10/88
-------
TABLE 9-4
Formaldehyde Cyanohydrln, LactonUrlle, Benzaldehyde Cyanohydrln
and Acetone Cyanohydrln
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Insufficient data are available for derivation of an RQ.
0115d -57- * 05/10/88
-------
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0115d -67- 09/19/88
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OllSd -68- j. 09/19/88
-------
APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted 1n October 1987, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2A. John WHey and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0115d -69- *' 05/10/88
-------
Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John WHey and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Meek Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of.Industrial Materials, 6th
ed. Van Nostrand Relnhold- Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0115d -70- * 05/10/88
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed. Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0115d -71- * 05/10/88
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