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#### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

**WASHINGTON, D.C. 20460**

**OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES**

**[MEMORANDUM]{.underline}**

July 10, 2006

**SUBJECT: Sodium Cyanide** Revised HED Risk Assessment for Tolerance
Reassessment Eligibility Decision (TRED) Document PC Code No. 074002; DP
Barcode No. 318015

**FROM:** Becky Daiss

Environmental Health Scientist

> Reregistration Branch 4
>
> Health Effects Division (7509C)

**THROUGH:** Susan V. Hummel

Branch Senior Scientist

> Reregistration Branch 4
>
> Health Effects Division (7509C)

**TO:** Wilhelmena Livingston

Chemical Review Manager

Reregistration Branch 1

Special Review and Registration Division (7508C)

Attached is Health Effects Division's (HED's) revised risk assessment of
sodium cyanide for purposes of issuing a Tolerance Reassessment
Eligibility Decision (TRED) Document for this active ingredient. The
risk assessment has been revised to incorporate new residue data
submitted by the registrant and water monitoring data provided by the
Arizona Department of Environmental Quality. The disciplinary science
chapters and other supporting documentation are incorporated into the
risk assessment or included as appendices as follows:

> Hazard Identification Assessment; Bill Dykstra - Section 4 and
> Appendices 1 & 2
>
> Residue Chemistry Assessment; Thurston Morton (D30275, 6/29/06)
>
> Dietary Exposure and Risk Assessment; Becky Daiss - Section 6

Occupational and Residential Exposure Assessment, David Jaquith
(D318017, 4/4/06)

> Drinking Water Assessment; Faruque Khan (D318020, 2/7/06)

**TABLE OF CONTENTS**

pg.

1.0 EXECUTIVE SUMMARY 4

2.0 INGREDIENT PROFILE 8

2.1 Summary of Registered and Proposed Uses 8

2.2 Structure, Nomenclature and Physical/Chemical Properties 9

3.0 METABOLISM ASSESSMENT 9

3.1 Comparative Metabolic Profile 9

> 3.1.1 Metabolism in Mammals 9
>
> 3.1.2 Plant Metabolism 10
>
> 3.1.3 Livestock Metabolism 10

3.2 Environmental Degradation 10

3.3 Metabolites and Degradates 11

3.4 Summary of Residues for Tolerance Expression and Risk Assessment 11

4.0 HAZARD CHARACTERIZATION/ASSESSMENT 11

4.1 Hazard Characterization 11

4.2 FQPA Hazard Considerations 19

> 4.2.1 Adequacy of the Toxicity Data Base 19
>
> 4.2.2 Evidence of Neurotoxicity 19
>
> 4.2.3 Developmental Toxicity Studies 21
>
> 4.2.4 Reproductive Toxicity Studies 23
>
> 4.2.5 Pre-and/or Postnatal Toxicity 25
>
> 4.2.6 Recommendation for a Developmental Neurotoxicity Study 25

4.3 FQPA Safety Factor 25

4.4 Hazard Identification and Toxicity Endpoint Selection 26

> 4.4.1 Acute Reference Dose - General Population 26
>
> 4.4.2 Chronic Reference Dose 27
>
> 4.4.3 Dermal Absorption 29
>
> 4.4.4 Dermal Exposure All Durations 29
>
> 4.4.5 Inhalation Exposure All Durations 29
>
> 4.4.6 Margins of Exposure 30
>
> 4.4.7 Recommendation for Aggregate Exposure Risk Assessments 30
>
> 4.4.8 Classification of Carcinogenic Potential 30
>
> 4.4.9 Summary of Endpoints Selected for Risk Assessment 31

4.5 Endocrine Disruption 31

5.0 PUBLIC HEALTH DATA 32

6.0 DIETARY EXPOSURE ASSESSMENT 32

6.1 Dietary Profile 32

> 6.1.1 Magnitude of the Residue in Plants and Animals 32
>
> 6.1.2 Residue Analytical Method 33

6.2 Drinking Water Profile 33

6.3 Dietary Exposure and Risk 33

7.0 OCCUPATIONAL EXPOSURE AND RISK 36

7.1 Regulatory Standards 36

7.2 Exposure Monitoring Study 36

7.3 Inhalation Exposure and Risk 37

7.4 Dermal Exposure and Risk 38

8.0 AGGREGATE EXPOSURE AND RISK 38

9.0 CUMULATIVE RISK 38

10.0 DATA NEEDS 38

10.1 Residue Chemistry Data Requirements 38

10.2 Toxicology Data Requirements 39

APPENDICES

1.0 GUIDELINE TOXICOLOGY DATA SUMMARY 40

2.0 NON-CRITICAL TOXICOLOGY STUDIES 41

3.0 REFERENCES 41

**1.0 EXECUTIVE SUMMARY**

This assessment provides information to support the issuance of a risk
management decision document known as a Tolerance Reassessment
Eligibility Decision (TRED) Document for sodium cyanide. EPA's pesticide
reregistration process provides for the review of older pesticides
(those initially registered prior to November 1984) under the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) to ensure that they
meet current scientific and regulatory standards. The process considers
the human health and ecological effects of pesticides and incorporates a
reassessment of tolerances (pesticide residue limits in food) to ensure
that they meet the safety standard established by the Food Quality
Protection Act (FQPA) of 1996. This document addresses the exposures and
risks associated with dietary, drinking water, and residential uses of
cyanide. Occupational exposures were partially addressed in
Reregistration Eligibility Decision (RED) for Sodium Cyanide published
in 1994. Occupational exposures not addressed in the RED are also
assessed in this document.

**Use Profile**

Sodium cyanide is used as a predacide/rodenticide and as a pesticide. As
a predacide/rodenticide, it is used as a single dose poison in the M-44
ejector device to control animals that prey upon livestock and
threatened or endangered species or that are vectors of communicable
disease. For application, each capsule is loaded into an ejector
mechanism of an M-44 device which has been pounded into the ground for
use. The capsule holder is treated with a scent used to attract canids
to the unit. When an animal tugs at the capsule holder, a spring-driven
plunger ejects the sodium cyanide capsule into its mouth. This product
is limited to use only by trained and certified applicators under the
direct supervision of a government agency.

As an insecticide, sodium cyanide is used a source of hydrocyanic gas
for quarantine fumigation of surface pests on citrus. Currently, there
are no active registrations for sodium cyanide with food/feed uses.
However, there is one Special Local Needs (SLN) food/feed use
registration for sodium cyanide. The SLN end-use product is formulated
as a granular containing 98% sodium cyanide as the active ingredient
(ai). Sodium cyanide is applied to citrus as a post-harvest fumigant. It
used as a source of hydrogen cyanide gas. Sodium cyanide is used in
California to control red scale on fresh market citrus bound for
Arizona. It is applied by professional applicators only. A tolerance for
residues of the insecticide hydrogen cyanide from postharvest fumigation
as a result of application of sodium cyanide is established at 50 ppm in
or on citrus fruit (40 CFR §180.130). There are no products available
for residential application. OPP's Biological and Economical Analysis
Division (BEAD) estimates that approximately 2800 pounds of sodium
cyanide are used annually on agricultural crops (i.e., fresh citrus
commodities) in California (personal communication, Bill Chism, BEAD).

**Regulatory History**

Sodium Cyanide is a FIFRA List C reregistration pesticide. The 1994 RED
assessed only the use of sodium cyanide as a predacide/rodenticide. The
Agency issued a Data Call-In (DCI) for sodium cyanide in September, 1992
requiring additional product chemistry and ecological effects data. The
1994 RED reflects a reassessment of all data submitted in response to
the 1992 DCI. The 1994 RED determined that the data were sufficient to
allow the Agency to assess the registered predacide uses of sodium
cyanide and to determine that sodium cyanide could be used without
resulting in unreasonable adverse effects to humans and the environment.
This TRED addresses the FQPA requirement for reassessment of tolerances
for hydrogen cyanide and provides an assessment of worker exposure
associated with use of sodium cyanide as a source of hydrocyanic gas for
fumigation of surface pests on citrus.

**Hazard Identification**

The toxicology database for hydrogen cyanide is incomplete. No guideline
studies are available. All of the critical studies are cited from the
open literature. Data on all forms of cyanide (e.g., hydrogen, sodium,
potassium cyanide etc.) have been used to identify hydrogen cyanide
toxicity for this assessment. Hydrogen cyanide is extremely acutely
toxic by all exposure routes.

All forms of cyanide, hydrogen, sodium, and potassium, are extremely
acutely toxic by the oral route. Based on an analysis of case history
data the lowest fatal oral dose of hydrogen cyanide for an average adult
human is estimated by FDA to be 1 mg/kg. The lowest reported fatal dose
of cyanide (unspecified form) in humans was estimated to be 0.56 mg/kg
based on incidence data published in 1938. The acute oral fatal dose of
potassium cyanide in rats is 10-15 mg/kg, which is equivalent to 4-6
mg/kg hydrogen cyanide. Results of clinical trials of Laetrile to treat
cancer also provide evidence of the acute oral toxicity of hydrogen
cyanide. Laetrile, also known as amygdalin, is a plant compound that
produces cyanide. Use of Laetrile has been shown to produce side effects
of cyanide poisoning---which can produce a range of symptoms, including
death. In a clinical trial of Laetrile to treat human cancer, the single
dose of 0.5 g of amygdalin was determined to be minimally toxic; a
single dose of 0.5 g of amygdalin is equivalent to 0.4 mg/kg hydrogen
cyanide/day. The double dose (two 0.5 g doses at an administration) was
generally regarded as frankly toxic producing increased blood levels and
associated increase in the incidence and severity of some of the toxic
signs and symptoms.

The dose-effect curve of the acute inhalation effects in humans is
steep. Slight effects occur at exposure levels of 20-40 mg/m^3^, 150
mg/m^3^ is likely to be fatal within 30 minutes, 200 mg/m^3^ is likely
to be fatal after 10 minutes, and 300 mg/m^3^ is immediately fatal.

An average LD~50~ value for human dermal exposure is estimated to be 100
mg/kg HCN (Toxicity Category I). Air concentrations of 7000-12,000
mg/m^3^ HCN were estimated to be fatal after a 5 minute exposure of
workers with self-contained respirators without effective skin
protection. Cyanides are weakly irritating to the skin and eye. No data
are available on sensitizing properties.

The primary effects of acute cyanide exposure in humans are central
nervous system and cardiovascular disturbances. Typical signs of acute
cyanide poisoning include tachypnea, headache, vertigo, lack of motor
coordination, weak pulse, cardiac arrhythmias, vomiting, stupor,
convulsions, and coma.

Hydrogen cyanide exhibits relatively low subchonic and chronic toxicity
by the oral route. In a 13 week repeated dose toxicity study in which
sodium cyanide was administered in the drinking water, there were no
mortalities, no clinical signs, and no histopathological effects in the
brain, thyroid, or other organs of rats and mice exposed to doses up to
12.5 and 26 mg/kg/day. A 2-year rat feeding study with hydrogen cyanide
fumigated food containing residues up to 10.8 mg/kg/day showed no
treatment-related effects. In this 2-year study, rats ingested 2 to 3
times the fatal acute dose of hydrogen cyanide each day throughout their
lifetime without any measurable effects. Significantly, animals in the
subchronic and chronic studies showed definite increases in thiocyanate
concentrations indicating that metabolic detoxification of hydrogen
cyanide had occurred. Thiocyanate is the less toxic primary metabolite
of cyanide. Hydrogen cyanide is readily converted to thiocyanate in the
liver by the enzyme rhodanese. This metabolic conversion is the major
detoxification mechanism for hydrogen cyanide. Results of both animal
and human FDA studies indicate that as long as the oral intake of
hydrogen cyanide does not exceed the body's detoxification mechanisms
via the formation of thiocyanate, hydrogen cyanide can be ingested in
the form of dietary residues for prolonged periods without harm.

There are neurotoxicity, developmental and reproductive studies
available with naturally occurring cyanides or cyanide salts in the open
literature. However, there are no EPA guideline studies of these types
of studies available. Based on literature studies, neurotoxic effects
are a major occurrence across species from exposure to cyanide in its
various forms. There are no developmental or reproductive toxicity
studies for hydrogen cyanide. Developmental and reproductive studies
with other forms of cyanide were available and reviewed for this
assessment. The weight of the evidence of available data indicates that
cyanide induces developmental effects only at doses or concentrations
that are overtly toxic to the maternal animals.

Because there are no EPA guideline neurotoxicity, developmental and
reproductive studies available, an assessment of FQPA hazard
considerations are based on the available open literature citations.
Based on the available data, there was no qualitative or quantitative
increased susceptibility in postnatal offspring toxicity and there is a
low degree of concern for residual uncertainties for pre and/or
post-natal susceptibility. Therefore, it is recommended that the FQPA
safety factor be reduced to 1x for the hydrogen cyanide risk assessment.

There are no guideline studies and no available open literature studies
on the carcinogenic potential of cyanide. However, acute lethal effects
of cyanide likely preclude the need for carcinogenic evaluation.
Hydrogen cyanide has been evaluated for mutagenic potential with mixed
results.

Cyanide gas and salts are rapidly absorbed following inhalation and oral
exposure. They are more slowly absorbed by dermal exposure. Animal
studies have shown that cyanide does not accumulate in the blood and
tissues following chronic oral exposure. Cyanide metabolites are mainly
excreted in the urine, with small amounts excreted through the lungs
(ATSDR, 2004). Following inhalation, cyanide is rapidly distributed
throughout the body, with measurable levels detected in all organs.

Cyanide is a rapid acting blocker of oxygen utilization at the cellular
level. Hydrogen cyanide binds with cytochrome oxidase (a ferric enzyme)
in the electron transport system and inhibits the exchange of oxygen
from the blood to the tissues by the mechanism of competitive
inhibition.

**Dose Response Assessment**

Toxicological endpoints were selected for dietary and occupational
exposure via inhalation, the relevant scenarios for exposure to hydrogen
cyanide for this TRED. The acute RfD for the general population was
selected based on published data from a clinical trial of amygdalin
(Laetrile) to treat human cancer. Hydrogen cyanide is extremely acutely
toxic at doses lower than doses at which chronic effects are observed.
Therefore, the acute endpoint is considered protective for chronic
toxicity and a chronic RfD was not selected. An inhalation exposure
endpoint for all durations was selected from a subchronic hydrogen
cyanide inhalation toxicity study in rats based on the effect of
mortality.

An uncertainty factor (UF) of 100 was applied to the acute RfD based on
application of a 10X for intraspecies variations, and 10X for lack of a
LOAEL, steep dose-response curve, and severity of toxic effect. The
target level of concern (LOC) or margin of exposure (MOE) for
occupational exposure via inhalation is 30X (3X interspecies factor and
10x intraspecies factor).

**Exposure/Risk Assessment and Risk Characterization**

Risk assessments were conducted for acute dietary and occupational
exposure pathways only based on label prescribed uses. Chronic dietary
exposure was not assessed because hydrogen cyanide is severely acutely
toxic at doses lower than those at which chronic effects are observed
i.e., protecting for acute effects will also protect against chronic
toxicity. Drinking water exposures were not assessed because the
Environmental Fate and Effects Division (EFED) does not anticipate
significant exposure from hydrogen cyanide in surface or ground water
based on the use pattern. An aggregate assessment of risk from the
combined food and non-food exposures was not conducted because there are
no residential uses of hydrogen cyanide. Residential exposures resulting
from citrus fumigation are not expected based on monitoring data from
the single facility at which hydrogen cyanide fumigation occurs. HED
conducted a somewhat-refined acute probabilistic dietary assessment for
hydrogen cyanide. Recently submitted field trial data were used to
assess potential exposure and risk from consumption of citrus treated
with hydrogen cyanide. HED's acute dietary assessment indicates that
acute dietary exposure estimates are below HED's level of concern. Data
from a worker exposure inhalation monitoring study on fumigations
conducted at the hydrogen cyanide fumigation facility were used to
assess occupational exposure and risk from citrus fumigation. Dermal
exposures are not expected based on the limited use pattern and were
therefore not assessed. Worker exposure and risk estimates indicate that
occupational exposures are below HED's level of concern.

**Use of Human Studies**

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical. These studies, listed below, have been determined to require a
review of their ethical conduct. They are also subject to review by the
Human Studies Review Board (HSRB). All of the listed studies have
received the appropriate review by the HSRB and have been determined to
be ethically and scientifically acceptable.

> Moertel, CG et al (1982) A Clinical Trial of Amygdalin (Laetrile) in
> the Treatment of Human Cancer. New England Journal of Medicine, Vol.
> 306, No.4: 201-206 (MRID 46769602).
>
> Moertel, CG et al (1981) A Pharmacologic and Toxicological Study of
> Amygdalin. JAMA, Vol. 245, No. 6:591-594 (MRID 46769601)

**2.0 INGREDIENT PROFILE**

**2.1 Summary of Registered and Proposed Uses**

There are eight active registrations for sodium cyanide and one SLN
according to the Office of Pesticide Programs Information Network
(OPPIN). Table 1 provides summary information on registered products and
uses.

  ------------------------------------------------------------------------------------------
  **Table 1.                                                                       
  Active Label                                                                     
  Registrations                                                                    
  for Sodium                                                                       
  Cyanide**                                                                        
  --------------- ------------------ ----------------- --------------------------- ---------
  **Reg \#**      **Name**           **Formulation**   **Government                **%ai**
                                                       Entity/Company**            

  13808-8         M-44 Cyanide       Capsule           South Dakota Dept of        91.06
                  Capsules                             Agriculture                 

  33858-2         M-44 Cyanide       Capsule           Texas Department of         91.06
                  Capsules                             Agriculture                 

  35975-2         M-44 Cyanide       Capsule           Montana Department of       91.06
                  Capsules                             Livestock                   

  35978-1         M-44 Cyanide       Capsule           Wyoming Dept of Agriculture 91.06
                  Capsules                                                         

  39260-1         M-44 Cyanide       Capsule           Navajo Fish & Wildlife      91.06
                  Capsules                             Department                  

  39508-1         M-44 Cyanide       Capsule           New Mexico Department of    91.06
                  Capsules                             Agriculture                 

  56228-15        M-44 Cyanide       Capsule           U.S. Department of          91.06
                  Capsules                             Agriculture                 

  56228-32        M-44 Cyanide       Capsule           U.S. Department of          91.06
                  Capsules                             Agriculture                 

  CA840006        Sodium Cyanide     Powder            Washburn & Sons             98
  ------------------------------------------------------------------------------------------

**2.2 Structure, Nomenclature, and Physical/Chemical Properties**

The nomenclature and physicochemical properties of hydrogen cyanide are
provided in Tables 2 and 3.

  ------------------------------------------------------------------------
  **TABLE 2. Test                                 
  Compound                                        
  Nomenclature**                                  
  ---------------------- ------------------------ ------------------------
  **Compound**           **Sodium Cyanide**       **Hydrogen Cyanide**

  Chemical Structure     NaCN                     HC=N

  Common Name            sodium cyanide           hydrogen cyanide

  Synonyms               Hydrocyanic acid,        cyanobrik, cyanogran,
                         prussic acid,            sodium cyanide,
                         formonitrile, formic     hydrocyanic acid sodium
                         anammonide, carbon       salt, cymag
                         hydride nitride, cyclon  

  CAS \#                 74-90-8                  143-33-9

  PC Code                045801                   074002

  Current Food/Feed Site Citrus                   Citrus
  Registration                                    
  ------------------------------------------------------------------------

Source: OSHA, 2004

  -----------------------------------------------------------------------
  **TABLE 3.                                     
  Physicochemical                                
  Properties of the                              
  Technical Grade Test                           
  Compound**                                     
  ---------------------- ----------------------- ------------------------
  **Parameter**          **Sodium Cyanide**      **Hydrogen Cyanide**

  Molecular Weight       49.01                   27.03

  Boiling Point          1496 C at 760 mm Hg     26 C at 760 mm Hg

  Melting Point          564 C                   -13.4 C

  Specific Gravity       1.7                     0.7 at 20 C

  Vapor Density          \--                     0.94

  Vapor Pressure         Negligible              620 mm Hg at 20C

  Solubility             Soluble in water (37    Miscible with water and
                         g/100mL)                alcohol, slightly
                                                 soluble in ether.

  pKa                    \--                     9.22
  -----------------------------------------------------------------------

Source: OSHA, 2004

**3.0 METABOLISM ASSESSMENT**

**3.1 Comparative Metabolic Profile**

> **3.1.1 Metabolism in Mammals**

Cyanide gas and salts such as sodium and potassium cyanide are rapidly
absorbed following inhalation and oral exposure, but are more slowly
absorbed by dermal exposure. Following inhalation, cyanide is rapidly
distributed throughout the body, with measurable levels detected in all
organs. Cyanide can be distributed in the body within seconds and death
can occur within minutes. Animal studies have shown that cyanide *per
se* does not accumulate in the blood and tissues following chronic oral
exposure, however. This is due to the fact that cyanide is transformed
to the much less toxic thiocyanate in the body, with a plasma half-life
of 20 minutes to 1 hour. Hydrogen cyanide is readily converted to
thiocyanate in the liver by the enzyme rhodanese and this metabolic
conversion is the major detoxification mechanism for hydrogen cyanide.
Once thiocyanate is formed, it is not converted back to cyanide. Cyanide
metabolites are mainly excreted in the urine, with small amounts
excreted through the lungs.

> **3.1.2 Plant Metabolism**

The nature of the residue in citrus is adequately defined. The residue
of concern is hydrogen cyanide *per se*. Hydrogen cyanide is rapidly
absorbed by fresh citrus, and depending upon conditions, between 70 to
95% of available hydrogen cyanide is absorbed within one hour. Upon
aeration, less than 5 percent of the sorbed hydrogen cyanide is
desorbed. After 48 hours, most of the sorbed hydrogen cyanide is
\"irreversibly bound.\" There is no evidence that any of the sorbed
hydrogen cyanide is degraded; hydrogen cyanide is stable under acidic
conditions. The available data show that over 90% of the hydrogen
cyanide can be accounted for as such in the treated citrus or as
unsorbed hydrogen cyanide. A study subsequently obtained from University
of California, Riverside indicates that when citrus is fortified with
hydrogen cyanide about 10% of the hydrogen cyanide is unrecoverable. The
studies and data, which the petition response cites, were not available,
however, to verify these claims (PP#1E1124; 2/17/71; W. Cox).

**3.1.3 Livestock Metabolism**

The nature of the residue in livestock has not been defined. However,
there is limited potential for exposure to livestock though feed items
because citrus treated with hydrogen cyanide is destined for fresh
market only. (Personal communication, Bill Chism, BEAD). Additionally,
the Agency response to PP#1E1124 indicates that hydrogen cyanide, when
ingested by animals at subtoxic levels, is rapidly detoxified into
carbon dioxide and thiocyanate, which is largely excreted by the kidneys
(2/17/71; W. Cox).

**3.2 Environmental Degradation**

Sodium cyanide hydrolyzes readily to gaseous hydrogen cyanide when
dissolved in water or in contact with moisture. This reaction is the
primary reaction in the environment. EFED does not anticipate
significant exposure from sodium cyanide or hydrogen cyanide in surface
water and ground water, when it is used as a fumigant under controlled
delivery system of gaseous hydrogen cyanide into an airtight enclosure
as described in the sodium cyanide label (SLA CA 840006). Residual
hydrogen cyanide will be vented from the treated containers through a
exhaust system. In a recent air monitoring study (MRID \# 46648901),
eight-hour time-weighted average concentration of hydrogen cyanide in
ambient air after fumigation of citrus truck trailers was zero ppm.
Based on the nature of the fumigation operation, and due to the high
vapor pressure (620 mm Hg at 20C) and Henry\'s Law Constant (1.33 x
10^-4^ atm-m^3^/mole) of hydrogen cyanide, redeposition of volatilized
hydrogen cyanide in surface water does not appear to be significant,
thus suggesting that contamination of surface waters and ground water by
hydrogen cyanide is unlikely.

3.  **Metabolites and Degradates**

A summary of hydrogen cyanide parent and metabolite matrices is provided
in Table 4.

+-------------+-----------+---------------+-------------+-------------+
| Table 4.    |           |               |             |             |
| Tabular     |           |               |             |             |
| Summary of  |           |               |             |             |
| Metabolites |           |               |             |             |
| and         |           |               |             |             |
| Degradates  |           |               |             |             |
+-------------+-----------+---------------+-------------+-------------+
| Chemical    | Commodity | M             | Mat         | Chemical    |
| Name        |           | atrices-Major | rices-Minor | Structure   |
|             |           | Residue       | Residue     |             |
|             |           |               | (\<10%TRR)  |             |
|             |           | (\>10%TRR)    |             |             |
+-------------+-----------+---------------+-------------+-------------+
| Hydrogen    | Citrus    | 90%           | NA          | HC=N        |
| Cyanide     |           |               |             |             |
+-------------+-----------+---------------+-------------+-------------+
|             | Ruminants | NA            | NA          |             |
+-------------+-----------+---------------+-------------+-------------+
|             | Poultry   | NA            | NA          |             |
+-------------+-----------+---------------+-------------+-------------+

**3.4 Summary of Residues for Tolerance Expression and Risk Assessment**

A summary of metabolites and degradates included in the risk assessment
and tolerance expression is provided in Table 5. The Agency concluded in
the response to petition PP#1E1124 that feed uses of treated citrus are
of little concern because the proposed use is for fruit destined for the
fresh market only. Therefore livestock commodities were not included in
the dietary risk assessment and tolerances for ruminant and poultry
commodities are not required. Based on available data, the established
tolerance for this commodity is adequate (Table 6). Codex maximum
residue limits (MRLs) do not currently exist for hydrogen cyanide;
therefore, no questions of compatibility with U.S. tolerances exist.

  ------------------------------------------------------------------------
  **Table 5.                                            
  Metabolites                                           
  and Degradates                                        
  to be included                                        
  in the Risk                                           
  Assessment and                                        
  Tolerance                                             
  Expression**                                          
  -------------- ------------ ------------------------- ------------------
  **Matrix**                  **Residues included in    **Residues
                              Risk Assessment**         included in
                                                        Tolerance
                                                        Expression**

  Plant          Citrus       Hydrogen Cyanide          Hydrogen Cyanide

  Livestock      Ruminant     NA                        NA

                 Poultry      NA                        NA

  Drinking Water              NA                        NA
  ------------------------------------------------------------------------

+-----------------+--------------+-------------+-----------------------+
| **Table 6.      |              |             |                       |
| Tolerance       |              |             |                       |
| Summary for     |              |             |                       |
| Hydrogen        |              |             |                       |
| Cyanide**       |              |             |                       |
+-----------------+--------------+-------------+-----------------------+
| **Commodity**   | *            | **          | **Comments**          |
|                 | *Established | Recommended |                       |
|                 | Tolerance    | Tolerance   | **(correct commodity  |
|                 | (ppm)**      | (ppm)**     | definition)**         |
+-----------------+--------------+-------------+-----------------------+
| Fruit, citrus   | 50           | 50          | Fruit, citrus, group  |
|                 |              |             | 10                    |
+-----------------+--------------+-------------+-----------------------+

**4.0 HAZARD CHARACTERIZATION/ASSESSMENT**

1.  **Hazard Characterization**

The toxicology database for hydrogen cyanide is incomplete. No guideline
studies are available. All of the critical studies are cited from the
open literature. Data on all forms of cyanide (e.g., hydrogen, sodium,
potassium cyanide etc.) have been used to identify hydrogen cyanide
toxicity for this assessment. Hydrogen cyanide is extremely acutely
toxic by all exposure routes.

All forms of cyanide, hydrogen, sodium, and potassium, are extremely
acutely toxic by the oral route. Based on an analysis of case history
data the lowest fatal oral dose of hydrogen cyanide for an average adult
human is estimated by FDA to be 1 mg/kg (FDA, 1956). The lowest reported
fatal dose of cyanide (unspecified form) in humans was estimated to be
0.56 mg/kg based on incidence data published in 1938 (Gettler and Baine,
1938). It is important to note that analytical measurements at the time
these studies were conducted lack the precision of current technology.
Both sodium and potassium cyanide have lethal doses of 200 mg total,
representing 81 and 110 mg total hydrogen cyanide, respectively. The
acute oral fatal dose of potassium cyanide in rats is 10-15 mg/kg, which
is equivalent to a 4-6 mg/kg hydrogen cyanide.

Results of clinical trials of Laetrile to treat cancer also provide
evidence of the acute oral toxicity of hydrogen cyanide. Laetrile, also
known as amygdalin, is a plant compound that produces cyanide. Use of
Laetrile has been shown to produce side effects of cyanide
poisoning---which can produce a range of symptoms, including death. In a
clinical trial of Laetrile to treat human cancer, the single dose of 0.5
g of amygdalin was determined to be minimally toxic; a single dose of
0.5 g of amygdalin is equivalent to 0.4 mg/kg hydrogen cyanide/day
(Moertel et al, 1982). Blood levels of cyanide rose when the single 0.5
g dose was doubled to two 0.5 g doses at an administration. These
increased blood levels were associated with an increase in the incidence
and severity of some of the toxic signs and symptoms due to the release
of hydrogen cyanide from amygdalin by the enzymatic action of
B-glucosidase, an intestinal enzyme. Therefore, the single dose of 0.5 g
of amygdalin was determined to be a minimally toxic dose, whereas the
double dose was generally regarded as frankly toxic.

Hydrogen cyanide is also acutely toxic via inhalation. The dose-effect
curve of the acute inhalation effects in humans is steep. Whereas slight
effects occur at exposure to hydrogen cyanide levels of 20-40 mg/m^3^,
50-60 mg/m^3^ can be tolerated without immediate or late effects for 20
minutes to 1 hour, 120-150 mg/m^3^ is dangerous to life and may lead to
death after 0.5-1 hour, 150 mg/m^3^ is likely to be fatal within 30
minutes, 200 mg/m^3^ is likely to be fatal after 10 minutes, and 300
mg/m^3^ is immediately fatal. It should be emphasized that this
represents crude average exposure estimates, based on various studies
(WHO, 2004).

An average LD50 value for dermal exposure of 100 mg/kg was estimated for
humans (Rieders, 1971). Concentrations of 7000-12,000 mg/m^3^ were
estimated to be fatal after a 5 minute exposure of workers with
self-contained respirators without effective skin protection (Minkina,
1988). Cyanides are weakly irritating to the skin and eye. No data are
available on sensitizing properties.

The primary effects of acute cyanide exposure in humans are central
nervous system and cardiovascular disturbances. Typical signs of acute
cyanide poisoning include tachypnea, headache, vertigo, lack of motor
coordination, weak pulse, cardiac arrhythmias, vomiting, stupor,
convulsions, and coma.

Hydrogen cyanide exhibits relatively low subchronic and chronic toxicity
by the oral route. A 2-year rat feeding study (Howard and Hanzal, 1955)
with hydrogen cyanide fumigated food containing residues up to 300 ppm
(10.8 mg/kg/day) showed no treatment-related effects in clinical signs,
body weight, food consumption, hematology, gross necropsy or
histopathological changes in the organs examined (heart, lung, liver,
spleen, gastrointestinal tract, kidneys, adrenal, thyroid, testes,
uterus, ovaries, cerebrum, cerebellum, and brain). The rats in the
2-year study ingested 2 to 3 times the fatal acute dose of hydrogen
cyanide in rats each day throughout their lifetime without any
measurable effects. In a 13 week repeated dose toxicity study in which
sodium cyanide was administered in the drinking water, there were no
mortalities, clinical signs or histopathological effects in the brain,
thyroid, or other organs of rats and mice exposed to doses up to 12.5
and 26 mg/kg/day respectively.

Hydrogen cyanide is readily converted to thiocyanate in the liver by the
enzyme rhodanese. This metabolic conversion is the major detoxification
mechanism for hydrogen cyanide. The conversion of cyanide to thiocyanate
was first demonstrated in 1894. Conversion of cyanide to thiocyanate is
enhanced when cyanide poisoning is treated by intravenous administration
of a sulfur donor (e.g., sodium thiosulfate). Definite increases in
thiocyanate concentrations were found in the treated tissues of the
experimental animals indicating that metabolic detoxification of
hydrogen cyanide had occurred (Howard and Hanzal, 1956). Residues of
thiocyanate, the less toxic primary metabolite of cyanide, increased
3.5-fold in plasma, 3.5 fold in erythrocytes, 1.3 fold in liver, and
2.5fold in kidneys of the rats exposed to hydrogen cyanide in the diet.
The rapidity of this conversion was demonstrated in a case of humans
where one-twentieth the lethal dose (0.1-0.2 mg/kg BW) of soluble
cyanide was injected intravenously every ten minutes. In this case, more
than the equivalent of an acutely fatal dose was administered without
any apparent harm to the individual (FDA, 1956). Based on the FDA study,
as long as the oral intake of hydrogen cyanide does not exceed the
body's detoxification mechanisms via the formation of thiocyanate,
hydrogen cyanide can be ingested in the form of dietary residues for
prolonged periods without harm. Once thiocyanate is formed, it is not
converted back to cyanide. It has been estimated that based on
established tolerances and percentage in the daily diet, the TMRC for
the total daily diet could represent about 14 ppm hydrogen cyanide (FDA,
1956).

Cyanogenic glycosides are present in major edible plants (WHO, 2004).
Amygdalin occurs in almonds, dhurrin in sorghum, linamarin in cassava,
lotaustralin in cassava and lima beans, prunasin in stone fruit, and
taxiphyllin in bamboo shoots (WHO, 2004). Cassava is an important
subsistence crop for 450-500 million people in 26 tropical countries in
the expanding populations of Africa and South America. World production
in 1980 was estimated to be 118 million tons. Cassava has been suspected
as a cause of human congenital defects (ATSDR, 2004).

There are neurotoxicity, developmental and reproductive studies
available with naturally occurring cyanides or cyanide salts in the open
literature, but there are no EPA guideline studies of these types of
studies in the available database. Neurotoxic effects are a major
occurrence across species and in humans from exposure to cyanide in its
various forms. In several animal studies, developmental CNS and heart
malformations occur in the presence of overt maternal toxicity
(including death), whereas, parental findings (mortality) occur at
slightly higher doses in the absence of reported reproductive results in
inhalation studies with acetone cyanohydrin (ACH) in rats. ACH rapidly
converts to hydrogen cyanide at physiological pH. The effects of acute
cyanide exposure in humans are dominated by CNS and cardiovascular
disturbances (ATSDR, 2004). Typical signs of acute cyanide poisoning
include tachypnea, headache, vertigo, lack of motor coordination, weak
pulse, cardiac arrhythmias, vomiting, stupor, convulsions, and coma. No
additive or synergistic effect was observed in the fatalities between
cyanide and other factors, such as carbon monoxide, alcohol, age of
victims, and presence of heart disease (WHO, 2004)

There are no guideline studies of carcinogenicity of hydrogen cyanide or
its alkali salts. There are no available open literature studies on the
carcinogenic potential of cyanide. The classification of the
carcinogenic potential could not be determined due to the absence of
acceptable cancer studies in rats and mice. Because of cyanide's high
toxicity, it would be difficult to conduct a meaningful cancer study in
rats and mice over a two-year period. Hydrogen cyanide has been
evaluated for mutagenic potential with mixed results and several open
literature references are available.

Cyanide gas and salts such as sodium and potassium cyanide are rapidly
absorbed following inhalation and oral exposure. Cyanide compounds are
more slowly absorbed by dermal exposure. Cyanide can be distributed in
the body within seconds and death can occur within minutes. Following
oral exposure, the highest levels have been detected in lungs and blood.
Following inhalation, cyanide is rapidly distributed throughout the
body, with measurable levels detected in all organs. Animal studies have
shown that cyanide does not accumulate in the blood and tissues
following chronic oral exposure. Cyanide is transformed to the much less
toxic thiocyanate in the body, with a plasma half-life of 20 minutes to
1 hour. Cyanide metabolites are mainly excreted in the urine, with small
amounts excreted through the lungs (ATSDR, 2004).

Hydrogen cyanide does not react with bivalent iron of hemoglobin (Fe++).
It does however, bind with cytochrome oxidase (a ferric enzyme) in the
electron transport system and inhibits the exchange of oxygen from the
blood to the tissues by the mechanism of competitive inhibition. Cyanide
can also inhibit approximately 40 enzymes, including a number of other
metalloenzymes containing, for the most part, iron, copper, or
molybdenum (e.g, alkaline phosphatase, carbonic anhydrase, catalase,
peroxidase, ascorbic acid oxidase, xanthine oxidase, and succinic
dehydrogenase). These reactions may also contribute to cyanide toxicity
(WHO, 2004). Due to its high dependency on oxidative metabolism and
limited anaerobic capacity, the central nervous system is particularly
vulnerable to cyanide intoxication. The CNS symptoms observed in cyanide
toxicity parallel those observed following accumulation of calcium in
the brain and cytosolic calcium ion overload has been implicated as an
intracellular mediator of cellular injury during and after anoxic
hypoxia (WHO, 2004).

Tables 7 and 8 provide the toxicity profile for hydrogen cyanide.

  ------------- ---------------------------- ------------- ------------- ------------
  **Table 7.                                                             
  Acute                                                                  
  Toxicity                                                               
  Profile -                                                              
  Hydrogen                                                               
  Cyanide**                                                              

  **Guideline   **Study Type**               **MRID(s)**   **Results**   **Toxicity
  No.**                                                                  Category**

  870.1100      Acute oral \[rat\] Potassium N/A\*         LD~50~ = 4-6  I
                Cyanide expressed as                       mg/kg         
                equivalents of hydrogen                                  
                cyanide                                                  
  ------------- ---------------------------- ------------- ------------- ------------

\*Handbook of Toxicology, (1956), Vol.1, Ed. William S. Spector, p.242,
Toxicity of Potassium Cyanide; W.B. Saunders Co., Philadelphia and
London.

+-----------+---------------------+-----------------------------------+
| **Table   |                     |                                   |
| 8.        |                     |                                   |
| Su        |                     |                                   |
| bchronic, |                     |                                   |
| Chronic   |                     |                                   |
| and Other |                     |                                   |
| Toxicity  |                     |                                   |
| Profile - |                     |                                   |
| Hydrogen  |                     |                                   |
| Cyanide** |                     |                                   |
+===========+=====================+===================================+
| **        | **MRID No. (year)/  | **Results**                       |
| Guideline | Classification      |                                   |
| No./      | /Doses**            |                                   |
| Study     |                     |                                   |
| Type**    |                     |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3100  | (NTP, 1993)         | NOAEL = 2.5 mg/HCNkg/day          |
|           |                     |                                   |
| 90-Day    | Accep               | LOAEL = 8.9 mg/HCNkg/day based on |
| oral      | table/Non-guideline | slight changes in the             |
| toxicity  |                     | reproductive tract in male rats.  |
| (rats,    | 0, 0.2, 0.5, 1.4,   | No adverse effects in female rats |
| mice)     | 4.5, 12.5 mg        | or mice.                          |
|           | NaCN/kg/day (M) and |                                   |
|           | 0, 0.2, 1.7, 4.9,   |                                   |
|           | 12.5 mg NaCN/kg/day |                                   |
|           | (F) in rats in      |                                   |
|           | drinking water and  |                                   |
|           | 0, 0.3, 1, 3, 9,    |                                   |
|           | and 26 mg           |                                   |
|           | NaCN/kg/day in mice |                                   |
|           | in drinking water   |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3465  | Monsanto Co.        | NOAEL = not established           |
|           | (1985),             |                                   |
| 4-Week    | Accep               | LOAEL = 71 mg HCN/m3 produced 30% |
| i         | table/Non-guideline | mortality (3/10) among rats       |
| nhalation |                     | exposed part of one day.          |
| toxicity  | Dose: 207 mg        |                                   |
| (rat)     | acetone cyanohydrin |                                   |
|           | (ACH)/ m3           |                                   |
|           | calculated as 71 mg |                                   |
|           | HCN/ m3.            |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3465  | Kamalu (1993)       | NOAEL = not established           |
|           |                     |                                   |
| 14-week   | Unaccept            | LOAEL = 1.08 mg HCN/kg BW (NaCN + |
| dietary   | able/Non-guideline, | rice) based on altered profile of |
| toxicity  | Doses: (1) control  | free amino acids, but no effects  |
| study     | (zero mg HCN/kg     | on histology of liver, kidney or  |
| (dogs)    | rice diet), (2)     | heart, although serum enzymes     |
|           | cassava \["gari"\]  | (plasma glutamyl transferase,     |
|           | (believed to        | ALAT, isocitrate dehydrogenase)   |
|           | liberate 10.8 mg    | were altered. Adrenal hyperplasia |
|           | HCN/kg cassava      | and hypertrophy, and pancreatic   |
|           | diet), (3) rice +   | nephrosis and fibrosis were       |
|           | added NaCN (10.8 mg | observed with rice + NaCN.        |
|           | NaCN added/kg rice  | Additionally, a significantly     |
|           | diet) 10.8 mg       | reduced frequency of testicular   |
|           | HCN/kg diet         | tubules in Stage 8 of sperm cycle |
|           | calculated as 1.08  | as well as marked germ sloughing  |
|           | mg HCN/kg BW        | off and testicular degeneration   |
|           |                     | was also seen in the rice + NaCN  |
|           |                     | test animals (6 dogs/group).      |
|           |                     | Thiocyanate levels in NaCN + rice |
|           |                     | treated dogs increased during the |
|           |                     | study. In contrast, results of    |
|           |                     | the "gari" diet (cassava) showed  |
|           |                     | generalized congestion and        |
|           |                     | hemorrhage, liver vacuolation,    |
|           |                     | kidney vacuolation, myocardial    |
|           |                     | degeneration, adrenal gland       |
|           |                     | degeneration, pancreatic          |
|           |                     | necrosis, decreased T3 and        |
|           |                     | thyroid effects consistent with   |
|           |                     | goiter.                           |
+-----------+---------------------+-----------------------------------+
| 870.3465  | Monsanto Co.        | NOAEL = 65 mg HCN/ m3 or 15 mg    |
|           | (1984a),            | HCN/kg/day                        |
| 90-Day    | Accept              |                                   |
| i         | able/Non-guideline, | LOAEL = not established.          |
| nhalation | Doses 0, 36, 101,   |                                   |
| toxicity  | 204 mg/ m3 acetone  |                                   |
| (rat)     | cyanohydrin (ACH)   |                                   |
|           | calculated as 0,    |                                   |
|           | 11, 32, 65 mg HCN/  |                                   |
|           | m3                  |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3465  | Lewis et al (1984)  | NOAEL = 25 ppm HCN                |
|           | Accept              |                                   |
| 6-Month   | able/Non-guideline, | LOAEL = 56 ppm HCN based on       |
| i         | Doses 0, 11 ppm, 25 | doubling of the rate of           |
| nhalation | ppm cyanogen        | responding on a variable interval |
| toxicity  | calculated as 25,   | 2.9 min schedule of               |
| (monkey,  | or 56 mg HCN/ m3.   | reinforcements and decreased lung |
| rat)      |                     | moisture content in monkeys and   |
|           |                     | decreased body weights in rats.   |
+-----------+---------------------+-----------------------------------+
| 870.3700a | Doherty et al       | Maternal NOAEL = 0.07 mmol/kg HCN |
|           | (1982)              | BW/hour                           |
| Prenatal  | Accep               |                                   |
| deve      | table/Non-guideline | Maternal LOAEL = 0.073 mmol/kg    |
| lopmental |                     | HCN BW/hr                         |
| in        | Doses 0, 0.125,     |                                   |
| (golden   | 0.133 mmol NaCN/kg  | based on maternal deaths and      |
| hamster)  | BW/hour using       | dyspnea, incoordination, reduced  |
|           | osmotic minipumps   | body temperature, and loss of     |
|           | (preliminary study) | body weight                       |
|           | given on days 6-9   |                                   |
|           | of gestation        | Developmental NOAEL = 0.07        |
|           |                     | mmol/kg HCN BW/hour               |
|           |                     |                                   |
|           |                     | Developmental LOAEL = 0.073       |
|           |                     | mmol/kg HCN BW/hr based on 100%   |
|           |                     | resorptions                       |
+-----------+---------------------+-----------------------------------+
| 870.3700a | Doherty et al       | Maternal NOAEL = not established  |
|           | (1982)              |                                   |
| Prenatal  | Accep               | Maternal LOAEL = 0.126 mmol       |
| deve      | table/Non-guideline | NaCN/kg BW/hr                     |
| lopmental | Doses: 0, 0.126,    |                                   |
| in        | 0.1275, or 0.1295   | based on salivation, shortness of |
| (golden   | mmol NaCN/kg        | breath, ataxia, reduced body      |
| hamster)  | BW/hour using       | temperature, and loss of body     |
|           | osmotic minipumps   | weight                            |
|           | equivalent to 0,    |                                   |
|           | 78.7, 79.6, and     | Developmental NOAEL = not         |
|           | 80.9 mg NaCN/kg     | established                       |
|           | BW/day given on     |                                   |
|           | days 6-9 of         | Developmental LOAEL = 0.126 mmol  |
|           | gestation           | NaCN/kg BW/hr based on            |
|           |                     | resorptions, non-closure of       |
|           |                     | neural tube, exencephaly,         |
|           |                     | encephalocoele, and malformations |
|           |                     | of the heart, limb, or tail.      |
|           |                     |                                   |
|           |                     | Co-administration of thiosulfate  |
|           |                     | eliminated the teratogenic        |
|           |                     | effect, protecting the dams and   |
|           |                     | fetuses from the toxic effects of |
|           |                     | cyanide                           |
+-----------+---------------------+-----------------------------------+
| 870.3700a | Monsanto Co. (1982, | Maternal NOAEL = 0.3 mg HCN/kg    |
|           | 1983a)              | BW/day                            |
| Prenatal  | A                   |                                   |
| deve      | cceptable/Guideline | Maternal LOAEL = 0.9 mg HCN/kg    |
| lopmental | Doses: 0, 1, 3, 10  | BW/day based on slight reductions |
| in (rats) | mg Acetone          | in weight gain and significant    |
|           | cyanohydrin/kg BW   | decreases in high dose group plus |
|           | (equivalent to 0,   | decrease in implantations         |
|           | 0.3, 0.9, or 3 mg   |                                   |
|           | cyanide/kg BW/day)  | Developmental NOAEL = 3 mg HCN/kg |
|           | during days 6-15 of | BW/day                            |
|           | gestation           |                                   |
|           |                     | Developmental LOAEL = not         |
|           |                     | established                       |
+-----------+---------------------+-----------------------------------+
| 870.3700a | Singh (1981)        | Maternal LOAEL = 50% milled       |
|           | Unaccep             | cassava resulted in decreased     |
| Prenatal  | table/Non-guideline | weight gain                       |
| deve      |                     |                                   |
| lopmental | Doses: 50% and 80%  | Developmental LOAEL = 50% milled  |
| in (rats) | milled cassava      | cassava resulted in increased     |
|           | powder in diet      | resorptions, decreased body       |
|           | given during first  | weight, and open eye,             |
|           | 15 days of          | microcephaly, limb defects at 80% |
|           | gestation (CN       | milled cassava                    |
|           | content not         |                                   |
|           | specified)          |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3700a | Willhite (1982)     | Maternal oral LOAEL = 11 mg       |
|           | Unaccept            | HCN/kg BW /day, effects not       |
| Prenatal  | able/Non-guideline, | specified.                        |
| deve      | Doses of 200, 250,  |                                   |
| lopmental | or 275 mg/kg BW of  | Developmental oral LOAEL = 11 mg  |
| in        | d/l-amygdalin or    | HCN/kg BW/day based on            |
| (golden   | 177 mg/kg BW of     | exencephaly, encephalocoele,      |
| hamster)  | d-prunasin          | skeletal malformations            |
|           | equivalent to 11,   |                                   |
|           | 14, or 16 mg CN/kg  | No developmental effects were     |
|           | BW, respectively,   | seen at 16 mg HCN/kg BW/day given |
|           | or 16 mg CN/kg BW   | intravenously                     |
|           | administered orally |                                   |
|           | on day 8 of         |                                   |
|           | gestation or 16 mg  |                                   |
|           | CN/kg BW/day given  |                                   |
|           | intravenously       |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3700a | Frakes et al (1985) | Maternal NOAEL = 70 mg            |
|           | Accept              | linamarin/kg/day                  |
| Prenatal  | able/Non-guideline, |                                   |
| deve      | Doses: 0, 70, 100,  | LOAEL = 100 mg/kg/day based on    |
| lopmental | 120, or 140 mg      | dyspnea, tremors, and ataxia,     |
| in        | linamarin/kg BW/day | Developmental NOAEL = 100 mg      |
| (golden   | on day 8 of         | linamarin /kg/day                 |
| hamster)  | gestation           |                                   |
|           | (primitive streak)  | LOAEL = 120 mg linamarin /kg/day  |
|           |                     | based on vertebral and rib        |
|           |                     | anomalies and Encephalocoele.     |
+-----------+---------------------+-----------------------------------+
| 870.3700a | Frakes et al (1986) | Maternal LOAEL = based on         |
|           | Unaccept            | significant decreases in weight   |
| Prenatal  | able/Non-guideline, | gain.                             |
| deve      | Doses of high       |                                   |
| lopmental | cyanide (bitter     | Developmental LOAEL = based on    |
| in        | cassava, 7.9 mmol   | decreased fetal body weight,      |
| (golden   | CN/kg)) and low     | reduced ossification of           |
| hamsters) | cyanide (sweet      | sacrocaudal vertebrae,            |
|           | cassava, 0.7 mmol   | metatarsals, and sternebrae.      |
|           | CN/kg)) mixed in an |                                   |
|           | 20:80 ratio given   |                                   |
|           | on days 3-14 of     |                                   |
|           | gestation to        |                                   |
|           | pregnant hamsters   |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3800  | Olusi et al (1979)  | Parental/Systemic NOAEL = not     |
|           | Accept              | established                       |
| Rep       | able/Non-guideline, |                                   |
| roduction | Doses of 1000 or    | LOAEL = 1000 mg HCN /kg/day based |
| and       | 2000 mg CN/kg       | on decreased weight gain, blood   |
| fertility | BW/day administered | hemoglobin, serum T4              |
| effects   | to females (10/sex) | concentration.                    |
|           | for 2-weeks and     |                                   |
| (rat)     | then mated to       | Reproductive NOAEL = not          |
|           | untreated males     | established                       |
|           |                     |                                   |
|           |                     | LOAEL = 1000 mg HCN/kg/day based  |
|           |                     | on no pregnancies.                |
+-----------+---------------------+-----------------------------------+
| 870.3800  | Monsanto Co.        | Parental/Systemic NOAEL = 64 mg   |
|           | (1985a)             | HCN/ m3 based on no deaths,       |
| Rep       |                     | clinical signs of toxicity LOAEL  |
| roduction | Accept              | = not established.                |
| and       | able/Non-guideline, |                                   |
| fertility | Inhalation doses of | Reproductive NOAEL = 64 mg HCN/   |
| effects   | 0, 35, 101, or 202  | m3 based on mating efficiency,    |
|           | mg acetone          | number of live implants, and pre- |
| (male     | cyanohydrin (ACH)/  | and post-implantation loss        |
| rat)      | m3 equivalent to 0, |                                   |
|           | 11, 32, or 64 mg    | LOAEL = not established.          |
|           | HCN/ m3 for 6       |                                   |
|           | hours/day, 5        | Offspring NOAEL = not established |
|           | days/week during a  | LOAEL = not established.          |
|           | period of 69 days   |                                   |
|           | (48 exposure days). |                                   |
|           | Following exposure, |                                   |
|           | the males were      |                                   |
|           | mated with 3        |                                   |
|           | untreated           |                                   |
|           | females/male        |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3800  | Monsanto Co.        | Parental/Systemic NOAEL = 66 mg   |
|           | (1985b)             | HCN/ m3 based on absence of       |
| Rep       |                     | clinical signs, except for red    |
| roduction | Accept              | nasal discharge, mortality,       |
| and       | able/Non-guideline, | weight gain and necropsy, LOAEL = |
| fertility | Inhalation doses of | not established.                  |
| effects   | 0, 38, 108, or 207  |                                   |
|           | mg acetone          | Reproductive NOAEL = 66 mg HCN/   |
| (rat)     | cyanohydrin (ACH)/  | m3 based on no effect on          |
|           | m3 equivalent to 0, | fertility, LOAEL = not            |
|           | 12, 34, or 66 mg    | established.                      |
|           | HCN/ m3 for 6       |                                   |
|           | hours/day, 7        | Offspring NOAEL = not             |
|           | days/week up to day | established, LOAEL = not          |
|           | of mating (34-36    | established.                      |
|           | exposures).         |                                   |
|           | Following exposure, |                                   |
|           | the females were    |                                   |
|           | mated with          |                                   |
|           | untreated males;    |                                   |
|           | females were        |                                   |
|           | sacrificed at       |                                   |
|           | gestation days      |                                   |
|           | 13-15.              |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3800  | Tewe and Maner      | Parental/Systemic LOAEL = 207 HCN |
|           | (1981a)             | ppm in diet based on decreased    |
| Rep       | Unaccept            | body weight gain during           |
| roduction | able/Non-guideline, | lactation.                        |
| and       |                     |                                   |
| fertility | Doses: 0, 500 ppm   | Reproductive NOAEL = 207 KCN ppm  |
| effects   | dietary KCN added   | in diet did not cause marked      |
|           | to cassava flour    | effect in gestation and lactation |
| (rat)     | fed to pregnant     | performance                       |
|           | female rats during  |                                   |
|           | gestation and       | Offspring LOAEL = 207 HCN ppm in  |
|           | lactation           | diet based on decreased food      |
|           |                     | consumption and body weight       |
|           |                     | during lactation.                 |
+-----------+---------------------+-----------------------------------+
| 870.3800  | Tewe and Maner      | Parental/Systemic NOAEL = 104 HCN |
|           | (1981b)             | ppm in diet                       |
| Rep       |                     |                                   |
| roduction | Accep               | LOAEL = 500 ppm in diet based on  |
| and       | table/Non-guideline | increased thyroid weight and      |
| fertility |                     | thyroid and kidney                |
| effects   | Doses: 0, 250, 500  | histopathology.                   |
|           | ppm KCN added to    |                                   |
| (         | fresh cassava diets | Reproductive NOAEL = 207 HCN ppm  |
| Yorkshire | and fed to maternal | in diet did not affect the        |
| pigs)     | animals during      | production or lactation of the    |
|           | gestation and       | first litter of offspring and did |
|           | lactation           | not affect either the number or   |
|           |                     | weight of 110-day old fetuses     |
|           |                     |                                   |
|           |                     | LOAEL not established             |
|           |                     |                                   |
|           |                     | Offspring NOAEL = 104 HCN ppm in  |
|           |                     | diet                              |
|           |                     |                                   |
|           |                     | LOAEL = 207 HCN ppm in diet based |
|           |                     | on increased fetal serum          |
|           |                     | thiocyanate levels, increased     |
|           |                     | relative fetal spleen and heart   |
|           |                     | weight.                           |
+-----------+---------------------+-----------------------------------+
| 870.4100a | Howard and Hanzal,  | NOAEL = 10.8 mg HCN /kg/day (HDT) |
|           | 1955, Acceptable/   |                                   |
| Chronic   |                     | LOAEL = not established.          |
| toxicity  | Non-guideline,      |                                   |
|           |                     |                                   |
| (rat)     | Doses: 0, 100, 300  |                                   |
|           | ppm calculated as   |                                   |
|           | 0, 4.3, 10.8        |                                   |
|           | mg/kg/day of HCN    |                                   |
+-----------+---------------------+-----------------------------------+
| 870.6200a | Fechter et al       | HCN plus noise produced impaired  |
|           | (2002),             | auditory function by producing    |
| Acute     | Accept              | significant oxidative stress in   |
| Neur      | able/Non-guideline, | the cochlea. HCN alone did not    |
| otoxicity | Dose: 34 mg HCN/ m3 | cause significant hearing loss or |
| (rats)    | for 3.5 hours       | hair cell loss.                   |
+-----------+---------------------+-----------------------------------+
| 870.6200b | Mathangi &          | Reductions of memory (T-maze      |
|           | Namasivayam (2000), | test), along with reductions in   |
| S         | Accept              | the level of dopamine and         |
| ubchronic | able/Non-guideline, | 5-hydroxytryptamine and increases |
| neur      | Dose: 2 mg NaCN/kg  | in norepinephrine and epinephrine |
| otoxicity | given               | levels in the hippocampus,        |
| (rats)    | intraperitoneally   | measured after a month of         |
|           | followed by 25 ip   | treatment.                        |
|           | doses which was 25% |                                   |
|           | of LD50.            |                                   |
+-----------+---------------------+-----------------------------------+
| 870.6200b | Hertting et al      | NOAEL = not established           |
|           | (1960)              |                                   |
| S         | Unaccept            | LOAEL = 0.27 mg HCN/kg/day based  |
| ubchronic | able/Non-guideline, | on degenerative changes in the    |
| neur      | Doses: 0, 0.5, 2,   | ganglia cells of CNS, interpreted |
| otoxicity | 1-4 mg NaCN         | to be caused by multiple episodes |
| (dogs)    | capsule/kg/day for  | of acute cerebral hypoxia.        |
|           | 13-15 months (only  |                                   |
|           | one dog at each     |                                   |
|           | dose level)         |                                   |
+-----------+---------------------+-----------------------------------+
| 870.6200b | Jackson (1988)      | NOAEL = not established           |
|           | Accept              |                                   |
| S         | able/Non-guideline, | LOAEL = 0.5 mg HCN/kg/day based   |
| ubchronic | Doses: 0, 0.4, 0.7, | on dose related decreased T3 and  |
| neur      | 1.2 KCN/kg/day      | T4 and increased fasting blood    |
| otoxicity | dosed by gavage     | sugar plus decreased exploration  |
| (         | once daily for 24   | and aggression, slower eating,    |
| miniature | weeks               | more frequent drinking and        |
| pigs)     |                     | shivering consistent with         |
|           |                     | decreased thyroid activity.       |
+-----------+---------------------+-----------------------------------+
| 870.3100  | FDA (1956)          | Oral NOAEL = 0.2 mg HCN/kg/day    |
|           | Administration of   |                                   |
| S         | NaCN to measure     |                                   |
| ubchronic | thiocyanate in      |                                   |
| oral      | saliva              |                                   |
| (human)   |                     |                                   |
+-----------+---------------------+-----------------------------------+
| 870.3100  | Moertel et al       | Oral LOAEL = 0.4 mg HCN/kg/day    |
| S         | (1982), MRIDs       | based on symptoms and clinical    |
| ubchronic | 46769601 46769602 A | signs of hydrogen cyanide         |
| oral and  | clinical trial of   | toxicity                          |
| in        | amygdalin           |                                   |
| travenous | (laetrile) in the   |                                   |
| (human)   | treatment of human  |                                   |
|           | cancer and Moertel  |                                   |
|           | et al (1981) A      |                                   |
|           | pharmacological and |                                   |
|           | toxicological study |                                   |
|           | of amygdalin        |                                   |
+-----------+---------------------+-----------------------------------+

+-----------------+------------+--------+----------+------------+-----+
| *               |            |        |          |            |     |
| *Mutagenicity** |            |        |          |            |     |
+=================+============+========+==========+============+=====+
| **Test System** | **         | **     | **Result | **R        | **  |
|                 | Endpoint** | Result | W        | eference** | For |
|                 |            | With** | ithout** |            | m** |
|                 |            |        |          |            |     |
|                 |            | **     | **Acti   |            |     |
|                 |            | Activa | vation** |            |     |
|                 |            | tion** |          |            |     |
+-----------------+------------+--------+----------+------------+-----+
| S. typhimurium  | Reverse    | \-     | Not      | DeFlora et | KCN |
| TA82, TA102     | Mutation   |        | tested   | al, 1984   |     |
+-----------------+------------+--------+----------+------------+-----+
| S. typhimurium  | Reverse    | \-     | \-       | DeFlora    | KCN |
|                 | Mutation   |        |          | 1981       |     |
| TA98, TA100,    |            |        |          |            |     |
| TA1535, TA1537, |            |        |          |            |     |
| TA1538          |            |        |          |            |     |
+-----------------+------------+--------+----------+------------+-----+
| S. typhimurium  | Reverse    | \- (+) | \- +     | Kushi et   | HCN |
| TA98, TA100     | Mutation   |        |          | al, 1983   |     |
+-----------------+------------+--------+----------+------------+-----+
| S. typhimurium  | Reverse    | \-     | \-       | Kubo et    | KCN |
| TA98, TA100     | Mutation   |        |          | al, 2002   |     |
+-----------------+------------+--------+----------+------------+-----+
| S. typhimurium  | Reverse    | \-     | \-       | NTP 1993   | N   |
| TA97, TA98,     | Mutation   |        |          |            | aCN |
| TA100, TA1535   |            |        |          |            |     |
+-----------------+------------+--------+----------+------------+-----+
| E.coli WP67,    | DNA Repair | \-     | \-       | DeFlora et | KCN |
| CM871, WP2      | Test       |        |          | al, 1984   |     |
+-----------------+------------+--------+----------+------------+-----+
| HeLa cells      | DNA        | \-     | \-       | Painter    | KCN |
|                 | Synthesis  |        |          | and        |     |
|                 | Inhibition |        |          | Howard,    |     |
|                 |            |        |          | 1982       |     |
+-----------------+------------+--------+----------+------------+-----+
| Human A549 lung | DNA        |        | +(cyt)   | Vock et    | KCN |
| carcinoma cells | Breakage   |        |          | al, 1998   |     |
+-----------------+------------+--------+----------+------------+-----+
| Human TK6       | DNA        |        | +(cyt)   | Henderson  | KCN |
|                 | Breakage   |        |          | et al,     |     |
| lymphoblastoma  |            |        |          | 1998       |     |
| cells           |            |        |          |            |     |
+-----------------+------------+--------+----------+------------+-----+
| Rat thymocytes  | DNA        |        | +(cyt)   | B          | KCN |
|                 | Breakage   |        |          | hattachrya |     |
|                 |            |        |          | et al,1997 |     |
+-----------------+------------+--------+----------+------------+-----+
| Hamster BHK-21  | DNA        |        | +(cyt)   | B          | KCN |
| cells           | Breakage   |        |          | hattachrya |     |
|                 |            |        |          | et al,1997 |     |
+-----------------+------------+--------+----------+------------+-----+
| Rat hepatocytes | DNA        |        | +(cyt)   | Storer et  | KCN |
|                 | Breakage   |        |          | al, 1996   |     |
+-----------------+------------+--------+----------+------------+-----+
| Mitochondrial   | Mit        |        | \+       | Yamamoto,  | KCN |
| fraction from   | ochondrial |        |          | 2002       |     |
| brain of male   | DNA        |        |          |            |     |
| ddy mice        | Breakage   |        |          |            |     |
+-----------------+------------+--------+----------+------------+-----+
| \- = negative   |            |        |          |            |     |
| result, + =     |            |        |          |            |     |
| positive        |            |        |          |            |     |
| result, (+) =   |            |        |          |            |     |
| weakly positive |            |        |          |            |     |
| result, +(cyt)  |            |        |          |            |     |
| = DNA breakage  |            |        |          |            |     |
| associated with |            |        |          |            |     |
| cytotoxicity;   |            |        |          |            |     |
| DNA =           |            |        |          |            |     |
| d               |            |        |          |            |     |
| eoxyribonucleic |            |        |          |            |     |
| acid, HCN =     |            |        |          |            |     |
| hydrogen        |            |        |          |            |     |
| cyanide, KCN =  |            |        |          |            |     |
| potassium       |            |        |          |            |     |
| cyanide, NaCN = |            |        |          |            |     |
| sodium cyanide  |            |        |          |            |     |
+-----------------+------------+--------+----------+------------+-----+

**4.2 FQPA Hazard Considerations**

> **4.2.1 Adequacy of the Toxicity Data Base**

The toxicology database for hydrogen cyanide is not complete. No
guideline studies are available. All of the critical studies are cited
from the open literature. Data on all forms of cyanide (e.g., hydrogen,
sodium, potassium cyanide etc) have been used to identify hydrogen
cyanide toxicity for this assessment.

> **4.2.2 Evidence of Neurotoxicity**

There is a concern for neurotoxicity resulting from exposure to cyanide,
since several of the reviewed literature studies show signs of
neurotoxic clinical effects or neuropathology. The assessment of
hydrogen cyanide neurotoxicity was based on studies conducted with
hydrogen cyanide, potassium cyanide, sodium cyanide, and cyanogen.

> **4.2.2.1 Behavioral Study in Pigs**

The effects of cyanide on behavior were studied in fasted 25-week old
miniature pigs (12 litter mates: 5 females and 7 castrated males)
randomized in four groups (Jackson, 1988). The animals were dosed daily
for 24 weeks with a single bolus of cyanide as aqueous potassium cyanide
just prior to daily feeding. The doses were 0, 0.4, 0.7, or 1.2 mg
cyanide/kg BW, chosen to be equivalent to those consumed by West
Africans in their diet. Every six weeks, thyroid function (T3 and T4)
and fasting blood glucose were measured, but not thyroid-stimulating
hormone (TSH). Daily observations were made of clinical signs and
various behavioral measurements, including social, antagonistic,
exploratory, learning, feeding, and excretory behavior. In all treatment
groups, dose related decreases were evident from week 6 in blood levels
of T3 and T4 and an increase in fasting blood glucose was noted,
particularly in top-dose animals. Statistical analysis was not provided
for each dose group versus the control, but changes in top dose animals
appeared significant by week 18; by week 24, decreases of 35% for T3 and
15% for T4 and an increase of 60% in fasting blood glucose were
observed. Behavioral observations revealed a picture of decreased
high-energy demanding behavior, such as exploration and aggression,
slower eating, more frequent drinking, and shivering consistent with the
decreased thyroid activity. A LOAEL of 0.5 mg HCN/kg BW/day could be
suggested from this study. It is important to note major weaknesses of
this study. The study used a bolus dose with consequent high peaks of
cyanide concentration in the organism and involved a very small number
of animals (three animals in four groups) and limited statistical
analysis.

> **4.2.2.2 Chronic Toxicity Study in Dogs**

Dogs administered sodium cyanide in capsules at levels of 0, 0.5, 2, or
1-4 mg/kg BW (one dog at each dose level) daily for 13-15 months showed
severe signs of acute cyanide poisoning right after the daily dosing
(the dog at the lowest dose died). In the autopsy, the only significant
finding were degenerative changes in the ganglia cells of the central
nervous system, interpreted to be caused by multiple episodes of acute
cerebral hypoxia (Hertting et al, 1960).

> **4.2.2.3** **Inhalation Toxicity Study in Monkeys and Rats**

In a 6 month inhalation toxicity study in rhesus monkeys and CD rats,
Lewis, Anger and Vault (1984) exposed groups of 5 rhesus monkeys and 30
male rats for 6 hr/day, 5 days/week to (A) Control group (B) 11 ppm
cyanogen or (C) 25 ppm cyanogen. This corresponded to 25, or 56 mg
hydrogen cyanide/m^3^. At the outset of exposures, there was a doubling
of the rate of responding on a variable interval 2.9 min schedule of
reinforcement in monkeys exposed to 25 ppm cyanogen, and increases were
also seen in the monkeys receiving 11 ppm exposures; the increases were
transitory as the rate returned to control levels before exposures were
terminated. At the end of the 6 month exposure period, there were no
effects in hematologic or clinical chemistry parameters attributable to
the inhalation exposure to cyanogen. The electrocardiograms, and gross
pathologic and histopathologic examinations of test animals were normal
when compared to the control animals. Total lung moisture content was
significantly lower in monkeys exposed to either 11 or 25 ppm cyanogen
than in control animals. Body weights were significantly lower in rats
exposed to 25 ppm cyanogen than in controls. The results suggest that
subchronic 25 ppm cyanogen exposures are marginally toxic, but that 11
ppm cyanogen may be considered a no adverse-effect level (NOAEL). The 11
and 25 ppm cyanogen concentrations corresponds to 25 and 56 mg HCN/m^3^.

> **4.2.2.4 Other Indications of Neurotoxic Effects**

Potentiation to noise-induced hearing loss by exposure of rats to low
concentrations of hydrogen cyanide was reported by Fechter et al (2002).
It was suggested that hydrogen cyanide (34 mg/ m^3^ for 3.5 hours) plus
noise produced impaired auditory function by producing significant
oxidative stress in the cochlea. Hydrogen cyanide alone did not cause
significant hearing loss or hair cell loss (WHO, 2004). A single
intraperitoneal dose and 25 repeated intraperitoneal doses of sodium
cyanide (2 mg/kg (1 mg hydrogen cyanide/kg)), stated to represent 25% of
the LD50, administered to Wistar strain albino rats resulted in similar
reductions of memory (T-maze test), along with reductions in the level
of dopamine and 5-hydroxytryptamine and increases in norepinephrine and
epinephrine levels in the hippocampus, measured after a month of
treatment (Mathangi & Namasivayam, 2000). There is also a
neuropathological study in goats (Soto-Blanco et al, 2002), which
reported ultrastructural changes in animals given [\>]{.underline} 0.48
mg cyanide/kg BW/day in drinking water for 5 months. However this study
did not present quantitative data or statistical analysis, since it was
essentially a morphometric evaluation.

> **4.2.3 Developmental Toxicity Studies**

There are no developmental toxicity studies available for hydrogen
cyanide. Developmental studies with sodium cyanide, cassava meal/powder
(cassava plant contains a cyanogen called linamarin), cyanogenic
glycoside linamarin, amygdalin, and acetone cyanohydrin were available
and reviewed for this assessment. The weight of the evidence of
available data indicates that cyanide induces developmental effects only
at doses or concentrations that are overtly toxic to the maternal
animals.

**4.2.3.1 Developmental Toxicity Studies in Hamsters**

Preliminary experiments with sodium cyanide given to pregnant Golden
Syrian hamsters using osmotic minipumps implanted subcutaneously, showed
that at a dose rate of 0.125 mmol/kg BW/hour, no effects on the fetus
were observed, while at a dose rate of 0.133 mmol/kg BW/hour or more,
there was a 100% resorption rate and maternal deaths. Toxicity to dams
increased with increasing dose levels and included dyspnea, ataxia,
reduced body temperature, and loss of body weight. Co-administration of
thiosulfate eliminated the teratogenic effect, protecting the dams and
fetuses from the toxic effects of cyanide (Doherty et al, 1982).

In a follow-up experiment, pregnant Golden Syrian hamsters (5-7 per
group) were continuously exposed to sodium cyanide from day 6 to day 9
of gestation at 0, 0.126, 0.1275, or 0.1295 mmol/kg BW/hour using
osmotic minipumps implanted subcutaneously. These doses are equivalent
to 0, 78.7, 79.6, and 80.9 mg/kg BW/day. Toxicity to dams increased with
increasing dose levels and included salivation, dyspnea, ataxia, reduced
body temperature, and loss of body weight. The treatment induced a
remarkable increase in resorptions as well as fetal malformations. These
included non-closure of the neural tube, exencephaly, encephalocoele,
and malformations of the heart, limbs or tail. Co-administration of
thiosulfate eliminated the teratogenic effect, protecting the dams and
fetuses from the toxic effects of cyanide (Doherty et al, 1982).

Groups of pregnant hamsters were fed diets consisting of two types of
cassava meal, either a "low-cyanide" (sweet cassava meal) or a
"high-cyanide" (bitter cassava meal) variety. These were mixed (80:20)
with laboratory chow and administered on days 3-14 of gestation (Frakes
et al, 1986). The cyanide concentration of the sweet cassava meals was
0.6-0.7 mmol/kg; that of the bitter cassava meal was 5-11 (mean 7.9)
mmol/kg. Cassava fed dams gained significantly less weight than did
control animals (fed diet similar in nutritional values as cassava, but
without cyanogenic glycosides) and their offspring showed evidence of
fetotoxicity (reduced fetal body weight and reduced ossification of
sacrocaudal vertebrae, metatarsals and sternebrae). The bitter cassava
also produced a significant increase in the number of runts compared
with litters from dams fed either low-protein or laboratory-stock diets.
The only teratogenic effects noted were hydrocephalus in three animals
in the low-cyanide (sweet cassava) test group and one encephalocoele
found in one animal at the high-cyanide (bitter cassava) test group.

Additionally, Frakes et al (1985) studied the developmental toxicity of
the cyanogenic glycoside linamarin in the golden hamster at doses of 0,
70, 100, 120, or 140 mg/kg. This dosing regiment resulted in an
increased incidence of vertebral and rib anomalies as well as the
production of encephalocoele in the offspring at a dose of 120 or 140
mg/kg BW, which was a maternally toxic dose. The developmental LOAEL was
estimated to be 120 mg/kg/day based on skeletal effects and the maternal
LOAEL was estimated to be 100 mg/kg concentration based on cyanide
intoxication (dyspnea, tremors, ataxia, etc.). A NOAEL was established
for linamarin fetal and maternal effects at 100 mg/kg and 70 mg/kg,
respectively, in the study. Frakes et al (1985) estimates that a 50 kg
person would have to consume about 2.7 kg of cassava flour containing
200 mg/kg HCN in order to receive a dose of linamarin equal to the 100
mg/kg dose used in the study. Therefore, ingestion of a
toxic/teratogenic dose of linamarin by a human female seems unlikely.

A single oral dose of d/l-amygdalin at gestational day 8 resulted in
exencephaly, encephalocoele, and skeletal malformations at doses of
\>250 mg/kg (\>14 mg cyanide/kg) in hamsters (these doses were also
clearly toxic to the mothers). At the lowest dose tested, 200 mg/kg (11
mg cyanide/kg), fused ribs were observed in two offspring of one mother
(maternal toxicity not reported). Encephalocoele and rib anomalies were
also reported after a dose of d-prunasin (177 mg/kg (16 mg cyanide/kg))
in the absence of maternal toxicity in hamsters. No teratogenic effects
were noted when hamsters received d/l-amygdalin (275 mg/kg (16 mg
cyanide/kg)) intravenously (WHO, 2004). The teratogenic effects found
were considered to be due to cyanide released by bacterial
beta-glucosidase in the gastrointestinal tract (Willhite, 1982).

**4.2.3.2 Developmental Toxicity Study in Rats**

Singh (1981) reported a 28% increased incidence of open eye,
microcephaly, limb defects, and growth retardation in the offspring of
pregnant rats fed 80% milled cassava powder during the first 15 days of
gestation. In the preliminary study with limited experimental detail,
pregnant albino rats were fed milled cassava powder as 50% and 80% of
their diet during the fifteen days of gestation. Growth retardation and
an increased frequency of resorptions were observed at both dose levels;
in addition, limb defects were observed at the high dose. The weight
gain of the dams was lowered from day 6 onward; no further information
on maternal toxicity was given. No indication of the cyanide content of
the cassava was given.

Groups of 25 pregnant Sprague-Dawley rats were dosed by gavage on days
6-15 of gestation with 0, 1, 3, or 10mg acetone cyanohydrin /kg BW
(equivalent to 0, 0.3, 0.9, or 3 mg cyanide/kg) (Monsanto Co., 1982).
Maternal toxicity was evidenced by slight reductions in body weight gain
in the mid- and high-exposure groups, and statistically significant
differences between the high-dose group and controls were found for the
number of corpora lutea implantations per dam. There were no comparable
differences in the number of viable fetuses per dam, post-implantation
losses per dam, mean fetal body weight, or fetal sex distribution for
all dose groups and the controls. The incidences of fetal malformations
and developmental variations for all fetuses of treated animals and
controls were also comparable. It was concluded that 10 mg ACH/kg BW (3
mg cyanide/kg) was not teratogenic in the rat in the presence of
maternal toxicity (Monsanto Co., 1982, 1983a, WHO, 2004).

> **4.2.4 Reproductive Toxicity Studies**

There are relatively few data available on the reproductive toxicity of
cyanides. There are no reproductive toxicity studies available for
hydrogen cyanide. Reproductive studies with sodium cyanide, potassium
cyanide, cassava, and acetone cyanohydrin were available and reviewed
for this assessment.

> **4.2.4.1 Reproductive Toxicity Studies in Rats**

A subchronic, 13-week repeated dose toxicity study was conducted in
which sodium cyanide was administered in the drinking water (NTP, 1993)
at doses of 0, 0.2, 0.5, 1.4, 4.5, and 12.5 mg/kg BW/day for males and
0, 0.2, 1.7, 4.9, and 12.5 mg/kg BW/day for female rats and 0, 0.3, 1,
3, 9, and 26 mg/kg BW/day for mice. There were no deaths, clinical signs
associated with CNS effects, body or organ weights, or histopathological
effects in the brain or thyroid of rats exposed to doses up to 12.5
mg/kg BW/day, respectively. At the LOAEL of 12.5 mg/kg BW/day in rats,
there were slight changes in the reproductive tract of male rats
including decreased left epididymis weight, left caudal epididymis
weight, left testis weight, spermatids heads, and spermatid counts
which, although they apparently did not affect the fertility in rats,
are possibly significant to humans. The NOAEL for these effects in male
rats was 4.5 mg/kg BW/day. The examination of neurotoxicity in this
study was limited to clinical observations and optical microscopy at
autopsy. At 4.9 and 12.5 mg/kg BW/day, there was an increase in the time
spent by female rats in proestrus and diestrus relative to estrus and
metestrus. The finding in female rats were not considered adverse. In
male mice, there was a statistically significant decrease in epidiymidis
weight at 26 mg/kg BW/day, but no changes in sperm motility or spermatid
head density were observed. No estrus effects were seen in female mice.
The overall NOAEL for the NTP study was selected as 4.5 mg/kg BW/day,
based on findings in the male reproductive tract at the LOAEL of 12.5
mg/kg BW/day

After 2 weeks on a diet containing 5 or 10 g potassium cyanide /100 g of
diet, female rats (10/group) were mated with untreated males (Olusi et
al, 1979). No pregnancies resulted. The dose corresponds to roughly 1000
and 2000 mg cyanide/kg BW /day. There was a dose-dependent decrease in
body weight gain, blood hemoglobin (18% and 23%) and serum T4
concentration (54% and 75%).

In a male fertility study (Monsanto Co., 1985a), Sprague-Dawley rats (n
= 15) were exposed by inhalation to acetone cyanohydrin (0, 35, 101, or
202 mg/ m^3^; 0, 11, 32, or 64 mg HCN/ m^3^) 6 hours/day, 5 days/week,
during a period of 69 days (i.e., 48 exposure days). After the treatment
period, the males were mated with three non-exposed females each. There
were no deaths, clinical signs of toxicity, changes in body weight, or
changes in gross necropsy after 48 exposures to up to 202 mg acetone
cyanohydrin (64 mg hydrogen cyanide/ m^3^). The mating efficiency,
number of live implants, and pre- and post-implantation losses were not
different between treated and control groups (WHO, 2004).

Female Sprague-Dawley rats were exposed by inhalation (6 hours/day, 7
days/week) for 21 days to acetone cyanohydrin at 38, 108, and 207 mg/
m^3^ and then mated to untreated males. Exposure of the females, which
was equivalent to 12, 34, and 66 mg hydrogen cyanide/ m^3^, was
continued until the day of mating, and the females were sacrificed at
mid-gestation (gestation days 13-15). No treatment-related effects on
female clinical signs of toxicity, mortality, body weight gain or gross
necropsy during or after 34-36 exposures up to 207 mg acetone
cyanohydrin/ m^3^ (66 mg hydrogen cyanide/ m^3^). Additionally, no
treatment-related effects on female fertility were observed in any of
the exposure groups. The only frequently observed clinical sign
post-exposure was red nasal discharge or encrustation. The highest
exposure in the study (207 mg acetone cyanohydrin/ m^3^) could be
considered as the NOAEL for female reproductive effects (Monsanto,
1985b, WHO, 2004).

In a study on the long-term and carry-over effect of control and 500 ppm
dietary potassium added to a cassava root flour-based basal diet in the
life cycle performance and metabolism of Wistar rats, Tewe and Maner
(1981a) demonstrated that there was no marked effect in gestation and
lactation performance in female rats. No carry-over effect of the
cyanide treated diet fed during gestation was observed on lactation
performance of female rats, although females exposed to fortified diets
gained less weight than controls. However, the high cyanide-containing
diet significantly reduced the food consumption and growth of offspring
when fed during the post-weaning growth period. Serum thiocyanate was
significantly increased in the potassium cyanide group in lactating rats
and their offspring during lactation and in the post-weaning growth
phase of the pups. Rhodenase, the enzyme which converts cyanide to
thiocyanate, activity in liver and kidney was unaffected by feeding the
high cyanide diet during gestation, lactation, and/or during
post-weaning growth.

> **4.2.4.2 Reproductive Toxicity Study in Pigs**

In a second study by Tewe and Maner (1981b), groups of six pregnant
Yorkshire pigs were fed fresh cassava diets containing 0, 250, and 500
ppm of potassium cyanide. Dietary cyanide level had no significant
effect on either the number or weight of 110-day old fetuses. Serum
thiocyanate concentration was slightly but not significantly increased
in the 500 ppm cyanide group and serum PBI decreased during gestation in
all maternal groups, including controls. Fetal serum thiocyanate
concentration was significantly higher (p\<0.05) in the group fed 500
ppm added cyanide. A small increase in maternal thyroid weight with
increasing level of cyanide was observed. Pathological studies showed
proliferation of glomerular cells of the kidney in maternal animals in
all groups, including controls. Both slaughtered 500 ppm "gilts"
-maternal animals - had thyroid glands with epithelial follicular cells
which were low in height and had an accumulation of colloid. In the
presence of maternal histopathologic effects to the thyroid and kidney,
fetal spleen and heart to body weight ratios were decreased. Cyanide fed
during gestation did not affect the production or lactation of the first
litter of offspring, although metabolic and pathologic differences did
occur. Milk thiocyanate and colostrum iodine concentrations were
significantly higher (p\<0.05) in the group fed 500 ppm cyanide.

**4.2.5 Pre-and/or Postnatal Toxicity**

> **4.2.5.1 Determination of Susceptibility**

Significant developmental effects from exposure to cyanides have been
observed across species, but appear in the presence of serious overt
maternal toxicity, including death. There is no quantitative or
qualitative increased susceptibility of fetuses and offspring across
species in comparison to maternal and parental animals. Serious
offspring developmental effects of the CNS have also been associated
with acute maternal CNS clinical findings, as well as other maternal
effects (death, dyspnea, tremors, ataxia, decreased body weight, etc.).
There was no qualitative or quantitative increased susceptibility in
postnatal offspring toxicity, since both offspring and parental effects
occurred at similar toxic dose levels.

> **4.2.5.2 Degree of Concern Analysis and Residual Uncertainties for
> Pre and/or Post-natal Susceptibility**

There are no quantitative or qualitative increased susceptibilities
associated with the serious offspring and parental findings resulting
from exposure to cyanides. These results indicate low residual concern
due to the fact that the developmental and postnatal findings occurred
in the presence of maternal/parental effects.

**4.2.6 Recommendation for a Developmental Neurotoxicity Study**

There is not a concern for developmental neurotoxicity resulting from
exposure to Hydrogen cyanide. There is a concern for serious neurotoxic
findings in both offspring and maternal animals i.e., hydrogen cyanide
is a neurotoxic chemical which produces neurotoxic clinical signs in
both offspring and maternal animals and there is evidence of
neuropathology resulting from exposure to hydrogen cyanide in both
offspring and maternal animals. However, there is no evidence of
increased susceptibility in the several developmental and reproduction
studies. Therefore, since the neuropathology seen in offspring in both
developmental and reproduction studies is a result of the acute effects
of cyanide which are also seen in adult animals a developmental
neurotoxicity study is not required for hydrogen cyanide at this time.

**4.3 FQPA Safety Factor**

There was no qualitative or quantitative increased susceptibility in
postnatal offspring toxicity, since both offspring and parental effects
occurred at similar toxic dose levels. Similarly, there is low residual
concern due to the fact that the developmental and postnatal findings
occurred in the presence of maternal/parental effects. Additionally, the
mechanism of action for hydrogen cyanide toxicity is well established.
Hydrogen cyanide binds with cytochrome oxidase in the electron transport
system and inhibits the exchange of oxygen from the blood to the tissues
by competitive inhibition. Since the cytochrome oxidase system is fully
functional in newborns, offspring and parental effects would occur at
similar toxic dose levels.

Therefore, it is recommended that the FQPA safety factor be reduced to
1x for the hydrogen cyanide risk assessment.

**4.4 Hazard Identification and Toxicity Endpoint Selection**

**4.4.1 Acute Reference Dose (aRfD) - General Population**

Selection of an acute RfD for hydrogen cyanide was based on published
data from a clinical trial of amygdalin (Laetrile) in the treatment of
human cancer (Moertel, CG et al. 1982 (MRIDs Nos 46769602, 46769601).
One hundred seventy-eight patients with cancer were treated with
amygdalin (Laetrile) plus a "metabolic therapy" program consisting of
diet, enzymes and vitamins. Amygdalin was administered at an intravenous
dose of 4.5 g/m^2^ of body surface area /day for 21 days in the Standard
Dose or 7 g/m^2^ of body surface area /day for 21 days at the High Dose.
Following intravenous treatment, amygdalin was administered orally at
0.5 g, three times daily at the Standard Dose Regimen or 0.5 g, four
times daily at the High Dose Regimen. All patients were fully informed
about the experimental and unorthodox nature of the treatment program as
well as any possible alternative treatment available to them. No placebo
group was administered. Clinical signs and symptoms consisting of
nausea, vomiting, headaches, dizziness, mental obtundation and, on a few
occasions, dermatitis, occurred in some patients on occasion following a
single 0.5 g oral dose of amygdalin or when two 0.5 g oral doses were
administered at the same time, or shortly apart, to compensate for a
missed dose or in one patient who consumed raw almonds following oral
therapy (Moertel et al, 1981). Blood levels of patients who received a
single dose ranged between 1-2 μgCN/ml whole blood. Blood levels of
cyanide rose to 2-3 μgCN/ml when the single 0.5 g dose was doubled to
two 0.5 g doses at an administration. These increased blood levels were
associated with an increase in the incidence and severity of some of the
toxic signs and symptoms due to the release of Hydrogen cyanide from
amygdalin by the enzymatic action of B-glucosidase, an intestinal
enzyme. If the blood cyanide level was found to be 3 μgCN/ml or greater
at any time, therapy was permanently discontinued. Therefore, the single
dose of 0.5 g of amygdalin was determined to be a minimally toxic dose,
whereas the double dose was generally regarded as frankly toxic. No
substantive benefit was observed in terms of cure, improvement, or
stabilization of cancer, or extension of life span. Amygdalin (laetrile)
is a toxic drug that is not effective as a cancer treatment. In the
Standard Dose study, a single dose 0.5 g of amygdalin results in 29.4 mg
of Hydrogen cyanide (500 mg/17.1 mw of laetrile/hydrogen cyanide = 29.4
mg of HCN). When the Hydrogen cyanide content is divided by the
approximate BW of 70 kg, the result is 0.4 mg/kg BW/day.

Supporting evidence comes from the 1956 Quarterly Report of the FDA,
which demonstrates that total oral doses of 20 to 30 mg NaCN (the
equivalent of 11.0 to 16.5 mg hydrogen cyanide or 0.2 mg HCN/kg BW) have
been administered to man to demonstrate thiocyanate in saliva. This
total oral dose level (0.2 mg/kg BW) has been estimated as a NOAEL in
comparison to the human LOAEL for mortality of 0.56 - 1.0 mg/kg BW.

The single oral dose level of 0.4 mg/kg/BW for HCN has therefore been
identified as a LOAEL in comparison to the estimated hydrogen cyanide
human NOAEL of 0.2 mg/kg BW for thiocyanate determinations in human
saliva (FDA 1956) and the LOAEL for cyanide mortality of 0.56-1.0 mg/kg
BW.

[Dose and Endpoint for Establishing aRfD:]{.underline} 0.4 mg/kg BW/day
LOAEL based on symptoms and clinical signs of hydrogen cyanide toxicity

[Uncertainty Factor (UF)]{.underline}: 100 (10X for intraspecies
variations and 10X for steep dose-response curve, severity of effects,
and lack of a NOAEL.

[Comments about Study/Endpoint/Uncertainty Factor:]{.underline} The
Moertel clinical trial study arrived at the dose of amygdalin (0.5 g)
that results in clinical signs in humans. The estimated human dose of
0.4 mg/kg BW can be used for risk assessment purposes. The uncertainty
factor of 100 incorporates 10X for intraspecies variations and 10X for
lack of a NOAEL, severity of effects, and a steep dose-response curve.

**4.4.2 Chronic Reference Dose (cRfD)**

A chronic RfD was not selected because the range of appropriate systemic
NOAELs in mammalian species is from 4.5 - 15 mg HCN/kg BW/day. These
NOAELs far exceed the estimated human LOAEL of 0.4 mg/kg BW used for the
acute dietary RfD. If these substantially higher NOAELs were used for
the cRfD, they would result in chronic exposures which would be greater
than and possibly lethal in comparison to an acute dose. A summary of
these mammalian studies is presented as follows:

The chronic ingestion of food fumigated with Hydrogen cyanide and
containing residues up to 300 ppm has been fed to 10 rats/sex/dose in a
2-year feeding study (Howard and Hanzal, 1955). There were no systemic
effects, including neurotoxicity, up to the highest dose tested of 300
ppm in the food. Based on the food intake and body weight of young and
old rats, the estimated dietary NOAEL was 10.8 mg/kg BW/day. Since the
acute oral fatal dose of potassium cyanide for rats is between 10-15
mg/kg BW (Handbook of Toxicology, (1956)), yielding 4.0 to 6.0 mg/kg BW
Hydrogen cyanide, the rats in the 2-year study ingested 1.8 to 2.7 times
the fatal dose of hydrogen cyanide each day throughout their lifetime
without any measurable effects. Virtually no cyanide was found in plasma
and kidneys. Low levels were found in erythrocytes (mean of 1.9
μg/100g). In the 2-year rat feeding study, residues of thiocyanate, the
less toxic primary liver metabolite of cyanide, increased 3.5-fold in
plasma, 3.3-fold in erythrocytes, 1.3-fold in liver, and 2.5-fold in
kidneys of the rats exposed to Hydrogen cyanide in the diet (Howard and
Hanzal, 1955).

The systemic NOAEL of 10.8 mg/kg BW/day in the 2-year study in rats
provides data which are supported by the results and NOAELs of other
available studies.

In the 13 week repeated-dose toxicity study (NTP, 1993) in which sodium
cyanide was administered in the drinking water, there were no
mortalities or clinical signs (associated with central nervous system
effects) or histopathological effects in the brain, thyroid, or other
organs of rats and mice exposed to doses up to 12.5 and 26 mg/kg BW/day,
respectively. The reproductive tract in males was the most sensitive
organ to cyanide exposure in this study: In rats at 12.5 mg/kg BW/day,
there were lowered weight of testis and epididymis, together with a
decrease in the number of spermatid heads in the testis and decreased
motility of epididymal sperm. The NOAEL in this study, 4.5 mg/kg BW/day,
is consistent with the 2-year study in rats which had a NOAEL of 10.8
mg/kg BW/day (Howard and Hanzal, 1955).

These results are also roughly consistent with the NOAEL in the 14 week
inhalation study (Monsanto Co., 1984a) in which the airborne systemic
no-effect level of 204 mg acetone cyanohydrin (ACH)/ m^3^ can be
estimated to correspond to a daily dose of approximately 15 mg HCN/kg
BW/day.

The other available studies specifically intended to investigate
neurotoxicity or other effects of cyanides have major weaknesses: the
study in miniature pigs (Jackson, 1988), which reported slight
functional thyroid changes and behavioral aberrations at 1.2 mg
cyanide/kg BW/day, used a bolus dose with consequent high peaks of
cyanide concentration in the organism and involved a very small number
of animals (three animals in four groups) and limited statistical
analysis. Similarly, the neuropathological study in goats (Soto-Blanco
et al, 2002), which reported ultrastructural changes in animals given
[\>]{.underline}0.48 mg cyanide/kg BW/day in drinking water for 5
months, did not present quantitative data or statistical analysis, since
it was essentially a morphometric evaluation.

Studies by Philbrick et al (1979) showed decreased weight gain and
thyroxin levels and myelin degeneration in rats (10 males/dose, females
were not investigated) fed CN for one year at the LOAEL of 30 mg/kg
BW/day (only dose tested). A NOAEL was not established.

> **4.4.3 Dermal Absorption**

Dermal absorption of Hydrogen cyanide is much slower than pulmonary
absorption, and the amount and speed of absorption through human skin
are dependent on the amount of skin moisture and duration of skin
contact. There are no adequate dermal penetration studies with hydrogen
cyanide. Since dermal exposure is not expected based on the use pattern,
a dermal assessment was not conducted and a dermal absorption factor was
not required for this assessment.

> **4.4.4 Dermal Exposure (All Durations)**

Worker and residential dermal exposures are not expected based on use
patterns and restrictions and were therefore not assessed for this TRED.

> **4.4.5 Inhalation Exposure (All Durations)**

The inhalation endpoint for all exposure durations was selected based on
a subchronic inhalation toxicity study in rats. In this study,
Sprague-Dawley rats (15/sex/dose) were exposed to acetone cyanohydrin
(ACH) \[which is rapidly hydrolyzed to hydrogen cyanide at physiological
pH\] at concentrations of 0, 36, 101, or 204 mg ACH/m^3^ for 6
hours/day, 5 days/week, for 14 weeks. The exposures were equivalent to
0, 11, 32, and 65 mg HCN/m^3^ (Monsanto Co., 1984a). There were no
treatment-related deaths or effects in body weight or hematology.
Irritation of the nose and eyes was observed, but no more in exposed
than in non-exposed animals. A decrease in blood glucose was recorded in
mid and high dose females and a decrease in total serum protein and
globulin was noted in mid-and low-dose females. There were no effects in
serum T3 or T4 and histopathology. The NOAEL reported from the study was
204 mg ACH/m^3^, corresponding to 65 mg HCN/m^3^. This can be estimated
to correspond to a daily dose of 15 mg cyanide/kg BW/day. However, in a
similar 4-week inhalation study at an average ACH concentration of 211
mg m^3^ (67 mg hydrogen cyanide/m^3^), no systemic effects were
observed, except on the first day of exposure, when the concentrations
in the chamber fluctuated and reached values of 225 mg ACH/m^3^ (71 mg
hydrogen cyanide/m^3^) at which dose 3 out of 10 animals died (Monsanto
Co., 1984a, 1985c).

[Dose/Endpoint for Risk Assessment:]{.underline} The NOAEL of 65 mg
HCN/m^3^ based on mortality in 3 of 10 rats at the LOAEL of 71 mg/m^3^
(HDT). For occupational exposures, the inhalation study NOAEL of 65 mg
HCN/m^3^ (60 ppm) would be converted to human equivalent dose of 50 mg
HCN/m^3^ (65 mg HCN/m^3^ x (6h/8h) assuming similar Regional Gas
Distribution Ratio (RGDR) between animals and humans (USEPA, 1994).

[Comments about Study/Endpoint:]{.underline} The NOAEL/LOAEL for the
inhalation endpoint is based on the effect of mortality for hydrogen
cyanide. The MOE is based on the uncertainty factor of 30X (3x
interspecies factor and 10x intraspecies factor). The traditional
interspecies factor of 10X is reduced to 3X since the doses are
expressed as air concentrations and the pharmacokinetics is assumed
similar between animals and humans. The interspecies factor of 3x is
considered sufficient to account for only pharmacodynamic differences
between animals and humans. An additional 10X for steepness of dose
response/severity of effect was considered unnecessary due to the
conservative nature of the selected endpoint, i.e., a subchronic
exposure endpoint is used to assess intermittent short-term exposure.

> **4.4.6 Margins of Exposure**

A summary of target Levels of Concern for risk assessment is provided in
Table 9.

+-----------------+----------------+-----------------+-----------------+
| **Table 9.      |                |                 |                 |
| Target Levels   |                |                 |                 |
| of              |                |                 |                 |
| Concern/Margin  |                |                 |                 |
| of Exposure for |                |                 |                 |
| Hydrogen        |                |                 |                 |
| Cyanide**       |                |                 |                 |
+=================+================+=================+=================+
| **R             | **Short-Term** | **Inte          | **Long-Term**   |
| oute/Duration** |                | rmediate-Term** |                 |
|                 | **(1-30        |                 | **(\> 6         |
|                 | Days)**        | **(1 - 6        | Months)**       |
|                 |                | Months)**       |                 |
+-----------------+----------------+-----------------+-----------------+
| **Occupational  |                |                 |                 |
| (Worker)        |                |                 |                 |
| Exposure**      |                |                 |                 |
+-----------------+----------------+-----------------+-----------------+
| Dermal          | N/A            | N/A             | N/A             |
+-----------------+----------------+-----------------+-----------------+
| Inhalation      | 30             | 30              | 30              |
+-----------------+----------------+-----------------+-----------------+
| **Residential   |                |                 |                 |
| (Non-Dietary)   |                |                 |                 |
| Exposure**      |                |                 |                 |
+-----------------+----------------+-----------------+-----------------+
| Oral            | N/A            | N/A             | N/A             |
+-----------------+----------------+-----------------+-----------------+
| Dermal          | N/A            | N/A             | N/A             |
+-----------------+----------------+-----------------+-----------------+
| Inhalation      | N/A            | N/A             | N/A             |
+-----------------+----------------+-----------------+-----------------+

The uncertainty factor for inhalation exposure is 30X (3x interspecies
factor and 10x intraspecies factor). For inhalation, the traditional
interspecies factor of 10X is reduced to 3X since the doses are
expressed as air concentrations and the pharmacokinetics is assumed
similar between animals and humans. The interspecies factor of 3x is
considered sufficient to account for only pharmacodynamic differences
between animals and humans.

> **4.4.7 Recommendation for Aggregate Exposure Risk Assessments**

Under FQPA, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures. Since there are no
residential uses, an assessment of aggregate exposure from risk from
food and non-food sources is not required.

> **4.4.8 Classification of Carcinogenic Potential**

The classification of the carcinogenic potential could not be determined
due to the absence of acceptable cancer studies in rats and mice.
Because of cyanide's high toxicity, it would be difficult to conduct a
meaningful cancer study in rats and mice over a two-year period. In
addition, regulation of cyanide's acute toxicity is considered to be
protective for potential carcinogenicity by the same rationale outlined
in Section 4.4.2. Hydrogen cyanide has been evaluated for mutagenic
potential with mixed results and several open literature references are
available (Table 8).

> **4.4.9 Summary of** **Endpoints Selected for Risk Assessment**

Toxicological doses/endpoints selected for the hydrogen cyanide risk
assessment are provided in Table 10.

+-----------+---------------+--------------+--------------------------+
| **Table   |               |              |                          |
| 10.       |               |              |                          |
| Summary   |               |              |                          |
| of        |               |              |                          |
| Toxi      |               |              |                          |
| cological |               |              |                          |
| Doses and |               |              |                          |
| Endpoints |               |              |                          |
| for       |               |              |                          |
| Chemical  |               |              |                          |
| for Use   |               |              |                          |
| in Human  |               |              |                          |
| Risk      |               |              |                          |
| Asse      |               |              |                          |
| ssments** |               |              |                          |
+===========+===============+==============+==========================+
| **E       | **Dose Used   | **FQPA SF\*  | **Study and              |
| xposure** | in Risk       | and Level of | Toxicological Effects**  |
|           | Assessment,   | Concern for  |                          |
| **S       | UF**          | Risk         |                          |
| cenario** |               | Assessment** |                          |
+-----------+---------------+--------------+--------------------------+
| Acute     | Oral dose of  | FQPA Safety  | Clinical trial study in  |
| Dietary   | 29.4 mg HCN   | Factor = 1   | humans, Moertel et al    |
|           | calculated as |              | (1982). LOAEL of 0.4     |
| (general  | single dose   | aPAD = 0.004 | mg/kg/day based on       |
| po        | LOAEL of 0.4  | mg/kg/day    | symptoms and clinical    |
| pulation) | mg/kg/day; UF |              | signs of hydrogen        |
|           | = 100;        |              | cyanide toxicity         |
|           |               |              |                          |
|           | aRfD = 0.004  |              |                          |
|           | mg/kg/day     |              |                          |
+-----------+---------------+--------------+--------------------------+
| I         | NOAEL of 65   | MOE          | Subchronic (14 weeks)    |
| nhalation | mg HCN/ m3    | requirement  | inhalation study with    |
|           | (60 ppm) (50  | = 30         | LOAEL of 71 mg HCN/m3    |
| (all      | mg/m3 or 46   |              | (64 ppm) based on        |
| d         | ppm adjusted  |              | mortality in 3 of 10     |
| urations) | for           |              | rats after a single dose |
|           | occupational  |              |                          |
|           | exposure)     |              |                          |
+-----------+---------------+--------------+--------------------------+
| Cancer    | Cl            |              |                          |
| (oral,    | assification: |              |                          |
| dermal,   | No available  |              |                          |
| in        | studies       |              |                          |
| halation) |               |              |                          |
+-----------+---------------+--------------+--------------------------+

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

Note: Study NOAEL is adjusted to human equivalent doses for occupational
scenario only e.g., animal NOAEL of 65 mg/m^3^ (6h/day, 5d/week) is
adjusted to human NOAEL of 50 mg/m^3^ (8 h/day, 5d/week), assuming the
regional gas dose ratio (RGDR) is similar between animals and humans (65
ppm x 6h/8h = 50 ppm) (USEPA,1994).

\* Refer to Section 4.3

**4.5 Endocrine Disruption**

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) "may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate."
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system. EPA also
adopted EDSTAC's recommendation that the Program include evaluations of
potential effects in wildlife. For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations. As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

In the available toxicity studies on hydrogen cyanide, there was no
estrogen or androgen, mediated toxicity. Thyroid effects in the presence
of liver toxicity were seen in both sexes at the highest dose tested in
the chronic dog study. When additional appropriate screening and/or
testing protocols being considered under the Agency's EDSP have been
developed, hydrogen cyanide may be subjected to further screening and/or
testing to better characterize effects related to endocrine disruption.

**5.0 PUBLIC HEALTH DATA**

Only five reports have been submitted by USDA APHIS concerning mishaps
with M-44 Capsules containing sodium cyanide since 1992 when EPA set up
the Incident Data System. None of the mishaps resulted in serious
medical outcomes. All resulted in transient symptoms which were minor to
moderate. Poison Control Centers have tracked rodenticide use of cyanide
over the years since 1985, however, their system does not specify the
form of the cyanide (e.g., calcium cyanide, sodium cyanide, or hydrogen
cyanide). On average Poison Control Centers receive only one report per
year. Most listed the outcome as not determined or, at most, minor
medical outcome.

**6.0 DIETARY EXPOSURE ASSESSMENT**

**6.1 Dietary Profile**

A tolerance of 50 ppm for citrus has been established under 40 CFR
§180.130 for residues of hydrogen cyanide from postharvest fumigation as
a result of application of sodium cyanide. There are no active national
registrations for sodium cyanide with food/feed uses. However, there is
one SLN for California for food/feed use registration for sodium
cyanide. Sodium cyanide is used in California as a source of hydrogen
cyanide gas to control red scale on fresh market citrus bound for
Arizona. The SLN end-use product is formulated as a granular containing
98% sodium cyanide and is used on citrus as a post-harvest fumigant.

> **6.1.1 Magnitude of the Residue in Plants and Animals**

In a recently submitted study (MRID 46868001), residues of hydrogen
cyanide in orange peel averaged 1.2 ppm 8 hours after fumigation with 1
ounce sodium cyanide/100 ft^3^, 0.9 ppm 24 hours after fumigation, and
0.45 ppm 48 hours after fumigation. Residues of hydrogen cyanide in
orange pulp averaged 0.06 ppm 8 hours after fumigation, 0.02 ppm 24
hours after fumigation, and \<0.01 ppm 48 hours after fumigation.
Residues in whole oranges were not determined. Additional data are
required for this study. Residue data from an additional two trials are
required along with residue data on whole oranges. A detailed
explanation of the modifications to EPA 335.2 along with validation of
this method at the reported LOD of 0.01 ppm is required.

Since the use on citrus is for citrus destined for the fresh market in
Arizona only, the 8 hour samples were not used in the dietary exposure
analysis. The residue data for the 24 and 48 hour samples will be used
to refine the dietary exposure analysis. The average residue input for
citrus peel in DEEM FCID model is 0.69 ppm and the residue input for
citrus pulp is 0.013 ppm. This recently submitted residue data for
citrus peel and citrus edible pulp should be used for the dietary
exposure analysis instead of previously submitted data which did not
reflect residues which would be incurred in/on pulp and peel.

**6.1.2 Residue Analytical Method**

The residue data for citrus were obtained by a GLC procedure using a
Coulson electrolytic nitrogen detector cell. No recovery data as such
were reported, but the report notes that virtually all the Hydrogen
cyanide gas was accounted for either as unabsorbed gas or as residues in
the treated citrus. In effect, recoveries were well in excess of 95%.
Background values were also not reported as such, but data in the
studies indicated blanks (residue values at 0 - 10 minutes) to be of the
order of 1 ppm or less. EPA's response to the citrus petition notes that
the method is adequate for obtaining residue data or as an alternate
enforcement method (PP#1E1124; 2/17/71; W. Cox).

The enforcement in PAM, Vol II is a titrimetric method. This method
involves the distillation of Hydrogen cyanide from acidified substrate
into an alkaline solution followed by titration with silver nitrate.
This method is considered adequate to determine residues of 1 ppm or
more (PP#1E1124; 2/17/71; W. Cox).

**6.2 Drinking Water Profile**

EFED does not anticipate significant exposure from sodium cyanide or
hydrogen cyanide in surface water and ground water when it is used as a
fumigant under controlled delivery system of gaseous hydrogen cyanide
into an airtight enclosure as described in the sodium cyanide label (SLA
CA 840006) (F. Kahn, D318020, 2/7/06). HED also evaluated potential
exposure and risk from cyanide in drinking water sources in Arizona.
Potential sources of cyanide drinking water contamination in Arizona
include mining, metal finishing, and organic chemical industries. HED
obtained monitoring data on total cyanide levels in public drinking
water systems throughout the State of Arizona from the Arizona
Department of Environmental Quality (ADEQ). ADEQ provided drinking water
monitoring data for a 13 year period - from January, 1993 through June,
2006. These data indicate that total cyanide concentrations are
non-detectable throughout the monitoring period (Personal communication,
John Calkins, ADEQ, 7/10/06). Based on this information, drinking water
exposure is expected to be negligible and was therefore not assessed for
this TRED.

**6.3 Acute Dietary Exposure and Risk**

Dietary risk assessment incorporates both exposure and toxicity of a
given pesticide. For acute assessments, the risk is expressed as a
percentage of a maximum acceptable dose (i.e., the dose which HED has
concluded will result in no unreasonable adverse health effects). This
dose is referred to as the population adjusted dose (PAD). The PAD is
equivalent to the reference dose (RfD) divided by the Food Quality
Protection Act (FQPA) Safety Factor.

For acute exposures, HED is concerned when estimated dietary risk
exceeds 100% of the PAD. References which discuss the acute and chronic
risk assessments in more detail are available on the EPA/pesticides web
site: "Available Information on Assessing Exposure from Pesticides, A
User's Guide," 6/21/2000, web link:
<http://www.epa.gov/fedrgstr/EPA-PEST/2000/July/Day-12/6061.pdf> ; or
see SOP 99.6 (8/20/99).

The acute dietary exposure assessment for hydrogen cyanide was conducted
using the Dietary Exposure Evaluation Model software with the Food
Commodity Intake Database (DEEM-FCID™, Version 2.03), which incorporates
consumption data from USDA's Continuing Surveys of Food Intakes by
Individuals (CSFII), 1994-1996 and 1998. The 1994-96, 98 data are based
on the reported consumption of more than 20,000 individuals over two
non-consecutive survey days. Foods "as consumed" (e.g., apple pie) are
linked to EPA-defined food commodities (e.g. apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA. For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events. Based on analysis of the 1994-96, 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (\<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis. The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or "matched" in multiple random
pairings with residue values and then summed in a probabilistic
assessment. The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis. In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis. However, for tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

HED conducted a somewhat refined probabilistic acute dietary exposure
analysis using recently submitted field trial data for the hydrogen
cyanide DEEM acute analysis. The recently submitted data for residues of
hydrogen cyanide in orange peel and orange pulp were used for the
dietary exposure analysis as it better reflects actual residues in the
edible pulp and peel portions of the treated citrus. Previously
submitted data provided whole fruit residues but did not provide
residues in/on pulp and peel. Citrus commodities are treated as
non-blended for this assessment because fumigation occurs post-harvest.
Therefore, blending of treated and non-treated commodities is not likely
to occur. Since treated fresh citrus commodities are non-blended,
residue distribution files (RDFs) created using field trial data were
used for this analysis. Two RDFs were used, one for edible pulp residues
and one for peel residues. Since there are so few commodities, all
commodities are non-blended, and only narrow range of residue values are
available for each type of treated commodity, and treated citrus is
destined for the fresh market in Arizona only, percent crop treated
information is not a factor in the analysis. Since citrus destined for
the fresh market only is fumigated, only fresh citrus commodities were
used in the dietary analysis. Since citrus is treated in California and
but shipped to and consumed only in Arizona, 8 hour residue samples were
not used the dietary exposure analysis; only the residue data for the 24
and 48 hour samples were used. Based on the new data, residues included
in the dietary analysis for edible citrus pulp ranged from \<0.005 --
0.04 ppm and residues in citrus peel ranged from 0.3 -- 1.3 ppm.

The results of the acute dietary exposure analyses at the 95^th^,
99^th^, and 99.9^th^ percentiles of exposure for consumption of fresh
citrus (edible pulp and peel) are presented in Tables 11 and 12. Data
from the food diaries provided in the Food Commodity Intake Database
(FCID) can be used to characterize assumptions regarding fresh citrus
consumption used in the DEEM analysis. Based on FCID data, young
children (1-2 years, 3-5 years) are estimated to consume approximately 1
orange per day at the 95^th^ percentile. For the general population,
95^th^ percentile consumption is estimated to be 2 to 3 peeled oranges
per day. As required in the HED policy, any significant differences in
user vs. per capita exposure/risk should be specifically identified and
noted in the risk assessment. A user is a survey participant who
consumes a treated target food during the period of analysis. The per
capita measure estimates exposure risk in the subpopulation of interest
as a whole, not just consumers of the treated commodity. Given that only
treated citrus commodities are likely to be consumed during a single
day, the period of analysis for acute dietary exposure, user exposure is
considered the most appropriate risk measure for this analysis. These
assessments conclude that acute dietary exposure estimates are below
HED's level of concern.

+-------------+-------+-------+------+--------+-----+--------+-------+
| **Table 11. |       |       |      |        |     |        |       |
| Hydrogen    |       |       |      |        |     |        |       |
| Cyanide     |       |       |      |        |     |        |       |
| DEEM Acute  |       |       |      |        |     |        |       |
| Dietary     |       |       |      |        |     |        |       |
| Exposure    |       |       |      |        |     |        |       |
| Analysis -  |       |       |      |        |     |        |       |
| Per Capita  |       |       |      |        |     |        |       |
| Exposure**  |       |       |      |        |     |        |       |
+=============+=======+=======+======+========+=====+========+=======+
| *           | **a   | **9   | **%  | **     | **% | **99   | **%   |
| *Population | PAD** | 5^th^ | a    | 99^th^ | a   | .9^th^ | aPAD  |
| Subgroup**  |       | %ile  | PAD. | %ile   | PAD | %ile   | (99.  |
|             | **(mg | Exp   | (95  | Ex     | (   | Ex     | 9^th^ |
|             | /kg/d | osure | ^th^ | posure | 99^ | posure | %)**  |
|             | ay)** | (mg   | %)** | (      | th^ | (      |       |
|             |       | /kg/d |      | mg/kg/ | %   | mg/kg/ |       |
|             |       | ay)** |      | day)** | )** | day)** |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| General     | 0.004 | 0     | 1    | 0.0002 | 4   | 0.0004 | 11    |
| U.S.        |       | .0001 |      |        |     |        |       |
| Population  |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| All Infants | 0.004 | \>0   | \>1  | 0.0001 | 1   | 0.0003 | 9     |
| (\< 1 year  |       | .0001 |      |        |     |        |       |
| old)        |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Children    | 0.004 | 0     | 3    | 0.0004 | 10  | 0.0009 | 23    |
| 1-2 years   |       | .0001 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Children    | 0.004 | 0     | 3    | 0.0003 | 9   | 0.0008 | 21    |
| 3-5 years   |       | .0001 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Children    | 0.004 | 0     | 2    | 0.0002 | 5   | 0.0005 | 11    |
| 6-12 years  |       | .0001 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Youth 13-19 | 0.004 | 0     | 1    | 0.0002 | 4   | 0.0004 | 10    |
| years old   |       | .0001 |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Adults      | 0.004 | \>0   | \>1  | 0.0001 | 3   | 0.0003 | 7     |
| 20-49 years |       | .0001 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Females     | 0.004 | \>0   | \>1  | 0.0001 | 3   | 0.0003 | 7     |
| 13-49 years |       | .0001 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Adults 50+  | 0.004 | \>0   | \>1  | 0.0001 | 2   | 0.0002 | 5     |
| years old   |       | .0001 |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+

+-------------+-------+-------+------+--------+-----+--------+-------+
| **Table 12. |       |       |      |        |     |        |       |
| Hydrogen    |       |       |      |        |     |        |       |
| Cyanide     |       |       |      |        |     |        |       |
| DEEM Acute  |       |       |      |        |     |        |       |
| Dietary     |       |       |      |        |     |        |       |
| Exposure    |       |       |      |        |     |        |       |
| Analysis -  |       |       |      |        |     |        |       |
| Per User    |       |       |      |        |     |        |       |
| Exposure**  |       |       |      |        |     |        |       |
+=============+=======+=======+======+========+=====+========+=======+
| *           | **a   | **9   | **%  | **     | **% | **99   | **%   |
| *Population | PAD** | 5^th^ | a    | 99^th^ | a   | .9^th^ | aPAD  |
| Subgroup**  |       | %ile  | PAD. | %ile   | PAD | %ile   | (99.  |
|             | **(mg | Exp   | (95  | Ex     | (   | Ex     | 9^th^ |
|             | /kg/d | osure | ^th^ | posure | 99^ | posure | %)**  |
|             | ay)** | (mg   | %)** | (      | th^ | (      |       |
|             |       | /kg/d |      | mg/kg/ | %   | mg/kg/ |       |
|             |       | ay)** |      | day)** | )** | day)** |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| General     | 0.004 | 0     | 3    | 0.0003 | 7   | 0.0006 | 16    |
| U.S.        |       | .0001 |      |        |     |        |       |
| Population  |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| All Infants | 0.004 | 0     | 7    | 0.0005 | 11  | 0.0009 | 20    |
| (\< 1 year  |       | .0003 |      |        |     |        |       |
| old)        |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Children    | 0.004 | 0     | 9    | 0.0007 | 18  | 0.0014 | 37    |
| 1-2 years   |       | .0004 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Children    | 0.004 | 0     | 7    | 0.0006 | 15  | 0.0013 | 32    |
| 3-5 years   |       | .0003 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Children    | 0.004 | 0     | 5    | 0.0004 | 9   | 0.0006 | 14    |
| 6-12 years  |       | .0002 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Youth 13-19 | 0.004 | 0     | 5    | 0.0003 | 8   | 0.0005 | 14    |
| years old   |       | .0002 |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Adults      | 0.004 | 0     | 3    | 0.0002 | 5   | 0.0005 | 12    |
| 20-49 years |       | .0001 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Females     | 0.004 | 0     | 3    | 0.0002 | 5   | 0.0004 | 10    |
| 13-49 years |       | .0001 |      |        |     |        |       |
| old         |       |       |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+
| Adults 50+  | 0.004 | 0     | 2    | 0.0001 | 3   | 0.0002 | 7     |
| years old   |       | .0001 |      |        |     |        |       |
+-------------+-------+-------+------+--------+-----+--------+-------+

**7.0 OCCUPATIONAL EXPOSURE AND RISK**

Workers are potentially exposed to hydrogen cyanide from its use in
post-harvest fumigation of citrus contained in closed transport
trailers. Sodium cyanide is used only in California to control red scale
on fresh market citrus bound for Arizona under the restrictions of the
SLN label. Consequently, fumigation of citrus with hydrogen cyanide is
limited to a single facility in California. Worker exposure monitoring
data from fumigations conducted at this facility were used to assess
occupational exposure and risk to hydrogen cyanide resulting from citrus
fumigation.

**7.1 Regulatory Standards**

The current Occupational Safety and Health Administration (OSHA)
permissible exposure limit (PEL) for hydrogen cyanide is 10 ppm (11
milligrams per cubic meter (mg/m^3^)) as an 8-hour time-weighted average
(TWA) concentration. The OSHA PEL also bears a "skin" notation, which
indicates that the cutaneous route of exposure (including mucus
membranes and eyes) contributes to overall exposure. The National
Institute for Occupational Safety and Health (NIOSH) has established a
recommend exposure limit (REL) for hydrogen cyanide of 4.7 ppm (5
mg/m^3^) as a short term exposure limit (STEL) or level at which an
unprotected worker can be exposed for 15 minutes without harm. NIOSH
also assigns a "skin" notation to hydrogen cyanide.

**7.2 Exposure Monitoring Study**

A monitoring study of worker exposure to hydrogen cyanide was conducted
in 1999 (MRID 46648901) (D. Jaquith, D318017, 3/30/06). The study
monitored air concentrations of cyanide in the breathing zone of the
applicators and in the ambient air resulting from fumigation of citrus
contained in transport trailers. Monitoring was conducted at Washburn
and Sons, Highgrove, CA, the only operators of a trailer/truck citrus
hydrogen cyanide fumigation facility. Air monitoring was conducted on 2
days during routine fumigation operations. Citrus containing trailers
were treated in a closed system at label specified rates. The trailers
were fumigated for 1 hour followed by aeration with more than 10 air
changes for ½ to 1 hour. Following fumigation, the trailers were
ventilated for 1 hour through a ventilation stack with a height of 20
feet 6 inches at a rate of 800 ft^3^/minute. A total of 10
fumigation/ventilations were monitored during the study.

Airborne hydrogen cyanide concentrations were measured using Safelog 100
datalogging monitors. One monitor was carried in the breast pocket of
the fumigator. One ambient monitor was located 50 feet from the trailer,
somewhat farther than the 20 foot buffer zone required by the label.
Additional area monitors were located downwind at distances of 50, 100,
and 200 feet from the trailer. The detection range was 0-50 ppm in
increments of 0.1 ppm with [+]{.underline} 5% sensor accuracy and \< 2%
drift. The high alarm for Hydrogen cyanide is 10 ppm, the STEL and TWA
Alarm is 4.7 ppm.

Hydrogen cyanide levels of the personal monitor worn by the fumigator
are presented in Table 13. Exposure was low and no alarms were noted at
any time. Peak 1-minute levels were 4.7 and 5.6 ppm for the two days.
The peak STEL was 0.4 for each of the days The results of the ambient
air monitoring are presented in Table 14. The TWAs were all zero. The
peak 15 minute STEL ranged from 0 to 0.6. The latter was judged to be
the result of displacement of a sunshade during monitoring.

  ------------------------------------------------------------------------------------------------------
  **Table 13.                                                                               
  Gas Detection                                                                             
  Report for                                                                                
  the                                                                                       
  Fumigator**                                                                               
  ------------- ----------------- ------------ ---------------- ------------- ------------- ------------
  **Date**      **Time            **\# of      **Hydrogen                                   
                Start-Stop**      Trailers**   cyanide Levels                               
                                               (ppm)**                                      

                                               **Peak(1min)**   **Average**   **STEL^1^**   **TWA^2^**

  2/18/99       10:27 am - 5:31   3            4.7              0             0.4           0
                pm                                                                          

  3/3/99        9:00 am - 8:19 pm 7            5.6              0             0.4           0
  ------------------------------------------------------------------------------------------------------

1 The Short Term Exposure Limit (STEL) to which an unprotected worker
may be exposed over a 15 min periods

2 The time-weighted average (TWA) is the average air concentration taken
over an eight-hour period

  ---------------------------------------------------------------------------------
  **Table 14.                                                             
  Ambient Air                                                             
  Monitoring                                                              
  Results**                                                               
  ------------ ----------- ------------ ------------ --------- ---------- ---------
  **Monitor    **Month**   **Distance   **Hydrogen                        
  No.**                    from Trailer cyanide                           
                           (ft)**       Levels                            
                                        (ppm)**                           

                                        **Peak (1    **Avg**   **STEL**   **TWA**
                                        min)**                            

  2            February    50           2.3          0         0          0

  3            February    100          0.5          0         0          0

  4            February    200          0.3          0         0          0

  5            February    45           5.9          0         0.3        0

  2            March       50           2.2          0         0          0

  3            March       100          1.2          0         0          0

  4            March       200          0.9          0         0.6        0

  5            March       45           1            0         0.1        0
  ---------------------------------------------------------------------------------

**7.3 Inhalation Exposure and Risk**

A NOAEL of 65 mg/m^3^ (60 ppm) has been established based on a
continuous 6 hour exposure for 14 weeks. Adjusted for occupational
exposure, the inhalation exposure endpoint for hydrogen cyanide is 50
mg/m^3^ (46 ppm). The target LOC or MOE for inhalation exposure to
hydrogen cyanide is 30. The peak 15 minute STEL for worker exposure from
the monitoring study was 0.4 ppm (0.36 mg/m^3^). It is important to note
that, based on the fumigation process and as indicated in the monitoring
study, worker exposure from hydrogen cyanide fumigation is likely to be
short-term and intermittent rather than continuous. Therefore, use of an
endpoint based on continuous exposure will result in a conservative
estimate of risk. The MOE calculated using the highest worker STEL from
the monitoring study is 115. Based on this analysis, calculated
inhalation MOEs are below HED's level of concern.

**7.4 Dermal Exposure and Risk**

Sodium cyanide is delivered to the container (transport trailer) without
handling by the fumigator and hydrogen cyanide is produced in a closed
system. Dermal exposure and risks to hydrogen cyanide residues following
sterilization cannot be fully determined without further information
regarding the nature and extent of post-sterilization activities (e.g.,
post-treatment handling of citrus). However, based on the fumigation
method and the physical/chemical nature of the fumigant, it is
reasonable to assume that handling of and exposure to treated citrus
during post-sterilization activities is limited and dermal exposure is
negligible.

**8.0 AGGREGATE EXPOSURE AND RISK**

Aggregate exposure is assessed when there are potential residential
exposures to the pesticide, aggregate risk assessment must consider
exposures from three major sources: oral, dermal and inhalation
exposures. Since there are no residential uses, an aggregate exposure
risk assessments was not conducted.

**9.0 CUMULATIVE RISK**

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether
to establish, modify, or revoke a tolerance, the Agency consider
"available information" concerning the cumulative effects of a
particular pesticide\'s residues and "other substances that have a
common mechanism of toxicity."

EPA does not have, at this time, available data to determine whether
hydrogen cyanide has a common mechanism of toxicity with other
substances. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity, EPA
has not made a common mechanism of toxicity finding as to hydrogen
cyanide and any other substances and, hydrogen cyanide does not appear
to produce a toxic metabolite produced by other substances which have
tolerances in the U. S. For the purposes of this tolerance reassessment
action, therefore, EPA has not assumed that hydrogen cyanide has a
common mechanism of toxicity with other substances. For information
regarding EPA's efforts to determine which chemicals have a common
mechanism of toxicity and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA's OPP concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA's website at
<http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/>.

**10.0 DATA NEEDS**

**10.1 Residue Chemistry Data Requirements**

\- Storage stability data for citrus are required - Guideline 860.1380

\- Analytical standards for sodium and hydrogen cyanide are not
currently available in the National Pesticide Standards Repository.
Analytical Reference standards of sodium and hydrogen cyanide must be
supplied and supplies replenished as requested by the Repository -
Guideline 860.1650

\- Additional data are required to validate newly submitted residue data
(MRID 46868001). Residue data from an additional two trials are required
along with residue data on whole oranges. A detailed explanation of the
modifications to EPA 335.2 along with validation of this method at the
reported LOD of 0.01 ppm is required.

**10.2 Toxicology Data Requirements**

\- None. The classification of the carcinogenic potential could not be
determined due to the absence of acceptable cancer studies in rats and
mice. However, because of cyanide's high toxicity, it would be difficult
to conduct a meaningful cancer study in rats and mice over a two-year
period.

**APPENDICES**

1.  **GUIDELINE TOXICOLOGY DATA SUMMARY**

Data requirements (40CFR 158.340) for hydrogen cyanide are provided in
the following table. Use of new GL numbers does not imply that new
(1998) guideline protocols were used.

+-----------------------------------------+-------------+-------------+
| **Test**                                | **          |             |
|                                         | Technical** |             |
+=========================================+=============+=============+
|                                         | *           | **          |
|                                         | *Required** | Satisfied** |
+-----------------------------------------+-------------+-------------+
| 870.1100 Acute Oral Toxicity            | yes         | yes         |
|                                         |             |             |
| 870.1200 Acute Dermal Toxicity          | yes         | yes         |
|                                         |             |             |
| 870.1300 Acute Inhalation Toxicity      | yes         | yes         |
|                                         |             |             |
| 870.2400 Primary Eye Irritation         | yes         | yes         |
|                                         |             |             |
| 870.2500 Primary Dermal Irritation      | yes         | yes         |
|                                         |             |             |
| 870.2600 Dermal Sensitization           | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3100 Oral Subchronic (rodent)       | yes         | yes         |
|                                         |             |             |
| 870.3150 Oral Subchronic (nonrodent)    | yes         | yes         |
|                                         |             |             |
| 870.3200 21-Day Dermal                  | no          | no          |
|                                         |             |             |
| 870.3250 90-Day Dermal                  | no          | no          |
|                                         |             |             |
| 870.3465 90-Day Inhalation              | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| 870.3700a Developmental Toxicity        | yes         | yes         |
| (rodent)                                |             |             |
|                                         | yes         | yes         |
| 870.3700b Developmental Toxicity        |             |             |
| (nonrodent)                             | yes         | yes         |
|                                         |             |             |
| 870.3800 Reproduction                   |             |             |
+-----------------------------------------+-------------+-------------+
| 870.4100a Chronic Toxicity (rodent)     | yes         | no          |
|                                         |             |             |
| 870.4100b Chronic Toxicity (nonrodent)  | yes         | yes         |
|                                         |             |             |
| 870.4200a Oncogenicity (rat)            | yes         | no          |
|                                         |             |             |
| 870.4200b Oncogenicity (mouse)          | yes         | no          |
|                                         |             |             |
| 870.4300 Chronic/Oncogenicity           | yes         | no          |
+-----------------------------------------+-------------+-------------+
| 870.5100 Mutagenicity\--Gene Mutation - | yes         | yes         |
| bacterial                               |             |             |
|                                         | yes         | yes         |
| 870.5300 Mutagenicity\--Gene Mutation - |             |             |
| mammalian                               | yes         | yes         |
|                                         |             |             |
| 870.5xxx Mutagenicity\--Structural      | yes         | yes         |
| Chromosomal Aberrations                 |             |             |
|                                         |             |             |
| 870.5xxx Mutagenicity\--Other Genotoxic |             |             |
| Effects                                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.6100a Acute Delayed Neurotox. (hen) | no          | \-          |
|                                         |             |             |
| 870.6100b 90-Day Neurotoxicity (hen)    | no          | \-          |
|                                         |             |             |
| 870.6200a Acute Neurotox. Screening     | yes         | yes         |
| Battery (rat)                           |             |             |
|                                         | yes         | yes         |
| 870.6200b 90 Day Neuro. Screening       |             |             |
| Battery (rat)                           | no          | no          |
|                                         |             |             |
| 870.6300 Develop. Neuro                 |             |             |
+-----------------------------------------+-------------+-------------+
| 870.7485 General Metabolism             | yes         | yes         |
|                                         |             |             |
| 870.7600 Dermal Penetration             | yes         | yes         |
+-----------------------------------------+-------------+-------------+
| Special Studies for Ocular Effects      | no          | no          |
|                                         |             |             |
| > Acute Oral (rat)                      | no          | no          |
| >                                       |             |             |
| > Subchronic Oral (rat)                 | no          | no          |
| >                                       |             |             |
| > Six-month Oral (dog)                  |             |             |
+-----------------------------------------+-------------+-------------+

**2.0 NON-CRITICAL TOXICOLOGY STUDIES**

None

**3.0 REFERENCES**

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