TABs
B-I. Chemical Properties of Sarin and Cyclosarin
B-II Summary of Acute Lethality Data for GB and GF; Toxicity Data for GB
TAB I to APPENDIX B Chemical Properties of Sarin and Cyclosarin
Table B-I-1. General Chemical Properties of Sarin and Cyclosarin
PROPERTY |
SARIN |
CYCLOSARIN |
Abbreviation | GB | GF |
Chemical Name | Isopropyl Methylphosphonofluoridate | Cyclohexyl Methylphosphonofluoridate |
Chemical Formula | CH3PO(F)OCH(CH3)2 | CH3PO(F)OC6H11 |
Molecular Weight1 | 140.1 | 180.2 |
State At 20� C1 | Colorless liquid | Liquid |
Odor1 | Almost none when pure | Sweet, musk, peaches, shellac |
Vapor Density (Air = 1 )1 | 4.86 | 6.2 |
Liquid Density (g/cc) | 1.0887 @ 25� C1 | 1.1278 @ 25� C2 |
Freezing/Melting Point (� C)1 | -56 | -30 |
Boiling Point (� C)1 | 158 | 239 |
Vapor Pressure (mm Hg)1 | 2.9 @ 25� C; 2.1 @ 20� C | 0.044 @ 20� C |
Volatility (mg/m3)1 | 22,000 @ 25� C; 16,090 @ 20� | 581 @ 25� C; 438 @ 20� C |
Flash Point1 | C Nonflammable | 94� C |
Decomposition Temp. (� C)1 | 150 | not available |
Heat of Vaporization (cal/g)1 | 80 | 90.5 |
Eye and Skin Toxicity1 | Very high | Very high |
Rate of Action1 | Very rapid | Very rapid |
Physiological Action1 | Cessation of breathing; death | Cessation of breathing; death |
Stability1 | Stable when pure | Relatively stable in steel |
Log Kow | 0.723 | 1.4934 |
Kh (atm-m3/mol) | 5.4 x 10-73 | 2.8 x 10-7 @ 20� C5 |
Aqueous Solubility | Miscible | Almost insoluble in water |
Log Koc | 0.593 | 1.823 |
Sources
1. OATSDNCB, 1997
2. Samuel et al., 1983
3. MacNaughton and Brewer, 1994
4. King and Brown, 1993
5. Rosenblatt, 1996
TAB
II to APPENDIX B Summary of Acute Lethality Data for Sarin and Cyclosarin;
Toxicity Data for Sarin
Table B-II-1. Summary of Acute Lethality Data for Sarin (GB)
Species |
Dose |
LCt mg-min/m3 |
Endpoint |
Reference |
Comments |
Inhalation Exposure |
|||||
human |
- |
50-100 |
LCt50 |
Somani et al., 1992 | |
human |
- |
35-100 |
LCt50 |
DHS, 1997a; Johns, 1952 |
Resting |
mouse |
- |
240-380 |
LCt50 |
McNamara and Leitmaker, 1971 | |
rat |
- |
80-300 |
LCt50 |
McNamara and Leitnaker, 1971 | |
guinea pig |
- |
100-200 |
LCt50 |
McNamara and Leitnaker, 1971 | |
rabbit |
- |
75-144 |
LCt50 |
McNamara and Leitnaker, 1971 | |
cat |
- |
42-100 |
LCt50 |
McNamara and Leitnaker, 1971 | |
monkey |
- |
25-300 |
LCt50 |
McNamara and Leitnaker, 1971 | |
dog |
- |
81-120 |
LCt50 |
McNamara and Leitnaker, 1971 | |
pig |
- |
34 |
LCt50 |
McNamara and Leitnaker, 1971 | |
goat |
- |
134 |
LCt50 |
McNamara and Leitnaker, 1971 | |
Dermal Exposure |
|||||
human |
28,000 |
- |
LD50 |
DHHS, 1995; in ORNL, 1996 | |
human |
24,000 |
- |
LD50 |
US Army ERDEC, 1994; Oak Ridge National Laboratory (ORNL); 1996 | |
human |
1,700 |
- |
LD50 |
Zajtchuk, et al., 1997 |
Based on 70 kg man |
human |
1,429-7,143 |
- |
LD50 |
Somani, et al., 1992 |
Based on 70 kg man |
pig |
115,900 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1996 | |
rat |
2,500 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1996 | |
mouse |
1,080 |
- |
LD50 |
DHHS, 1995; ORNL, 1996 | |
Intravenous Exposure |
|||||
human |
14 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1996 | |
monkey |
20 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1997 | |
pig |
15 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1998 | |
rat |
39 |
- |
LD50 |
DHHS, 1995; ORNL, 1996 | |
rat |
45 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1996 | |
Intramuscular Exposure |
|||||
human |
30 |
- |
Lethal Level |
Grob and Harvey, 1957; ORNL, 1996 | |
monkey |
22 |
- |
LD50 |
DHHS, 1995; ORNL, 1996 | |
rat |
170 |
- |
LD50 |
Grob and Harvey, 1957; ORNL, 1996 | |
rat |
108 |
- |
LD50 |
DHHS, 1995; in ORNL, 1996 | |
rat |
112 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1996 | |
Subcutaneous Exposure |
|||||
rat |
103-108 |
- |
LD50 |
DHHS, 1995; ORNL, 1996 | |
mouse |
200 |
- |
LD50 |
DA, 1990 | |
mouse |
170 |
- |
LD50 |
Clement, 1991; Clement, 1994 | |
Intraperitoneal Exposure |
|||||
rat |
218 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1996 | |
rat |
250 |
- |
LD50 |
DHHS, 1995; ORNL 1996 | |
Oral Exposure |
|||||
human |
71-285 |
- |
LD50 |
Somani, et al., 1992; ORNL, 1996 |
Assumes 70 kg man |
human |
140 |
- |
Lethal Level |
Grob and Harvey, 1957; ORNL, 1996 | |
rat |
550 |
- |
LD50 |
DHHS, 1995; ORNL, 1996 | |
rat |
600 |
- |
LD50 |
Grob and Harvey, 1957; ORNL, 1996 | |
rat |
870-1060 |
- |
LD50 |
US Army ERDEC, 1994; ORNL, 1996 |
Table B-II-2. Summary of Acute Lethality Data for Cyclosarin (GF)
Species |
Dose |
LCt mg-min/m3 |
Endpoint |
Reference |
Comments |
Inhalation Exposure |
|||||
human |
35 |
LCt50 |
Table B-II-3. |
Data questionable |
|
Dermal Exposure |
|||||
human |
350 |
- |
LD50 |
Table B-II-3. | |
Subcutaneous Exposure |
|||||
mouse |
16-400 |
- |
LD50 |
DA, 1990 | |
mouse |
243 |
- |
LD50 |
Clement, 1991; Clement, 1994 | |
mouse |
184 |
- |
LD50 |
Clement, 1994 |
GF/GB combined |
Table B-II-3. Summary of Toxicity Data for Sarin (GB)
Species
|
Study Type
or Limit |
Dosing
Paradigm |
Dose1
�g/kg |
Concentration mg min/m3
|
Endpoint
|
AChE Levela
|
Reference
|
Comments
|
|
Inhalation
Exposure
|
|||||||||
human
|
limit
|
~0.0028
(72 hr)
|
0.01296
(72 hrs) |
General population limit averaged |
|
DA, 1990; Fed. Reg., 1989; McNamara and Lietnaker, 1971 | As developed by McNamara and Leitnaker, 1971, based on plasma AchE inhibition and miosis | ||
human
|
limit
|
~0.0013
(1 hr) |
~0.006
(1 hr) |
General population ceiling limit for 1 hour |
|
DA, 1990; McNamara and Leitnaker, 1971 | |||
human
|
limit
|
~0.01
(8 hr) |
0.048
(8 hr) |
Occupational limit averaged over an 8 hour workday |
|
DA, 1990,
Fed. Reg, 1989; McNamara and Leitnaker, 1971 |
As developed by McNamara and Lietnaker, 1971, based on plasma A ChE inhibition and miosis. Originally posed 10 consecutive period limit. | ||
human
|
MSCb
|
~0.03
(8 hr) |
~0.144
(8 hr) |
Maximum safe concentration for single 8 hr occupational exposure |
|
McNamara and Lietnaker, 1971 | |||
human
|
MSCb
|
~0.013
(1 hr) |
0.06
(1 hr) |
Maximum safe concentration for single 1 hr occupational exposure |
|
McNamara and Lietnaker, 1971 | |||
human
|
|
~0.12
|
0.5
|
<1% of working population would show miosis, ChE depression, or other mildest symptoms. Approximately 10% RBC-AChE depression occurs per 1 ug/kg dose (no ref). |
<1% would show any depression
|
McNamara and Lietnaker, 1971 | Based on kinetic data, does may accumulate with daily exposure of 0.05 mg min/m3 | ||
human
|
limit
|
~0.21
|
1 mg min/m3
|
First level effects |
|
CIA and DoD, 1997 | |||
human
|
|
~0.43
0.64
|
2-3 mg min/m3
|
Miosis and rhinorrhea |
|
Johns, 1952 | % responding not identified in Z, 1997 | ||
human
|
|
~0.86
|
4
|
ECt50 for miosis (20 minute or less exposure) |
|
McNamara and Leitnaker, 1971 | 15 1/min. 8 hr [C] = 0.0083 mg/m3; 24 hr [C] = 0.0028 mg/m3 | ||
human
|
|
0.88
|
4.1
|
No systemic effects |
|
McNamara and Leitnaker, 1971 | 15 1/min. 8 hr [C] = 0.0085 mg/m3; 24 hr [C] = 0.0028 mg/m3 | ||
human
|
|
2.1
|
10
|
No deaths |
|
McNamara and Leitnaker, 1971 | 15 1/min. 8 hr [C] = 0.2 mg/m3; 24 hr [C] = 0.007 mg/m3 | ||
human
|
|
4.3
|
20
|
ECt50 for ChE depression |
|
||||
human
|
|
7.5
|
35
|
1Ct50 |
|
U.S. Army ERDEC, 1994 | Resting | ||
human
|
|
~15
|
70
|
LCt50 |
|
U.S. Army ERDEC, 1994; McNamara and Leitnaker, 1971 | 15 1/min. 8 hr [C] = 0.14 mg/m3; 24 hr [C] = 0.047 mg/m3 | ||
rat
|
multiple
|
0.001
mg/m3 6 hr/day, 5 days/week for up to 24 weeks |
|
0.151
|
No signs of toxicity |
|
Weimer
et al., 1979; ORNL, 1996 |
Also no effects at 0.0001 mg/m3 | |
rat
mouse dog
|
multiple
|
0.001
mg/m3 6 hr/day, 5 days/week for up to 52 weeks |
c
|
0.15
|
No signs of toxicity and no statistically significant dose-related changes in RBC-AChE. |
No
statistically significant changes
|
Weimer
et al., 1979; ORNL, 1996 |
5 of 20 dogs had abnormal EKGs at time of sacrifice; colony and Fischer rats had higher incidence of trachetis than controls; atrophy of eminiferous tubules occurred in one group of Fischer rats. | |
mouse
|
multiple
|
5 mg/m3 for 20 mins/day for 10 days |
d
|
|
Significant inhibition of brain, spinal cord and platelet NTE. Focal axonal degeneration in 6 animals. |
Blood
AChE decreased by 27.3% and brain AChE decreased by 19.2%
|
Husain
et al., 1992; ORNL, 1996 |
||
Oral
Exposure
|
|||||||||
human
|
RfD
|
|
0.02
|
RfD-no inhibition of RBC-AChE |
|
ORNL, 1996 | |||
human
|
acute
|
single dose |
2
|
|
Excessive dreaming and talking in sleep |
RBC
and plasma A ChE reduced ~ 15%
|
Thienes
and Haley, 1972; ORNL, 1996 |
||
human
|
multiple
|
Average daily dose of 2.3 �/kg for 3 days, given in 0.008 to 0.016 increments at average interval of 7.4 hrs |
2.3
|
2.3
|
RBC-AChE
reduced 27 and 33% but no toxic effects. (n = 2) |
RBC-AChE
decreased by 27 and 33%.
P-AChE reduced 14 and 29%. |
Grob and Harvey, 1957 | Small
number of subjects. Authors saw no change in EEGs in asymptomatic subjects,
slight changes with mild symptoms, and more irregularities with moderate
symptoms (p. 356). |
|
human
|
acute
|
single dose |
10
|
|
Oral EgD50 for inhibition of RBC-AChE |
RBC-AChE
reduced 50%
|
Grob and Harvey, 1957 | ||
human
|
acute
|
single dose |
20
|
|
Insomnia, excessive dreaming, withdrawal, depression |
|
Thienes and Haley, 1972; ORNL, 1996 | ||
human
|
acute
|
single dose |
22
|
|
Mild toxic effects, anorexia, nausea, heartburn, tightness in stomach and chest, increased fatigue, nervous tension, anxiety, and other CNS responses including insomnia and excessive dreaming |
RBC
and plasma AChE reduced ~75%
|
Grob and Harvey, 1957 | ||
human
|
acute
|
Single dose |
28
|
|
Moderate toxic effects |
|
Grob and Harvey, 1957 | ||
human
|
multiple
|
Average daily dose of 29 �g/kg for 3 days, given in 0.008 to 0.016 increments at average interval of 7.4 hrs |
29
|
29
|
Mild toxic effects |
RBC-AChE
decreased 97-99%.
P-AChE reduced 81-88% |
Grob and Harvey, 1957 | ||
human
|
multiple
|
Average daily dose of 34 �g/kg for 3 days, given in 0.008 to 0.016 increments at average interval of 7.4 hrs |
34
|
34
|
Moderate
toxic effects; >90% reduction in RBC-AChE activity |
RBC-AChE
decreased 99%.
P-AChE reduced 84-88% |
Grob and Harvey, 1957 | ||
human
|
acute
|
Single dose |
140
|
|
Estimated lethal dose |
|
Grob and Harvey, 1957 | ||
human
|
multiple
|
0.075
mg/kg 5 days per week for 13 weeks |
75
|
542
(7 days) |
LOAEL based on statistically significant reduction in RBC-AChE in male rats |
RBC-AChE
reduced to 77 and 63% of baseline
|
Bucci and Parker, 1992; ORNL, 1996 | GB Type II | |
rat
|
acute
|
Single dose |
600
|
|
LD50 |
|
Grob and Harvey, 1957 | ||
Dermal
Exposure
|
|||||||||
human
|
|
|
|
LD50 |
|
Zajchuk, et al., 1997 | 1,700 mg/70-kg man | ||
Intra-arterial
Exposure
|
|||||||||
human
|
acute
|
Single dose |
3
|
|
ED50
inhibition of RBC-AChE |
RBC-AChE
decreased by 48%.
P-AChE reduced by 30% |
Grob and Harvey, 1957 | Symptoms occur after RBC-AChE is depressed 88% (12% of baseline) after a single oral dose or 50% after a single intra-arterial dose. | |
human
|
acute
|
single dose |
5
|
|
Moderate symptoms |
RBC-AChE
decreased by 72%.
P-AChE reduced by 58% |
Grob and Harvey, 1957 | ||
Intravenous
Exposure
|
|||||||||
monkey
|
acute
|
5
|
|
Alterations
in EEG at 24 hr and 1 yr post exposure |
|
Burchfiel and Duffy, 1982 | All animals convulsed | ||
Intramuscular
Exposure
|
|||||||||
human
|
acute
|
Single dose |
30
|
|
Estimated lethal dose (LD50) |
|
Grob
and Harvey, 1957; ORNL, 1996 |
||
monkey
|
multiple
|
Ten 1 �g/kg doses at 1 week intervals |
3
|
|
Alterations in EEG at 24 hr and 1 yr post exposure |
|
Burchfiel and Duffy, 1983 | "A series of subclinical but near-threshold exposures showing few, if any, signs of overt poisoning. Stats on this study have been questioned." | |
rat
|
acute
|
Single dose |
170
|
|
LD50 |
|
Grob and Harvey, 1957 | ||
Subcutaneous
Exposure
|
|||||||||
rat
|
acute
|
157-177
|
|
Brain lesions; myocardial degeneration and necrosis |
|
Singer et al., 1987 | These were convulsant doses. Cardiomyopathy appeared reversible at these dose levels. | ||
Interperitoneal
Exposure
|
|||||||||
rat
|
acute
|
125
|
|
Behavior, motor performance, learning frequency, nociception |
|
Sirkka et al., 1990 | No significant effects | ||
rat
|
acute
|
50
|
|
Behavior, motor performance, learning frequency, nociception |
|
Sirkka et al., 1991 | Affected behavior and motor performance | ||
Oral
OPIDN Studies
|
|||||||||
hen
|
acute
|
70.2-280.7
|
|
No evidence of OPIDN at 8-48 days |
|
Bucci
et al., 1992; ORNL, 1996 |
GB Type II | ||
hen
|
multiple
|
70.2-280.7 divided into three increments given one week apart |
23.4-93.57
|
|
No evidence of OPIDN at 43 days |
|
Bucci
et al., 1992; ORNL, 1996 |
GB Type II | |
hen
|
acute
|
70.2-750
|
|
No dose-related changes in NTE |
|
Bucci
et al., 1992; ORNL, 1996 |
GB Type II | ||
Other
OPIDN Studies
|
|||||||||
hen
|
|
20-30
x LD50
|
|
OPIDN induced |
|
Davies
et al., 1960, Davies and Holland, 1972, Gordon et al., 1983 |
Animals
protected with atropine and oximes. LD50 = 25 �g/kg, i.m. |
1 Approximations assume a human weighing 70 kg, breathing 15 L/min, and complete absorption
2 75 x (5/7)
3 Assuming monkey weighing 0.35 kg, breathing 0.29 m3/day, and complete absorption
a AchE: Acetylcholinesterase
b MSC: Maximum Safe Concentration
c Concentration (mg/m3) = 0.001
d Concentration (mg/m3) = 5