ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)
FOR
FENAMIPHOS
CAS Reg. No. 22224-92-6
PROPOSED
-------
FENAMIPHOS
PROPOSED: November 2009
ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)
FOR
FENAMIPHOS
(CAS Reg. No. 22224-92-6)
PROPOSED
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
FENAMIPHOS
PROPOSED: November 2009
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of
1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous
Substances (NAC/AEGL Committee) has been established to identify, review and interpret
relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic
chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to
emergency exposure periods ranging from 10 minutes to 8 hours. Three levels — AEGL-1,
AEGL-2 and AEGL-3 — are developed for each of five exposure periods (10 and 30 minutes, 1
hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects.
The three AEGLs are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per
cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general
population, including susceptible individuals, could experience notable discomfort, irritation, or
certain asymptomatic, non-sensory effects. However, the effects are not disabling and are
transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
which it is predicted that the general population, including susceptible individuals, could
experience irreversible or other serious, long-lasting adverse health effects or an impaired ability
to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
which it is predicted that the general population, including susceptible individuals, could
experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce
mild and progressively increasing but transient and nondisabling odor, taste, and sensory
irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations
above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity
of effects described for each corresponding AEGL. Although the AEGL values represent
threshold levels for the general public, including susceptible subpopulations, such as infants,
children, the elderly, persons with asthma, and those with other illnesses, it is recognized that
individuals, subject to unique or idiosyncratic responses, could experience the effects described
at concentrations below the corresponding AEGL
3
-------
FENAMIPHOS
PROPOSED: November 2009
1 TABLE OF CONTENTS
2 PREFACE 3
3 LIST OF TABLES 6
4 EXECUTIVE SUMMARY 7
5 1. INTRODUCTION 9
6 2. HUMAN TOXICITY DATA 9
7 2.1. Acute Lethality 9
8 2.2. Nonlethal Toxicity 10
9 2.2.1. Odor Thre shold/Odor Awarene ss 10
10 2.2.2. Case Reports 10
11 2.2.3. Exposure Studies 10
12 2.3. Neurotoxicity 10
13 2.4. Developmental/Reproductive Toxicity 10
14 2.5. Genotoxicity 10
15 2.6. Carcinogenicity 10
16 2.7. Summary 10
17 3. ANIMAL TOXICITY DATA 10
18 3.1. Acute Lethality 10
19 3.1.1. Rats 11
20 3.2. Nonlethal Toxicity 12
21 3.2.1. Rats 12
22 3.3. Developmental/Reproductive Toxicity 13
23 3.4. Genotoxicity 14
24 3.5. Chronic Toxicity/Carcinogenicity 14
25 3.6. Summary 14
26 4. SPECIAL CONSIDERATIONS 15
27 4.1. Metabolism and Disposition 15
28 4.2. Mechanism of Toxicity 16
29 4.3. Structure Activity Relationships 16
30 4.4. Other Relevant Information 17
31 4.4.1. Species Variability 17
32 4.4.2. Susceptible Populations 17
33 4.4.3. Concentration-Exposure Duration Relationship 17
34 4.4.4. Concurrent Exposure Issues 17
35 5. DATA ANALYSIS FOR AEGL-1 18
36 5.1. Summary of Human Data Relevant to AEGL-1 18
37 5.2. Summary of Animal Data Relevant to AEGL-1 18
38 5.3. Derivation of AEGL-1 18
39 6. DATA ANALYSIS FOR AI Xi 1.-2 18
40 6.1. Summary of Human Data Relevant to AEGL-2 18
41 6.2. Summary of Animal Data Relevant to AEGL-2 18
42 6.3. Derivation of AEGL-2 18
4
-------
FENAMIPHOS PROPOSED: November 2009
1 7. DATA ANALYSIS FOR AEGL-3 19
2 7.1. Summary of Human Data Relevant to AEGL-3 19
3 7.2. Summary of Animal Data Relevant to AEGL-3 19
4 7.3. Derivation of AEGL-3 19
5 8. SUMMARY OF AEGLS 20
6 8.1. AEGL Values and Toxicity Endpoints 20
7 8.2. Comparison with Other Standards and Guidelines 20
8 8.3. Data Adequacy and Research 21
9 9. REFERENCES 22
10 APPENDIX A: DERIVATION OF AEGL VALUES 26
11 APPENDIX B: TIME-SCALING CALCULATIONS 29
12 APPENDIX C: DERIVATION SUMMARY FOR FENAMIPHOS AEGLS 31
13 APPENDIX D: CATEGORY PLOT FOR FENAMIPHOS 34
14 APPENDIX E: BENCHMARK EXPOSURE CALCULATIONS 37
15
16
5
-------
1
2
3
4
5
6
7
8
9
10
11
12
FENAMIPHOS
PROPOSED: November 2009
LIST OF TABLES
TABLE 1. Summary of AEGL Values for Fenamiphos 8
TABLE 2. Chemical and Physical Properties 9
TABLE 3. Summary of Acute Inhalation Data for Fenamiphos in Laboratory Animals 12
TABLE 4. AEGL-1 Values for Fenamiphos 18
TABLE 5. AEGL-2 Values for Fenamiphos 19
TABLE 6. AEGL-3 Values for Fenamiphos 20
TABLE 7. Summary of AEGL Values 20
TABLE 8. Extant Standards and Guidelines for Fenamiphos 21
6
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
FENAMIPHOS
PROPOSED: November 2009
EXECUTIVE SUMMARY
Fenamiphos is an organophosphate nematicide and insecticide that is used to control a
variety of nematodes, thrips, aphids, beetles, root weevils, and corn borers. It was first registered
in 1972 for use on annual field and vegetable crops or on established perennial, deciduous, and
tropical fruit crops. In the U.S., the registrant cancelled use and formulation for use of all of its
existing fenamiphos registrations in areas with predominantly sand or loamy sand, hydrologic
soil group A soils that are excessively drained, and shallow water tables effective May 31, 2005.
Registrations were cancelled for use on all other soils in the U.S. effective May 31, 2007. Prior
to cancellation, annual domestic use for the United States was approximately 780,000 pounds of
active ingredient. The U.S. EPA has tolerances for crops on which fenamiphos is used and for
food commodities imported into the U.S.
Fenamiphos is readily absorbed through the skin and numerous studies are available
describing the pharmacokinetics and toxicity after topical application. Dermal exposure may
increase the total absorbed dose when it occurs with oral or inhalation exposure. However,
because the dermal route is not relevant to the inhalation route of exposure, the data on dermal
exposure were not analyzed with regard to developing AEGL values for fenamiphos. Relative to
occupational dermal and oral exposure, inhalation is a minor exposure route and this is reflected
in the paucity of inhalation toxicity data. No quantitative data are available regarding the
inhalation toxicity of fenamiphos in humans.
No AEGL-1 values were established because the AEGL-1 values would have been too close
to or exceeded AEGL-2 values.
The AEGL-2 values were derived by dividing the AEGL-3 values by three. The lack of
experimental data and the steep exposure-response relationship justify estimating AEGL-2
values by a 3-fold reduction of AEGL-3 values (NRC 2001). Male rats experienced 5%
3 3
mortality after exposure to 75 mg/m for 1 hour; 30% mortality at 87 mg/m ; and 60% mortality
at 103 mg/m3. All 20 rats died after exposure to 187 mg/m3 (Kimmerle 1972). In a study by
Thyssen (1979a), 20% of the male rats died after exposure to 119 mg/m for 1 hour; 60% died
after exposure to 145 mg/m3; and 90% died after exposure to 148 mg/m3. Female rats had 70%
3 3
mortality at 145 mg/m and 90% mortality after exposure to 148 mg/m for 1 hour. In a 4-hour
study by Thyssen (1979a), male rats experienced 60% mortality at 100 mg/m3 and 100%)
3 3
mortality at 155 mg/m , and female rats experienced 50% mortality at 100 mg/m ; 90% mortality
at 155 mg/m3; and 100% mortality at 191 mg/m3.
The AEGL-3 was derived using the 4-hour BMCL05 of 46.6337 mg/m3 for lethality of
fenamiphos in female rats (Thyssen 1979a). This is considered a threshold for lethality for
fenamiphos and is the most conservative benchmark value calculated from the test animals used
in the study. Lethality data were sufficient for empirical derivation of a time-scaling factor (n)
for use in the equation Cn x t = k. The value of n was 4.8 and was used to time scale AEGL
values. The mechanism of action of organophosphate anticholinesterases is well understood;
their activity on cholinergic systems is the same across species. Variability in response is
primarily a function of varying cholinesterase activity level and types of cholinesterase. Humans
have greater levels of plasma cholinesterase than do other species which allows for greater
binding of anticholinesterase compounds such as fenamiphos, thereby decreasing the availability
of the compound to brain cholinesterase. Therefore, the interspecies uncertainty factor is limited
to 3. The documented variability in sensitivity among different age groups and genders, and the
7
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
FENAMIPHOS
PROPOSED: November 2009
known genetic polymorphisms in A-esterases justify retention of the intraspecies uncertainty
factor of 10. The uncertainty factor application and rationale are the same as those applied in the
derivation of AEGLs for other organophosphate anticholinesterases (NRC 2003).
TABLE 1. Summary of AEGL Values for Fenamiphos
Classification
10-minute
30-minute
1-hour
4-hour
8-hour
Endpoint (Reference)
AEGL-1
(Nondisabling)
NR
NR
NR
NR
NR
Not recommended due to
exceeding AEGL-2 values
AEGL-2
(Disabling)
1.0 mg/m3
0.80 mg/m3
0.70 mg/m3
0.53 mg/m3
0.43 mg/m3
Derived by 3-fold
reduction of the AEGL-3
values (NRC 2001;
Thyssen 1979a)
AEGL-3
(Lethal)
3.0 mg/m3
2.4 mg/m3
2.1 mg/m3
1.6 mg/m3
1.3 mg/m3
Derived based upon a 4-hr
BMCL05 of 46.6337 mg/m3
in rats (Thyssen 1979a)
NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect.
References
Kimmerle, G. 1972. Acute inhalation toxicity study with Nemacur active ingredient on rats.
Unpublished report. Bayer AG, Wuppertal, Germany.
NRC (National Research Council). 2001. Standing operating procedures for developing acute exposure
guideline levels for hazardous chemicals. Committee on Toxicology, Board on Toxicology and
Environmental Health Hazards, Commission on Life Sciences, National Research Council. National
Academy Press, Washington, DC.
NRC (National Research Council). 2003. Acute Exposure Guideline Levels for Selected Airborne
Contaminants: Nerve agents GA, GB, GD, GF, and VX. Vol. 3. Committee on Toxicology, Board on
Toxicology and Environmental Health Hazards, Commission on Life Sciences, National Research
Council. National Academy Press, Washington, DC.
Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute inhalational toxicity studies. Report no.
8210. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany.
8
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
FENAMIPHOS
PROPOSED: November 2009
1. INTRODUCTION
Fenamiphos is an organophosphate nematicide and insecticide that is used to control a
variety of nematodes, thrips, aphids, beetles, root weevils, and corn borers. Fenamiphos is
manufactured by reacting 4-methyl-m-creosol with ethylisopropylamido-phosphorochloride or
by condensing 4-methylthio-m-cresol with O-ethyl N-isopropyl phosphoramidochloride. It was
first registered in 1972 for use in plant control of nematodes on annual field and vegetable crops
or on established perennial, deciduous, and tropical fruit crops. In the U.S., the manufacturer
agreed to cancel use, and formulation for use, of all of its existing fenamiphos registrations in the
U.S. in areas with predominantly sand or loamy sand, hydrologic soil group A soils that are
excessively drained, and shallow water tables effective May 31, 2005. Registrations were
cancelled for use on all other soils in the U.S. effective May 31, 2007. Prior to cancellation, the
annual domestic use for the United States was approximately 780,000 pounds of active
ingredient (HSDB 2005). The U.S. EPA has tolerances set for crops on which fenamiphos is
used and for food commodities imported into the U.S. (U.S. EPA 2002).
TAB
2. Chemical and Physical Properties
Parameter
Value
References
Synonyms
Nemacur; NemacurPR; Phenamiphos;
Phosphoramidic acid; ENT 27572; Bay
68138, Bayer 68138, SRA-3886, Ethyl
3 -methyl-4-(methylthio)phenyl( 1 -
methylethyl)-phosphoramidate
HSDB 2005
NIOSH 2005
ACGIH 2006
Chemical formula
c13h22no3ps
HSDB 2005
Molecular weight
303.36
HSDB 2005
CAS Reg. No.
22224-92-6
HSDB 2005
Physical state
Technical fenamiphos- off-white to tan,
waxy solid.
Colorless crystals;
Pure fenamiphos: white crystals
ACGIH 2006
IPCS CEC 2005
IPCS 1994
Solubility in water
329 mg/L at 20°C
329 mg/L (crystals)
700 mg/L at 20°C
HSBD 2005
O'Neil 2001
IPCS 1994
Vapor pressure
4.7 x 10"5 torr at 20°C
1 x 10"7 mm HG at. 25 °C
ACGIH 2006
HSDB 2005
Vapor density (air =1)
1.191 at23°C
HSDB 2005
Liquid density (water =1)
-
-
Melting point
49.2°C (pure); 40°C (technical)
ACGIH 2006
Boiling point
450°C
U.S. EPA 1987
Flammability limits
-
-
Conversion factors
1.0 ppm = 12.4 mg/m3
1.0 mg/m3 = 0.08 ppm
ACGIH 2006
2. HUMAN TOXICITY DATA
2.1. Acute Lethality
No data were located.
9
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
FENAMIPHOS
PROPOSED: November 2009
2.2. Nonlethal Toxicity
2.2.1. Odor Threshold/Odor Awareness
No data were located.
2.2.2. Case Reports
Incidence reports of poisoning from fenamiphos noted nausea, vomiting, and abdominal
pain as effects of exposure (U.S. EPA 2002). The routes of exposure, concentrations, and
durations were not specified.
2.2.3. Exposure Studies
Knaak et al. (1986) measured inhalation exposure to fenamiphos in workers at a pesticide
application firm. Two mixer/loader workers were monitored for 2 hours during the workday.
Two applicator workers were monitored for 2.5 hours during the workday. Two additional
workers (mixer/loaders and applicators) were monitored for 4 hours during the workday.
Personal air pumps attached to shirt collars were used to measure fenamiphos concentration.
The sampling device consisted of a sampling tube connected in series with a fiberglass
particulate filter. The samples were analyzed by gas chromatography. Inhalation values were at
or below the detectable level of 0.001 mg/hour in all workers.
2.3. Neurotoxicity
No data were located.
2.4. Developmental/Reproductive Toxicity
No data were located.
2.5. Genotoxicity
No data were located.
2.6. Carcinogenicity
Fenamiphos is not classifiable as a human carcinogen (ACGIH 2006). There were no
data to evaluate inhalation carcinogenicity under EPA's IRIS program (U.S. EPA 1990).
2.7. Summary
Very few inhalation data are available for humans. In the data that were located,
fenamiphos toxicity was similar to that of other cholinesterase inhibitors in terms of effects. The
monitoring study revealed that very little fenamiphos is inhaled during mixing, loading, and
application.
3. ANIMAL TOXICITY DATA
3.1. Acute Lethality
10
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
FENAMIPHOS
PROPOSED: November 2009
3.1.1. Rats
Kimmerle (1972) exposed male and female Wistar II rats (20/sex/group) to fenamiphos
for 1 hour and observed the animals for 14 days. The exposure was carried out in a dynamic
inhalation apparatus in which fenamiphos was mixed with polyethylene glycol and ethanol (1:1)
and aerosolized. The concentration of fenamiphos in the chamber was determined by
spectrophotometry. The male rats were exposed to 0.029, 0.075, 0.087, 0.103, 0.140, 0.165, or
0.187 mg/L (29, 75, 87, 103, 140, 165, or 187 mg/m3). The female rats were exposed to 0.029,
0.070, 0.105, 0.117, 0.148, 0.170, 0.185, 0.195, or 0.320 mg/L (29, 70, 105, 117, 148, 170, 185,
195, or 320 mg/m3). All rats in all the groups except those exposed to 0.029 mg/L (29 mg/m3)
had inhibition of cholinesterase activity within 10-60 minutes of exposure. Mortality occurred at
concentrations greater than 0.029 mg/L (29 mg/m3) in both sexes as shown in Table 3. The
3 3
calculated LC50 for male rats was 0.11 mg/L (110 mg/m ) and was 0.150 mg/L (150 mg/m ) for
female rats. The calculated BMCL05 was 54.181 mg/m3 for male rats and 112.538 mg/m3 for
3 3
female rats. The BMC01 was 53.035 mg/m for male rats and 98.4546 mg/m for female rats
using the Benchmark Dose Software, version 2.0 (U.S. EPA 2008).
Thyssen (1979a) exposed male and female TNO/W 74 rats (10/sex/group) to fenamiphos
(89.8% pure) for 1 or 4 hours and determined the LC50. The rats were exposed nose-only in a
dynamic inhalation apparatus. The chamber concentration was analytically determined by
spectrophotometry. In the 1-hour exposure study, male and female rats were exposed to 83, 119,
145, 148, or 250 mg/m3. All rats in all the groups exhibited signs of cholinesterase inhibition
including muscle twitching and cramps which lasted for up to 7 hours post exposure. Inactivity
and stiff gait were observed in the rats for up to 5 days post exposure. Heavy drowsiness and
breathing disorders were observed at the highest concentrations. Mortality occurred at all
concentrations in male rats except 83 mg/m3 and in female rats at the three highest
concentrations as shown in Table 3. The 1-hour LC50S for male and female rats were 131 and
130 mg/m3, respectively. The calculated BMCL05 was 86.1218 mg/m3 for male rats and 113.898
3 3 3
mg/m for female rats. The BMC01 was 98.6107 mg/m for male rats and 122.75 mg/m for
female rats using the Benchmark Dose Software, version 2.0 (U.S. EPA 2008).
In the 4-hour exposure study, male and female rats were exposed to 57, 62, 100, or 155
3 3
mg/m . An additional group of female rats was exposed to 191 mg/m . All exposed rats
exhibited signs of cholinesterase inhibition similar to those observed in rats exposed for only 1
hour. Mortality occurred in both sexes as shown in Table 3. The female rats appeared to be
more sensitive than male rats as indicated by mortality at lower concentrations. The 4-hour LC50
3 3
was 100 mg/m for both sexes. The calculated BMCL05 was 59.2137 mg/m for male rats and
46.6337 mg/m3 for female rats. The BMC01 was 81.6062 mg/m3 for male rats and 49.4464
"3
mg/m for female rats using the Benchmark Dose Software, version 2.0 (U.S. EPA 2008).
The 4-hr LC50 for acute inhalation exposure in male and female THO/W74 rats was >0.1
mg/L (100 mg/m3). No other data were reported (U.S. EPA 1999).
11
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
FENAMIPHOS
PROPOSED: November 2009
TABLE 3. Summary of Acute Inhalation Data for Fenamiphos in Laboratory Animals
Species
Concentration
(mg/m3)
Exposure Time
Effect
Reference
Rat
male
29
75
87
103
140
165
187
110
1 hr
No effect
5% mortality; (1/20)
30% mortality, (6/20)
60% mortality; (12/20)
65%) mortality; (13/20)
95%o mortality; (19/20)
100% mortality; (20/20)
lc50
Kimmerle 1972
Rat
female
29
70
105
117
148
170
185
195
320
150
1 hr
No effect
Cholinesterase activity inhibition
5%o mortality; (1/20)
Cholinesterase activity inhibition
35% mortality; (7/20)
60%o mortality; (12/20)
90%o mortality; (18/20)
90%o mortality; (18/20)
100% mortality; (20/20)
lc50
Kimmerle 1972
Rat
male
83
119
145
148
250
131
1 hr
Cholinesterase activity inhibition
20%o mortality, (2/10)
60%o mortality, (6/10)
90%o mortality, (9/10)
100% mortality, (10/10)
lc50
Thyssen 1979a
Rat
female
83
119
145
148
250
130
1 hr
Cholinesterase activity inhibition
Cholinesterase activity inhibition
70%o mortality, (7/10)
90%o mortality, (9/10)
100% mortality, (10/10)
lc50
Thyssen 1979a
Rat
male
57
62
100
155
100
4 hr
Cholinesterase activity inhibition
Cholinesterase activity inhibition
60%o mortality, (6/10)
100% mortality, (10/10)
lc50
Thyssen 1979a
Rat
female
57
62
100
155
191
100
4 hr
Cholinesterase activity inhibition
10%o mortality, (1/10)
50%o mortality, (5/10)
90%o mortality, (9/10)
100% mortality, (10/10)
lc50
Thyssen 1979a
Rat
100
4 hr
Less than the LC50
U.S. EPA 1999
3.2. Nonlethal Toxicity
3.2.1. Rats
Repeat Dose
Male and female Wistar rats (10/sex/group) were exposed via inhalation to 0, 0.03, 0.25,
"3
or 3.5 |ig/L fenamiphos (0, 30, 250, or 350 mg/m ) for 6 hours/day, 5 days/week, for 21 days
(Thyssen 1979b; U.S. EPA 1999). No overt cholinergic symptoms were observed, and there
were no changes in physical appearance, behavioral patterns, body weight, hematology, clinical
chemistry, urinalysis, gross pathology, or organ weights. Plasma cholinesterase activity was
inhibited in males and females, 42-47% and 72-78%, respectively. Erythrocyte cholinesterase
activity was inhibited in female rats 15-19%. Brain cholinesterase activity in the treated rats was
"3
comparable to that of control rats. The LOAEL was 350 mg/m , and the NOAEL was 250
12
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
FENAMIPHOS
PROPOSED: November 2009
mg/m . No details were reported on atmosphere generation and analysis.
3.3. Developmental/Reproductive Toxicity
No inhalation developmental/reproductive studies were located.
Groups of rabbits were given fenamiphos by oral gavage at doses of 0, 0.1, 0.3, or 1.0
mg/kg on days 6-18 of pregnancy. A hint of maternal toxicity was shown by a trend toward
decreases in body weight gain at the highest two doses. The chemical was not fetotoxic or
embryotoxic at any dose; no statistically significant differences were seen in the mean numbers
of corpora lutea or implants, in implantation efficiency, litter size or sex ratio, or in the number
or percent of live or resorbed fetuses. The authors concluded that the finding of a fused "chain"
of sternebrae in five fetuses at the highest dose may have been a treatment-related anomaly, but
noted that the anomaly appeared at a maternally-toxic dose (Hazleton Raltech Inc. 1982).
Chinchilla rabbits (16/group) were given fenamiphos technical by oral gavage at doses of
0, 0.1, 0.5, or 2.5 mg/kg on days 6-18 of pregnancy. While no maternal toxicity was seen at the
lower two doses, maternal toxicity at the highest dose was shown by numerous cholinergic
effects and four treatment-induced deaths, decreased body weight gain, and decreased food
consumption. No effects were seen on the mean number of corpora lutea, number of live or dead
fetuses, litter size, sex ratio, or number of live or resorbed fetuses. At the highest dose only,
there was a slight reduction in mean live pup weight as well as an increase in preimplantation
loss. The only visceral anomaly seen was one malformation in the high dose group (Becker
1986; U.S. EPA 1999).
Long Evans rats (25/dose) were given fenamiphos by oral gavage at doses of 0, 0.3, 1.0,
or 3.0 mg/kg on days 6-15 of pregnancy. There were no treatment-related effects on the numbers
of live fetuses or abnormal fetuses at any dose level, and there was no increase in the incidence
of fetuses with gross visceral or skeletal anomalies. At the highest dose, evidence of toxicity to
the pregnant dams was seen and cholinergic signs were seen within 30 minutes after treatment.
Two dams in that group died, although the cause of death was not determined (Schlueter 1981).
Sprague-Dawley (Crl CDBR) rats were given fenamiphos by oral gavage at doses of 0,
0.25, 0.85, or 3.0 mg/kg on days 6-15 of pregnancy. Five females per group were killed on day
16 of pregnancy, and the rest at day 20 of pregnancy, for examination of uterine contents. At the
highest dose, all pregnant dams exhibited tremors, and 6 died during the treatment period. At
that dose level, body weight and food consumption were also reduced, and plasma and RBC (but
not brain) cholinesterase activity were significantly inhibited at 16 days of pregnancy. At 20
days of pregnancy (5 days after the treatment regimen ended), there was no significant inhibition
of plasma cholinesterase activity, and there was less inhibition of RBC cholinesterase activity
than was seen one day after the treatment regimen ended. No treatment-related maternal effects
were seen at the lower doses, and no embryotoxicity or teratogenicity was observed at any dose
level. There was no effect on fetal brain cholinesterase activity; brain cholinesterase activity was
the only cholinesterase tested in fetuses (Astroff and Young 1998).
In a 3-generation reproduction study, fenamiphos was fed to rats at concentrations of 0, 3,
10 or 30 ppm (equivalent to about 0, 0.15, 1.0, or 1.5 mg/kg/day as estimated by the EPA). At
the highest dose there was a reduction of body weight gain in the F2b generation males only.
There were no significant effects on fertility, litter size or pup weight, and no malformed pups
13
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
FENAMIPHOS
PROPOSED: November 2009
were seen at any treatment level. Histopathological examination revealed no treatment-related
effects in the F3b generation (Loser 1972).
In a 2-generation reproduction study, fenamiphos was fed to Sprague-Dawley rats at
concentrations of 0, 2.5, 10 or 40 ppm (0, 0.2, 0.73, or 3.2 mg/kg/day in females or 0, 0.17, 0.64,
or 2.8 mg/kg/day in males). There were no treatment-related endocrine or reproductive effects or
clinical signs seen in either adults or pups. However, at the highest dose, Fi pups showed
decreased body weight gain during lactation, and F0 and Fi females had reduced body weight
during lactation. Also at the highest dose, body weight of adult rats was significantly reduced at
the end of the experiment, and absolute and relative ovary weights were significantly decreased.
Plasma cholinesterase activity was significantly inhibited at all concentrations in adult females
but only at 10 and 40 ppm in adult males. RBC cholinesterase activity was significantly inhibited
at 10 ppm (but not at 40 ppm) in adults of both sexes as well as in 4-day-old pups. Brain
cholinesterase activity was significantly inhibited at 40 ppm in adults of both sexes but not in
pups, in which this activity was measured at 4 and 21 days of age (Eigenberg 1991).
3.4. Genotoxicity
Fenamiphos was not mutagenic in the dominant lethal test with NMRI mice (Herbold and
Lorke 1980).
Fenamiphos did not cause an increase in sister chromatid exchange in Chinese hamster
V-79 cells without S9 activation (Chen et al. 1982a) or with S9 activation (Chen et al. 1982b).
Fenamiphos was negative in the Ames test both with and without metabolic activation
using the following Salmonella typhimurium strains: TA1535, TA1537, TA1538, TA98, and
TA100 (Herbold 1985).
Results are considered equivocal in chromosomal aberration induction because
aberrations were induced only in the cytotoxic range (based on a significant reduction in the
mitotic index) in human lymphocytes with and without metabolic activation. Hemolysis also
occurred in the cells that yielded the positive result with metabolic activation (Herbold 1987).
3.5. Chronic Toxicity/Carcinogenicity
No inhalation data were located.
3.6. Summary
Fenamiphos exposure caused decreased plasma and erythrocyte cholinesterase activity
similar to other organophosphate pesticides. Information on the lethality of fenamiphos
following inhalation exposure was limited to rats. Signs of cholinesterase activity inhibition
were observed in male and female rats. Fenamiphos has a steep exposure-response curve. Male
rats experienced 5% mortality after exposure to 75 mg/m3 for 1 hour; 30% mortality at 87
3 3 3
mg/m ; and 60% mortality at 103 mg/m . All 20 rats died after exposure to 187 mg/m
(Kimmerle 1972). In a study by Thyssen (1979a), 20% of the male rats died after exposure to
3 3
119 mg/m for 1 hour; 60% died after exposure to 145 mg/m ; and 90% died after exposure to
148 mg/m3. Female rats had 70% mortality at 145 mg/m and 90% mortality after exposure to
-3
148 mg/m for 1 hour. In a 4-hour study by Thyssen (1979a), male rats experienced 60%
14
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
FENAMIPHOS
PROPOSED: November 2009
3 3
mortality at 100 mg/m and 100% mortality at 155 mg/m , and female rats experienced 50%
mortality at 100 mg/m3; 90% mortality at 155 mg/m3; and 100% mortality at 191 mg/m3. The 1-
3 3
hour LC50 ranged from 100 to 155 mg/m , and the 4-hour LC50 values were 100 mg/m or
greater.
4. SPECIAL CONSIDERATIONS
4.1. Metabolism and Disposition
Fenamiphos is absorbed from the gastrointestinal tract, by inhalation, or through intact
skin. It is oxidized to form sulfoxide and sulfone analogs (HSDB 2005). In an in vitro study
using rat liver preparations, fenamiphos was metabolized to its sulfoxide, an N-alkylated
product, and an unidentified product (ACGIH 2006). No information was located regarding
absorption in humans or animals after inhalation exposure to fenamiphos. Oral studies have
shown that distribution following oral absorption is rapid and excretion occurs within 8 hours of
the administered dose. A single oral exposure to 6 mg/kg fenamiphos in rats yielded a half-life
in brain of 100 hours and a half-life in plasma of 212 hours (HSDB 2005; ACGIH 2006).
Fenamiphos given to rats at 0.3 or 3 mg/kg both orally and by i.p. injection, was completely and
rapidly absorbed and eliminated, with 99% of the dose gone by 48 hours after treatment.
Residues found in the bodies represented only 0.045-0.23%) of the amount of fenamiphos
administered. The great majority (96-98%) was eliminated in the urine, with the rest being
eliminated in feces. Treatment with fenamiphos for 14 days prior to treatment with
[14C]fenamiphos did not change the absorption, distribution, or elimination patterns (ACGIH
2006). The proposed metabolic pathway of fenamiphos is shown in Figure 1 (IPCS 1997).
15
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
FENAMIPHOS
PROPOSED: November 2009
Figure 1. Proposed metabolic pathway of fenamiphos
xx s
h3c o-p-o ^ch3
NH
A
H3C ch3
fenamiphos
I
/\ s jnrs'cHi
h3c o-p-ct "^ch3
ho
wh2
DIF
f¥b"CHi
^^ch3
FP
0=8-0^^3
n
O
FP sulfate
/\ M
h3c o-p-o
jrr ^cHs
^CHj
inrs~cH3
/\ M
H3C O-P-O^^-CHs
WH
A
h3c ch3
FSO
WH
A
h3c ch3
fso2
/\ ° jcpch3
h3c o-p-o^^ch3
nh2
DIFSO
0
HO CH3
FSOP
-> jCPCH3
Ho-^-^-chj
FS02P
£rs'c"3
HQ^^cHjOH
oh-fso2p
0©fY "ens
J-. -"C-l
FSOP sulfate
f0a™"
0=S-0' v"CHi
n
0
FSO2P sulfate
I
°v°
?0fT CH3
i U J
0
0 = S-0
II
-CH20H
0H-FS02P sulfate
4.2. Mechanism of Toxicity
Fenamiphos directly inhibits cholinesterases. The sulfoxide and sulfone metabolites of
fenamiphos are more potent inhibitors than fenamiphos itself (ACGIH 2006). Inhibition of
cholinesterase results in the accumulation of acetylcholine in the synaptic cleft which continues
to stimulate the nicotinic and muscarinic receptors leading to increased secretions,
bronchoconstriction, gastrointestinal cramps, muscle fasciculation, tremors, weakness, mental
confusion, miosis, coma, and death. There is evidence that overstimulation of the receptors by
acetylcholine causes desensitization and down-regulation of receptor numbers that causes
persistent muscle weakness (Ecobichon 2001).
4.3. Structure Activity Relationships
Although all organophosphate cholinesterase inhibitors have the same mechanism of
16
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
FENAMIPHOS
PROPOSED: November 2009
action, their potency and physicochemical properties vary. The physicochemical differences
affect environmental persistence and metabolic fate. Development of AEGL values by structure-
activity analysis would be tenuous and uncertain without rigorous relative potency data.
4.4. Other Relevant Information
4.4.1. Species Variability
Variability in types of esterases and their respective activity is important in determining
interspecies variability in organophosphate poisoning. This affects susceptibility to
organophosphates due to differences in detoxification potential (NRC 2003). Baseline red blood
cell acetylcholinesterase activity is slightly higher in humans (12.6 (j,mol/mL/min) than in
monkeys (7.1 (j,mol/mL/min) and much higher compared to other species (4.7 [jmol/mL/min for
pigs; 4.0 [j,mol/mL/min for goats; 2.9 [jmol/mL/min for sheep; 2.4 ^mol/mL/min for mice; 2.0
[jmol/mL/min for dogs; 2.7 [jmol/mL/min for guinea pigs; 1.7 [jmol/mL/min for both rats and
rabbits; and 1.5 [jmol/mL/min for cats) (Ellin 1981). Similarly, humans tend to have greater
plasma cholinesterase activity levels than other species (Wills 1972). In humans, approximately
50% of the total blood cholinesterase consists of plasma cholinesterase. Plasma cholinesterase
activity constitutes approximately 40% of the total blood cholinesterase in dogs, 30% in rats,
20% in monkeys, and only 10% in sheep, horses, and cows. Both of these findings suggest that
humans will have greater potential for buffering the activity of organophosphate
anticholinesterases by preventing interaction with red blood cell and brain cholinesterase as well
as cholinesterase at neuromuscular junctions (NRC 2003). Carboxylesterases known to occur in
human erythrocytes, liver, lung, skin, and nasal tissue may also contribute to detoxification of
organophosphates but the quantitative aspect of this has not been fully characterized (NRC
2003).
4.4.2. Susceptible Populations
Individual variability in plasma cholinesterase activity is well documented (NRC 2003).
This variability includes age-related differences (neonates are more susceptible than adults),
gender differences (females tend to have approximately 10% lower plasma and red blood cell
cholinesterase activity), and genetic variations in plasma cholinesterase activity. This genetically
determined variability, sometimes resulting in greatly reduced (64% of normal) activity of
plasma cholinesterase may impart deficiencies in ability to detoxify organophosphates such as
fenamiphos. Additionally, polymorphic variability in A-esterases such as paraoxonase/
arylesterase, may contribute to individual variability in organophosphate ester detoxification
processes (NRC 2003).
4.4.3. Concentration-Exposure Duration Relationship
The concentration-time relationship for a single endpoint for many irritant and
systemically acting vapors and gases may be described by Cn x t = k (ten Berge et al. 1986).
Exposure-response data for time-scaling were available for two time points, 1 and 4 hours. The
estimation ratio between regression coefficients of In (concentration) and In (minutes) was 4.8
(Appendix B).
4.4.4. Concurrent Exposure Issues
Both concurrent exposure to other organophosphates and simultaneous exposure via other
17
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
FENAMIPHOS
PROPOSED: November 2009
exposure routes are of concern. Fenamiphos may enter the body and be bioavailable by
dermal, oral, and inhalation pathways. Animal studies show that fenamiphos is readily absorbed
through the skin and gastrointestinal tract, as evidenced by its high acute toxicity via these routes
of exposure (ACGIH 2006).
5. DATA ANALYSIS FOR AEGL-1
5.1. Summary of Human Data Relevant to AEGL-1
No human data relevant to derivation of AEGL-1 values were available.
5.2. Summary of Animal Data Relevant to AEGL-1
"3
Kimmerle (1972) exposed male and female Wistar II rats to 29 mg/m fenamiphos for 1
hour. The rats did not exhibit any signs of cholinesterase activity inhibition, and no mortality
occurred in these rats.
5.3. Derivation of AEGL-1
No AEGL-1 values were established because the AEGL-1 values were too close to, or
"3
exceeded AEGL-2 values. If a point of departure of 29 mg/m (no effect level) was used to
derive AEGL-1 values, values of 1.4, 1.1, 0.97, 0.72, and 0.63 mg/m3 for the 10-minute, 30-
minute, 1-hour, 4-hour, and 8-hour time points, respectively, would exceed the AEGL-2 values
(Appendix A).
TABLE 4. AEGL-1 Values for
fenamiphos
10-minute
30-minute
1-hour
4-hour
8-hour
NR
NR
NR
NR
NR
NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect.
6. DATA ANALYSIS FOR AEGL-2
6.1. Summary of Human Data Relevant to AEGL-2
No human data relevant to derivation of AEGL-2 values were available.
6.2. Summary of Animal Data Relevant to AEGL-2
No animal data relevant to derivation of AEGL-2 were located.
6.3. Derivation of AEGL-2
The AEGL-2 values were derived by dividing the AEGL-3 values by three. The lack of
experimental data and the steep exposure-response relationship justify estimating AEGL-2
values by a 3-fold reduction of AEGL-3 values (NRC 2001). Male rats experienced 5%
mortality after exposure to 75 mg/m3 for 1 hour; 30% mortality at 87 mg/m3; and 60% mortality
3 3
at 103 mg/m . All 20 rats died after exposure to 187 mg/m (Kimmerle 1972). In a study by
Thyssen (1979a), 20% of the male rats died after exposure to 119 mg/m3 for 1 hour; 60% died
3 3
after exposure to 145 mg/m ; and 90% died after exposure to 148 mg/m . Female rats had 70%
mortality at 145 mg/m3 and 90% mortality after exposure to 148 mg/m3 for 1 hour. In a 4-hour
"3
study by Thyssen (1979a), male rats experienced 60% mortality at 100 mg/m and 100%
18
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
FENAMIPHOS
PROPOSED: November 2009
3 3
mortality at 155 mg/m , and female rats experienced 50% mortality at 100 mg/m ; 90% mortality
at 155 mg/m3; and 100%) mortality at 191 mg/m3. The resulting AEGL-2 values compared to the
values derived from the no effect level demonstrate the conservative nature of using the 3-fold
reduction approach to derive AEGL-2 values. AEGL-2 values are shown in Table 5.
TABLE 5. AEGL-2 Values for Fenamiphos
10-minute
30-minute
1-hour
4-hour
8-hour
1.0 mg/m3
0.80 mg/m3
0.70 mg/m3
0.53 mg/m3
0.43 mg/m3
7. DATA ANALYSIS FOR AEGL-3
7.1. Summary of Human Data Relevant to AEGL-3
No human data relevant to derivation of AEGL-3 values were available.
7.2. Summary of Animal Data Relevant to AEGL-3
3 3
Kimmerle (1972) calculated a 1-hour LC50 of 100 mg/m for male rats and 150 mg/m for
female rats. Using the exposure-response data from this study, a BMCL05 of 54.181 mg/m3
(male) and 112.538 mg/m3 (female) and BMC01 of 53.035 mg/m3 (male) and 98.4546 mg/m3
(female) were calculated using Benchmark Dose Software, version 2.0 (U.S. EPA 2008).
3 3
Thyssen (1979a) calculated a 1-hour LC50 of 131 mg/m for male rats and 131 mg/m for female
rats. The calculated BMCL05 was 86.1218 mg/m3 for male rats and 113.898 mg/m3 for female
3 3
rats. The BMC01 was calculated to be 98.6107 mg/m for male rats and 122.75 mg/m for female
rats. The 4-hour LC50 was 100 mg/m3 for both sexes. The calculated BMCL05 was 59.2137
3 3 3
mg/m for male rats and 46.6337 mg/m for female rats. The BMC01 was 81.6062 mg/m for
male rats and 49.4464 mg/m3 for female rats (see Appendix E).
7.3. Derivation of AEGL-3
Due to the availability of group-specific response data, the Thyssen (1979a) report was
"3
selected as the key study, and the female rat 4-hour BMCL05 of 46.6337 mg/m was selected as
the point of departure for AEGL-3 derivation. This is considered a threshold for lethality and is
the most conservative benchmark value calculated from the test animal used in the study.
Lethality data were sufficient for empirical derivation of a time-scaling factor (n) for use in the
equation Cn x t = k. The value of n was 4.8 and was used to time scale AEGL values. As
described in Sections 4.2 and 4.4, the mechanism of action of organophosphate anti-
cholinesterases is well understood; their activity on cholinergic systems has been shown to be the
same across species. Variability in responses is primarily a function of varying cholinesterase
levels and types of cholinesterase. Humans have greater levels of plasma cholinesterase than do
other species which allows for greater binding of anticholinesterase compounds such as
fenamiphos, thereby decreasing the availability of the compound to critical targets such as brain
cholinesterase. Therefore, the interspecies uncertainty factor is limited to 3. The documented
variability in sensitivity among different age groups and genders, and the known genetic
polymorphisms in A-esterases justify retention of the intraspecies uncertainty factor of 10. The
uncertainty factor application and rationale are the same as those applied in the derivation of
other organophosphate anticholinesterases (NRC 2003). The AEGL-3 values for fenamiphos are
shown in Table 6, and the derivation is presented in Appendix A.
19
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
FENAMIPHOS
PROPOSED: November 2009
TABLE 6. AEGL-3 Values for
fenamiphos
10-minute
30-minute
1-hour
4-hour
8-hour
3.0 mg/m3
2.4 mg/m3
2.1 mg/m3
1.6 mg/m3
1.3 mg/m3
8. SUMMARY OF AEGLS
8.1. AEGL Values and Toxicity Endpoints
Very limited data are available regarding the inhalation toxicity of fenamiphos. Data
were available with which to derive AEGL-1 values, however, those values would have
exceeded AEGL-2 values. Therefore, AEGL-1 values are not recommended. Exposure-
response data for AEGL-2 tier severity effects were not available for single acute exposures.
However, the exposure-response curve for fenamiphos, like most organophosphate
anticholinesterases is steep, thereby allowing for estimation of the AEGL-2 values by a three-
fold reduction of the AEGL-3 values (NRC 2001; 2003). The AEGL-3 values were based upon
"3
the estimated lethality threshold (BMCLos of 46.6337 mg/m ) in female rats exposed for 4 hours.
AEGL values are summarized in Table 7.
TABLE 7. Summary of AEGL Values
Classification
Exposure Duration
10-minute
30-minute
1-hour
4-hour
8-hour
AEGL-1
(Nondisabling)
NR
NR
NR
NR
NR
AEGL-2
(Disabling)
1.0 mg/m3
0.80 mg/m3
0.70 mg/m3
0.53 mg/m3
0.43 mg/m3
AEGL-3
(Lethal)
3.0 mg/m3
2.4 mg/m3
2.1 mg/m3
1.6 mg/m3
1.3 mg/m3
NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect.
8.2. Comparison with Other Standards and Guidelines
AEGL values for fenamiphos are compared to other guidelines and standards for this
compound (Table 8). The AEGL values for fenamiphos are slightly lower than the other
guidelines and standards. The majority of the guidelines and standards were based on repeated
dose inhalation, oral toxicity, and dermal toxicity data in animals rather than acute inhalation
data.
20
-------
FENAMIPHOS
PROPOSED: November 2009
TABLE 8. Extant Standards and Guidelines for Fenamiphos
Guideline
Exposure Duration
10 minute
30 minute
1 hour
4 hour
8 hour
AEGL-1
NR
NR
NR
NR
NR
AEGL-2
1.0 mg/m3
0.80 mg/m3
0.70 mg/m3
0.53 mg/m3
0.43 mg/m3
AEGL-3
3.0 mg/m3
2.4 mg/m3
2.1 mg/m3
1.6 mg/m3
1.3 mg/m3
REL-TWA
(NIOSH)3
0.1 mg/m3
(skin)
TLV-TWA
(ACGM)b
0.05 mg/m3
(IFV, skin)
MAC-Peak
Category (The
Netherlands)0
0.1 mg/m3
1 NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect.
2 IFV= inhalable fraction and vapor
3
4 a NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - Time Weighted
5 Average) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA.
6
7 b ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time Weighted
8 Average) (ACGIH 2008) is the time-weighted average concentration for a normal 8-hour workday and a 40-hour work
9 week, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect
10
11 c MAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration - Peak Category]) (SDU Uitgevers
12 [under the auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) is defined
13 analogous to the ACGIH-Ceiling.
14
15 8.3. Data Adequacy and Research
16
17 Although toxicity data for fenamiphos are available for oral and dermal exposure routes,
18 acute inhalation data are limited. Limited quantitative data are available regarding human
19 inhalation exposures and very few detailed data regarding health effects from fenamiphos
20 exposure are documented. Animal inhalation studies were found for only one species and most
21 of the studies lacked data on effects other than death. The most useful data to allow for a more
22 robust analysis relative to AEGL development would be dose-response data identifying AEGL-2
23 severity effects.
24
21
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
FENAMIPHOS
PROPOSED: November 2009
9. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2008. Threshold limit
values (TLVs) for chemical and physical agents and biological exposure indices (BEIs). ACGIH,
Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hygienists). 2006. Fenamiphos.
Documentation of the Threshold Limit Values. 2006 Supplement to the 7th Edition. 1330 Kemper
Meadow Drive, Cincinnati, OH.
AIHA (American Industrial Hygiene Association). 2008. Emergency Response Planning Guide
Guideline (ERPG). Fairfax, VA: AIHA
Astroff, A.B., Young, A.D. 1998. The relationship between maternal and fetal effects following
maternal organophosphate exposure during gestation in the rat. Toxicol. Industrial Health 14:869-
889.
Becker, H. 1986. Embryotoxicity (including teratogenicity) study with SRA 3886 (nemacur) in the
rabbit. Report no. 94392. Unpublished study prepared by Research and Consulting Company AG for
Bayer, Stilwell, KS; submitted to U.S. EPA, MRID 40347602. U.S. EPA, FOI, Washington, DC.
(Cited in ACGIH 2006).
Chen, H.H., Sirianni, S.R., Huang, C.C. 1982a. Sister chromatid exchanges and cell-cycle delay in
Chinese hamster V79 cells treated with nine organophosphorus compounds (8 pesticides and 1
defoliant). Mutat. Res. 103:307-313.
Chen, H.H., Sirianni, S.R., Huang, C.C. 1982b. Sister chromatid exchanges in Chinese hamster ovary
cells treated with seventeen organophosphorus compounds in the presence of a metabolic activation
system. Environ. Mutagen. 4:621-624.
DFG (Deutsche Forschungsgemeinschaft). 2007. List of MAK and BAT Values 2007.
Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area,
Report No. 43. Weiheim, Federal Republic of Germany: Wiley VCH.
Ecobichon, D.J. 2001. Toxic Effects of Pesticides. Casarett & Doull's Toxicology: The Basic
Science of Poisons, 6th Ed., C.D. Klaassen, ed. New York: McGraw-Hill. pp. 774-784.
Eigenberg, D.A. 1991. A two-generation dietary reproduction study in rats using fenamiphos (Nemacur).
Unpublished report. Bayer, Stilwell, KS; submitted to U.S. EPA, MRID 42491701 supplement to
MRID 41908901. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006).
Ellin, R. I. 1981. Anomalies in theories and therapy of intoxication by potent organophosphorous
anticholinesterase compounds. U.S. Army Medical Research and Development Command,
Biomedical Laboratory, Report No. USABML-SP-81-003. Aberdeen Proving Ground, MD. DTIC,
AD A1010364.
Haber, F.R. 1924. Zur geschichte des gaskrieges [On the history of the gas war]. In: Fuenf Vortraege aus
den Jahren 1920-23 [Five lectures from the years 1920-1923], Berlin, Germany: Verlag von Julius
Springer; pp. 76-92.
Hazleton Raltech, Inc. 1982. Teratology study with Nemacur in rabbits. Unpublished final report.
Bayer, Stilwell, KS; submitted to US. EPA, MRID 00121286. U.S. EPA, FOI, Washington, DC.
22
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
FENAMIPHOS
PROPOSED: November 2009
(Cited in ACGIH 2006).
Herbold, B. 1987. SRA 3886: Cytogenetic study of human lymphocyte cultures in vitro to test
for chromosome damage: Lab project ID 94393. Unpublished study prepared by Bayer AG;
submitted to US EPA, MRID 40163501. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006).
Herbold, B. 1985. Fenamiphos: Salmonella!microsome test to evaluate for potential point
mutation: Report no. 89087, supplemental submission. Unpublished study prepared by Bayer AG;
submitted to U.S. EPA, MRID 40319001. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006).
Herbold, B., Lorke, D. 1980. SRA 3886: Dominant lethal study on male mouse to test for mutagenic
effects: Report n.8838 69377. Unpublished study received 11/09/1981 under 3125-237; prepared by
Bayer AG, West Germany, submitted by Mobay Chemical Corp., Kansas City, MO [CDL:246210-
A]; submitted to U.S. EPA, MRID 00086981. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH
2006).
HSDB (Hazardous Substances Data Bank). 2005. Fenamiphos. [Online] Available.
http://toxnet.nlm.nih.gov/ [07/17/2008], TOXNET, Toxicology Data Network. US. Natl. Library of
Medicine.
IPCS (International Programme on Chemical Safety). 1997. No 929. Fenamiphos. Pesticide
residues in food: 1987 evaluations Part II Toxicology & Environmental. [Online] Available.
http://www.inchem.org/documents/jmpr/jmpmono/v097pr06.htm. [09/05/2008],
IPCS (International Programme on Chemical Safety). 1994. WHO (World Health
Organization)/FAO (Food and Agriculture Organization of the United Nations) Data Sheet on
Pesticides No. 92. [Online] Available, http://www.inchem.org/documents/pds/pds/pest92_e.htm.
[08/28/2008],
IPCS, CEC (International Programme on Chemical Safety, Commission of the European
Communities). 2005. International Chemical Safety Card. [Online] Available.
http://www.inchem.org/documents/icsc/icsc/eics0483.htm. [08/28/2008].
Kimmerle, G. 1972. Acute inhalation toxicity study with Nemacur active ingredient on rats.
Unpublished report. Bayer AG, Wuppertal, Germany.
Knaak, J.B., Jacobs, K.C., Wang, G.M. 1986. Estimating the hazard to humans applying
Nemacur 3EC with rat dermal-dose ChE response data. Bull. Environ. Contam. Toxicol. 37:159-
163.
Loser, E. 1972. BAY 68 138 generation studies on rats. Reports no. 3424 and 34029.
Unpublished study; received 05/23/1973 under 3F1399. Prepared by Farbenfabriken Bayer, AG,
submitted by Chemargo Corp., Kansas City; MO [CDL:093742-M]; submitted to EPA, MRID
00037979. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006).
NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to
Chemical Hazards. NIOSH, Cincinnati, OH. [Online] Available.
http://www.cdc.gov/niosh/ [04/14/2008].
NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation for Immediately
Dangerous to Life and Health Concentrations (IDLH). [Online] Available.
http://www.cdc.gov/niosh/idlh/ [09/10/2006],
23
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
FENAMIPHOS
PROPOSED: November 2009
NRC (National Research Council). 2003. Acute Exposure Guideline Levels for Selected
Airborne Contaminants: Nerve agents GA, GB, GD, GF, and VX. Vol. 3. Committee on
Toxicology, Board on Toxicology and Environmental Health Hazards, Commission on Life Sciences,
National Research Council. National Academy Press, Washington, DC.
NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute
Exposure Guideline Levels for Hazardous Chemicals. The National Academy Press, Washington,
DC.
NRC (National Research Council). 1985. Emergency and Continuous Exposure Guidance Levels
for Selected Airborne Contaminants, Vol. 5. Washington, D.C., National Academy Press.
O'Neil, M.J., Smith, A., Heckelman, P.E. eds. 2001. The Merck Index, 13th ED. Whitehouse Station, NJ:
Merck and Co. 3984.
OSHA (Occupational Safety and Health Administration). 2005. Code of Federal
Regulations, CFR29, Part 1910, Table Z-l.
Rinehart, W. E., Hatch, T. 1964. Concentration-time product (CT) as an expression of dose in
sublethal exposures to phosgene. Ind. Hyg. J. 25: 545-553.
SDU Uitgevers 2000. MAC Ministry of Social Affairs and Employment. Nationale
MAC (Maximum Allowable Concentration) List, 2000. The Hague, The Netherlands.
Schlueter, G. 1981. SRA 3886 (Nemacur) study of embryotoxic and teratogenic effects on rats
after oral administration. Unpublished report; Bayer AG, Wuppertal, Germany; submitted to U.S.
EPA, MRID 40347601. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006).
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases. J. Hazard. Materials: 13: 301-309.
Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute inhalational toxicity studies. Report no.
8210. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany.
Thyssen, J. 1979b. Nemacur active ingredient (SRA 3886) subacute inhalational toxicity study on rats.
Report no. 8669. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany;
submitted to U.S. EPA, MRID 00154747. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006).
U.S. EPA (U.S. Environmental Protection Agency). 2008. Benchmark Dose Software. Version
2.0 National Center for Environmental Assessment, Office of Research and Development. [Online]
Available, http://www.epa.gov/ncea/bmds.htm [04/22/2008],
U.S. EPA (U.S. Environmental Protection Agency). 2002. Interim Reregistration Eligibility Decision
(IRED) Fenamiphos. EPA 738-R-02-004. U.S. EPA, PPTS (7505C), Washington, DC (May 2002).
U.S. EPA (U.S. Environmental Protection Agency). 2000. Office of Pesticides Programs science policy
on the use of data on cholinesterase inhibition for risk assessment of organophosphorus and
carbamate pesticides. Office of Pesticides Programs, U.S. EPA, Washington DC. August 18, 2000.
U.S. EPA (U.S. Environmental Protection Agency). 1999. Human health risk assessment fenamiphos; J.
Cruz, risk assessor, 9/2/1999. Part of EPA special docket EPA-HQ-OPP-2007-0151.
U.S. EPA (U.S. Environmental Protection Agency). 1990. Integrated Risk Information System.
24
-------
1
2
3
4
5
6
7
8
9
10
11
FENAMIPHOS
PROPOSED: November 2009
[Online] Available, http://www.epa.gov/iris/subst/0240.htm [09/04/2008],
U.S. EPA (U.S. Environmental Protection Agency) Federal Emergency Management Agency, U.S.
Department of Transportation. 1987. Technical Guidance for Hazards Analysis. EPA-OSWER-88-
0001.
Wills, J.H. 1972. The measurement and significance of changes in the cholinesterase activities of
erythrocytes and plasma in man and animals. CRC Crit. Rev. Toxicol. 1:153-202.
25
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
FENAMIPHOS
PROPOSED: November 2009
APPENDIX A: Derivation of AEGL Values
Derivation of AEGL-1
No AEGL-1 values were established because the AEGL-1 values would have been too close to
or exceeded AEGL-2 values.
The calculations for deriving AEGL values from the no effect level are presented below for comparison
with AEGL-2 values.
Key Study: Kimmerle, G. 1972. Acute inhalation toxicity study with Nemacur active
ingredient on rats. Unpublished report. Bayer AG, Wuppertal, Germany.
Toxicity endpoint: Male and female rats exposed to 29 mg/m3 for 1 hour did not exhibit any
effects of toxicity.
Time scaling: Cnxt = k, where n = 4.8
Uncertainty factors: Total uncertainty factor adjustment is 30.
Interspecies: 3: Variability is primarily a function of varying cholinesterase
activity levels and types of choline sterase present; humans have greater
levels of plasma cholinesterase with which to bind anticholinesterases such
as fenamiphos than do other species. This decreases the dose to critical
targets. Therefore, the interspecies uncertainty factor is limited to 3.
Intraspecies: 10: The documented variability in sensitivity among different
age groups and genders, and the known genetic polymorphisms in A-
e sterase s justify retention of the intraspecies uncertainty factor of 10.
None
29 mg/m3/ 30 = 0.96667 mg/m3
/~i4.8 a. 1
C xt = k
(0.96667 mg/m3)4 8 x 60 min = 50.998 mg/m31-48"1 min
C48 x 10 min = 50.998 mg/m3(4 8) min
C= 1.4 mg/m3
C4 8 x 30 min = 50.998 mg/m3(4 8) min
C= 1.1 mg/m3
C48 x 60 min = 50.998 mg/m3(48)-min
C = 0.97 mg/m3
C4 8 x 240 min = 50.998 mg/m3(4 8) min
C = 0.72 mg/m3
C4 8 x 480 min = 50.998 mg/m3(4 8) min
C = 0.63 mg/m3
Modifying factor:
Calculation:
10-minute AEGL-1
30-minute AEGL-1
1-hour AEGL-1
4-hour AEGL-1
8-hour AEGL-1
26
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
FENAMIPHOS
PROPOSED: November 2009
Derivation of AEGL-2
The AEGL-2 values were derived by dividing the AEGL-3 values by three. The lack of
experimental data and the steep exposure-response relationship justify estimating AEGL-2
values by a 3-fold reduction of AEGL-3 values (NRC 2001). Male rats experienced 5%
3 3
mortality after exposure to 75 mg/m for 1 hour; 30% mortality at 87 mg/m ; and 60% mortality
atl03 mg/m3. All 20 rats died after exposure to 187 mg/m3 (Kimmerle 1972). In a study by
"3
Thyssen (1979a), 20% of the male rats died after exposure to 119 mg/m for 1 hour; 60% died
after exposure to 145 mg/m3; and 90% died after exposure to 148 mg/m3. Female rats had 70%
3 3
mortality at 145 mg/m and 90% mortality after exposure to 148 mg/m for 1 hour. In a 4-hour
study by Thyssen (1979a), male rats experienced 60% mortality at 100 mg/m3 and 100%)
3 3
mortality at 155 mg/m , and female rats experienced 50% mortality at 100 mg/m ; 90% mortality
at 155 mg/m3; and 100% mortality at 191 mg/m3.
Calculations:
10-minute AEGL-2
3.0 mg/m3/3 = 1.0 mg/m3
30-minute AEGL-2
2.4 mg/m3/3 = 0.80 mg/m
1-hour AEGL-2
2.1 mg/m3/3 = 0.70 mg/m
4-hour AEGL-2
1.6 mg/m3/3 = 0.53 mg/m
8-hour AEGL-2
1.3 mg/m3/3 = 0.43 mg/m
27
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
FENAMIPHOS
PROPOSED: November 2009
Derivation of AEGL-3
Key Studies:
Toxicity endpoint:
Time scaling:
Uncertainty factors:
Modifying factor:
Calculation:
10-minute AEGL-3
30-minute AEGL-3
1-hour AEGL-3
4-hour AEGL-3
8-hour AEGL-3
Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute
inhalational toxicity studies. Report no. 8210. Unpublished study
prepared by Bayer AG, Institut fuer Toxikologie, Germany.
"3
4-hr BMCL05 of 46.6337 mg/m used as an estimate of lethality
threshold in female rats.
Cn x t = k, where n = 4.8
Total uncertainty factor adjustment is 30.
Interspecies: 3: Variability is primarily a function of varying
cholinesterase activity levels and types of cholinesterase present;
humans have greater levels of plasma cholinesterase with which to
bind anticholinesterases such as fenamiphos than do other species.
This decreases the dose to critical targets. Therefore, the interspecies
uncertainty factor is limited to 3.
Intraspecies: 10: The documented variability in sensitivity among
different age groups and genders, and the known genetic
polymorphisms in A-esterases justify retention of the intraspecies
uncertainty factor of 10.
None
46.6337 mg/m3/ 30 = 1.5545 mg/m3
r>4.8 + 1
C x t = k
_3\4.8
(1.5545 mg/nrX8 x 240 min = 1994.558 mg/m3(4'8) min
C4'8 x 10 min = 1994.558 mg/m^-min
C= 3.0 mg/m3
3(4.8). t
C4-8 X 30 min = 1994.558 mg/mJ^o; min
C= 2.4 mg/m3
3(4.8).
C4'8 x 60 min = 1994.558 mg/mJ^'o; min
C = 2.1 mg/m3
3(4.8).
C4-8 X 240 min = 1994.558 mg/nr^-min
C= 1.6 mg/m3
3(4.8).f
C4-8 X 480 min = 1994.558 mg/nr^-min
C = 1.3 mg/m3
3(4.8).f
28
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
FENAMIPHOS
PROPOSED: November 2009
APPENDIX B: Time-Scaling Calculations
The relationship between dose and time for any given chemical is a function of the
physical and chemical properties of the substance and the unique toxicological and
pharmacological properties of the individual substance. Historically, the relationship according
to Haber (1924), commonly called Haber's Law or Haber's Rule (i.e., Cxt = k, where C =
exposure concentration, t = exposure duration, and k= a constant) has been used to relate
exposure concentration and duration to effect (Rinehart and Hatch 1964). This concept states
that exposure concentration and exposure duration may be reciprocally adjusted to maintain a
cumulative exposure constant (k) and that this cumulative exposure constant will always reflect a
specific quantitative and qualitative response. This inverse relationship of concentration and
time may be valid when the toxic response to a chemical is equally dependent upon the
concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of
LC50 data for certain chemicals revealed chemical-specific relationships between exposure
concentration and exposure duration that were often exponential. This relationship can be
expressed by the equation C" x t = k, where n represents a chemical specific, and even a toxic
endpoint specific, exponent. The relationship described by this equation is basically in the form
of a linear regression analysis of the log-log transformation of a plot of C vs. ten Berge et al.
(1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship
relative to death for approximately 20 chemicals and found that the empirically derived value of
n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent (//) in
the equation C" x t = k quantitatively defines the relationship between exposure concentration
and exposure duration for a given chemical and for a specific health effect endpoint. Haber's
Rule is the special case where n = 1. As the value of n increases, the plot of concentration vs.
time yields a progressive decrease in the slope of the curve.
Filename: Fenamiphos Rat for Log Probit Model
Date: 29 June 2009 Time: 13:55:58
Used Probit Equation Y = B0 + B1*X1 + B2*X2
XI = cone ppm, ln-transformed
X2 = minutes, ln-transformed
ChiSquare = 85.89
Degrees of freedom = 32
Probability Model = 8.05E-07
Ln(Likelihood) = -70.87
B 0 =-6.0550E+00 Student t =
B 1 = 3.4435E+00 Student t =
B 2 = 7.2006E-01 Student t =
variance B 0 0 = 3.4514E+00
covariance B 0 1 =-6.7025E-01
covariance B 0 2 =-4.3645E-01
variance B 1 1 = 1.9621E-01
covariance B 1 2 = 4.9704E-02
-3.2592
7.7738
2.6363
29
-------
FENAMIPHOS
PROPOSED: November 2009
1 variance B 2 2 = 7.4601E-02
2
3 Estimation ratio between regression coefficients of ln(conc) and ln(minutes)
4 Point estimate = 4.782
5 Lower limit (95% CL) = 1.415
6 Upper limit (95% CL) = 8.150
7
8
30
-------
FENAMIPHOS
PROPOSED: November 2009
1
2
3
4
5
6
7
APPENDIX C: Derivation Summary for Fenamiphos AEGLs
ACUTE EXPOSURE GUIDELINE LEVELS FOR
FENAMIPHOS (CAS Reg. No. 22224-92-6)
DERIVATION SUMMARY
AEGL-1 VALUES
10-minute
30-minute
1-hour
4-hour
8-hour
NR
NR
NR
NR
NR
Key Reference: NA
Test Species/Strain/Number: NA
Exposure Route/Concentrations/Duration: NA
Effects: NA
Endpoint/Concentration/Rationale: NA
Uncertainty Factors/Rationale: NA
Modifying Factor: NA
Animal to Human Dosimetric Adjustment: NA
Time Scaling: NA
Data Adequacy: No AEGL-1 values were established because the AEGL-1 values would have been too close to or
exceeded AEGL-2 values. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are
without effect.
31
-------
FENAMIPHOS
PROPOSED: November 2009
AEGL-2 VALUES
10-minute
30-minute
1-hour
4-hour
8-hour
1.0 mg/m
0.80 mg/m
0.70 mg/m
0.53 mg/m
0.43 mg/m
Key Reference: Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute inhalational toxicity studies.
Report no. 8210. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany.
Test Species/Strain/Number: NA
Exposure Route/Concentrations/Durations: One-third the AEGL-3 values. Supported by steep concentration-
response curve. Male rats experienced 5% mortality after exposure to 75 mg/m3 for 1 hour; 30% mortality at 87
mg/m3; and 60% mortality at 103 mg/m3. All 20 rats died after exposure to 187 mg/m3 (Kimmerle 1972). In a
study by Thyssen (1979a), 20% of the male rats died after exposure to 119 mg/m3 for 1 hour; 60% died after
exposure to 145 mg/m3; and 90% died after exposure to 148 mg/m3. Female rats had 70% mortality at 145
mg/m3 and 90% mortality after exposure to 148 mg/m3 for 1 hour. In a 4-hour study by Thyssen (1979a), male
rats experienced 60% mortality at 100 mg/m3 and 100% mortality at 155 mg/m3, and female rats experienced
50% mortality at 100 mg/m3; 90% mortality at 155 mg/m3; and 100% mortality at 191 mg/m3.
Effects: NA
Endpoint/Concentration/Rationale: One-third the AEGL-3 values.
Uncertainty Factors/Rationale: NA
Modifying Factor: NA
Animal to Human Dosimetric Adjustment: NA
Time Scaling:NA
Data Adequacy: Data were not available on AEGL-2 tier effects.
32
-------
FENAMIPHOS
PROPOSED: November 2009
AEGL-3 VALUES
10-minute
30-minute
1-hour
4-hour
8-hour
3.0 mg/m
2.4 mg/m
2.1 mg/m
1.6 mg/m
1.3 mg/m
Key Reference: Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute inhalational toxicity studies.
Report no. 8210. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany.
Test Species/Strain/Number: Female Rat/TNO/W74 / 10/group
Exposure Route/Concentrations/Duration: Inhalation/ 57, 62, 100, 155, 191 mg/m /240 min
Effects:
57 mg/m3
62 mg/m3
100 mg/m3
155 mg/m3
191 mg/m3
Cholinesterase activity inhibition
10% mortality; (1/10)
50% mortality, (5/10)
90% mortality; (9/10)
100% mortality; (10/10)
Endpoint/Concentration/Rationale: Estimated threshold of lethality, BMCL05 of 46.6337 mg/m
Uncertainty Factors/Rationale:
Total uncertainty factor adjustment is 30
Interspecies: 3: Variability is primarily a function of varying cholinesterase activity levels and types of
cholinesterase present; humans have greater levels of plasma cholinesterase with which to bind
antichlolinesterase agents such as fenamiphos than do other species.
Intraspecies: 10: The documented variability in sensitivity among different age groups and genders, and the
known genetic polymorphisms in A-esterases .justify retention of the intraspecies uncertainty factor of 10.
Modifying Factor: none applied
Animal to Human Dosimetric Adjustment: NA
Time Scaling: C" x t = k, where n = 4.8
Data Adequacy: Data are limited to one species but consistent and adequate for AEGL-3 derivation.
33
-------
FENAMIPHOS
PROPOSED: November 2009
1
2
1000
100
S_10
APPENDIX D: Category Plot for Fenamiphos
Chemical Toxicity - TSD Data
Fenarriphos
AE3L-2
240 300
IVlnutes
480
34
-------
FENAMIPHOS
PROPOSED: November 2009
For Category 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal
Source
Species
Sex
# Exposures
Mg/mJ
Minutes
Category
Comments
NAC/AEGL-1
NR
10
AEGL
NAC/AEGL-1
NR
30
AEGL
NAC/AEGL-1
NR
60
AEGL
NAC/AEGL-1
NR
240
AEGL
NAC/AEGL-1
NR
480
AEGL
NAC/AEGL-2
1.0
10
AEGL
NAC/AEGL-2
0.80
30
AEGL
NAC/AEGL-2
0.70
60
AEGL
NAC/AEGL-2
0.53
240
AEGL
NAC/AEGL-2
0.43
480
AEGL
NAC/AEGL-3
3.0
10
AEGL
NAC/AEGL-3
2.4
30
AEGL
NAC/AEGL-3
2.1
60
AEGL
NAC/AEGL-3
1.6
240
AEGL
NAC/AEGL-3
1.3
480
AEGL
Kimmerle 1972
rat
m
1
29
60
0
No effect
Kimmerle 1972
rat
m
1
75
60
SL
5% mortality
Kimmerle 1972
rat
m
1
87
60
SL
30% mortality
Kimmerle 1972
rat
m
1
103
60
SL
60% mortality
Kimmerle 1972
rat
m
1
140
60
SL
65% mortality
Kimmerle 1972
rat
m
1
165
60
SL
95% mortality
Kimmerle 1972
rat
m
1
187
60
3
100% mortality
Kimmerle 1972
rat
f
1
29
60.0
0
No effect
Kimmerle 1972
rat
f
1
70
60.0
1
Cholinesterase activity
inhibition
Kimmerle 1972
rat
f
1
105
60
SL
5% mortality
Kimmerle 1972
rat
f
1
117
60
1
Cholinesterase activity
inhibition
Kimmerle 1972
rat
f
1
148
60
SL
35% mortality
Kimmerle 1972
rat
f
1
170
60
SL
60% mortality
Kimmerle 1972
rat
f
1
185
60
SL
90% mortality
Kimmerle 1972
rat
f
1
195
60
SL
90% mortality
Kimmerle 1972
rat
f
1
320
60
3
100% mortality
Thyssen 1979 a
rat
m
1
83
60
1
Cholinesterase activity
inhibition
Thyssen 1979 a
rat
m
1
119
60
SL
20% mortality
Thyssen 1979 a
rat
m
1
145
60
SL
60% mortality
Thyssen 1979 a
rat
m
1
148
60
SL
90% mortality
Thyssen 1979 a
rat
m
1
250
60
3
100% mortality
Thyssen 1979 a
rat
f
1
83
60
1
Cholinesterase activity
inhibition
Thyssen 1979 a
rat
f
1
119
60
1
Cholinesterase activity
35
-------
FENAMIPHOS
PROPOSED: November 2009
inhibition
Thyssen 1979 a
rat
f
1
145
60
SL
70% mortality
Thyssen 1979 a
rat
f
1
148
60
SL
90% mortality
Thyssen 1979 a
rat
f
1
250
60
3
100% mortality
Thyssen 1979 a
rat
m
1
57
240
1
Cholinesterase activity
inhibition
Thyssen 1979 a
rat
m
1
62
240
1
Cholinesterase activity
inhibition
Thyssen 1979 a
rat
m
1
100
240
SL
60% mortality
Thyssen 1979 a
rat
m
1
155
240
3
100% mortality
Thyssen 1979 a
rat
f
1
57
240
1
Cholinesterase activity
inhibition
Thyssen 1979 a
rat
f
1
62
240
SL
10% mortality
Thyssen 1979 a
rat
f
1
100
240
SL
50% mortality
Thyssen 1979 a
rat
f
1
155
240
SL
90% mortality
Thyssen 1979 a
rat
f
1
191
240
3
100% mortality
1 NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect.
2
36
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
FENAMIPHOS PROPOSED: November 2009
APPENDIX E: Benchmark Exposure Calculations
Kimmerle 1972, Male rat BMCoi & BMCL05
BMDS Model Run
The form of the probability function is: Pfresponse] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)),
where CumNorm(.) is the cumulative normal distribution function
Dependent variable = Incidence
Independent variable = DOSE
Slope parameter is restricted as slope >= 1
Total number of observations = 8
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -9.96579
slope = 2.17922
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
intercept slope
intercept 1 -1
slope -1 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
background 0 NA
intercept -15.5684 2.36683 -20.2073 -10.9295
slope 3.33473 0.502325 2.35019 4.31926
NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -46.5671 8
Fitted model -50.4366 2 7.73902 6 0.2579
Reduced model -109.889 1 126.644 7 <.0001
AIC: 104.873
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
20
0.000
29.0000
0.0000
0.000
0.000
20
-0.012
75.0000
0.1209
2.417
1.000
20
-0.972
87.0000
0.2496
4.992
6.000
20
0.521
103.0000
0.4551
9.102
12.000
20
1.301
140.0000
0.8188
16.375
13.000
20
-1.959
165.0000
0.9277
18.553
19.000
20
0.386
187.0000
0.9697
19.393
20.000
20
0.791
ChiA2 = 7.52 d.f. =
6 P-value = 0.2752
37
-------
1
2
3
4
5
6
7
8
9
10
11
FENAMIPHOS
PROPOSED: November 2009
Benchmark Dose Computation
Specified effect = 0.05 0.01
Risk Type = Extra risk Extra risk
Confidence level = 0.95 0.95
BMC = 65.0603 53.035
BMCL= 54.181 41.6366
LogProbit Model with 0.95 Confidence Level
LogProbit
1
0.8
0.6
0.4
0.2
0
BMDL
BMD
0
50
100
150
dose
10:48 09/28 2009
BMCL05 graph
38
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
T3
0)
O
,= 1
Total number of observations =10
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -9.31195
slope = 1.86448
Asymptotic Correlation Matrix of Parameter Estimates
39
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
FENAMIPHOS
PROPOSED: November 2009
background
background 1
intercept -0.14
slope 0.14
intercept
-0.14 0.14
1 -1
-1 1
slope
Parameter Estimates
Variable
background
intercept
slope
Estimate
0.0198728
-36.2316
7.13557
95.0% Wald Confidence Interval
Std. Err. Lower Conf. Limit Upper Conf. Limit
0.0144703 -0.00848849 0.048234
7.26212
1.41567
-50.465
4.36092
-21.9981
9.91023
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -47.3531 10
Fitted model -50.0328 3 5.35949 7 0.6162
Reduced model -133.292 1 171.877 9 <.0001
AIC: 106.066
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0199
0.397
0.000
20
-0.637
29.0000
0.0199
0.397
0.000
20
-0.637
70.0000
0.0199
0.397
1.000
20
0.965
105.0000
0.0211
0.422
1.000
20
0.899
117.0000
0.0318
0.637
0.000
20
-0.811
148.0000
0.2974
5.948
7.000
20
0.515
170.0000
0.6678
13.356
12.000
20
-0.644
185.0000
0.8489
16.978
18.000
20
0.638
195.0000
0.9200
18.400
18.000
20
-0.330
320.0000
1.0000
20.000
20.000
20
0.003
ChiA2 = 4.40 d.f. =
7 P-value = 0.7321
Benchmark Dose Computation
Specified effect = 0.05 0.01
Risk Type = Extra risk Extra risk
Confidence level = 0.95 0.95
BMC = 127.368 115.766
BMCL = 112.538 98.4546
40
-------
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
LogProbit
1
0.8
0.6
0.4
0.2
0
BMDL
BMD
0
50
100
150
200
250
300
dose
1 11:02 09/28 2009
2
3 BMCL05 graph
41
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
T3
0)
O
,= 1
Total number of observations = 6
Total number of records with missing values = 1
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -21.4189
slope = 4.41679
Asymptotic Correlation Matrix of Parameter Estimates
42
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
FENAMIPHOS
PROPOSED: November 2009
( *** The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
intercept
intercept 1
slope -1
slope
-1
1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
background 0 NA
intercept -37.4632 12.8407 -62.6304 -12.2959
slope 7.65312 2.60905 2.53947 12.7668
NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -14.985 5
Fitted model -15.8938 2 1.81769 3 0.6111
Reduced model -32.0518 1 34.1336 4 <.0001
AIC: 35.7876
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
10
0.000
83.0000
0.0001
0.001
0.000
10
-0.037
119.0000
0.1873
1.873
2.000
10
0.103
145.0000
0.7338
7.338
6.000
10
-0.957
148.0000
0.7826
7.826
9.000
10
0.900
ChiA2 = 1.74 d.f. = 3
P-value = 0.6284
Benchmark Dose Computation
Specified effect = 0.05 0.01
Risk Type = Extra risk Extra risk
Confidence level = 0.95 0.95
BMC = 107.795 98.6107
BMCL = 86.1218 72.8367
43
-------
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
1
2
3
4
T3
0)
O
,
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
T3
0)
O
,= 1
Total number of observations = 6
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -17.1708
slope = 3.48147
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background -slope have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
45
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
FENAMIPHOS
PROPOSED: November 2009
intercept
intercept
1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
background 0 NA
intercept -88.909 0.320323 -89.5369 -88.2812
slope 18 NA
NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f.
Full model -9.35947 6
Fitted model -9.54616 1 0.373373 5
Reduced model -41.0539 1 63.3889 5
AIC: 21.0923
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
P-value
0.996
<.0001
0.0000
0.0000
0.000
0.000
10
0.000
83.0000
0.0000
0.000
0.000
10
-0.000
119.0000
0.0020
0.020
0.000
10
-0.140
145.0000
0.7493
7.493
7.000
10
-0.359
148.0000
0.8510
8.510
9.000
10
0.435
250.0000
1.0000
10.000
10.000
10
0.000
ChiA2 = 0.34 d.f. =
5 P-value = 0.9969
Benchmark Dose Computation
Specified effect = 0.05 0.01
Risk Type = Extra risk Extra risk
Confidence level = 0.95 0.95
BMC = 127.487 122.75
BMCL = 113.898 106.19
46
-------
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
1
2
3
T3
0)
O
,
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
T3
0)
O
,= 1
Total number of observations = 5
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -16.1037
slope = 3.53434
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameters) -background have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
48
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
FENAMIPHOS
PROPOSED: November 2009
intercept slope
intercept 1 -1
slope -1 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
background 0 NA
intercept -58.192 6825.98 -13436.9 13320.5
slope 12.6913 1482.24 -2892.45 2917.84
NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -6.73012 5
Fitted model -6.73012 2 1.21757e-007 3 1
Reduced model -31.3435 1 49.2267 4 <.0001
AIC: 17.4602
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000 0.000
10
0.000
57.0000
0.0000
0.000 0.000
10
-0.000
62.0000
0.0000
0.000 0.000
10
-0.000
100.0000
0.6000
6.000 6.000
10
0.000
155.0000
1.0000
10.000 10.000
10
0.000
ChiA2 = 0.00 d.f. =
3 P-value = 1.0000
Benchmark Dose Computation
Specified effect = 0.05 0.01
Risk Type = Extra risk Extra risk
Confidence level = 0.95 0.95
BMC = 86.108 81.6062
BMCL= 59.2137 49.4938
49
-------
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
T3
0)
O
,
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
T3
0)
O
,= 1
Total number of observations = 6
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -12.8595
slope = 2.78692
Asymptotic Correlation Matrix of Parameter Estimates
51
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
FENAMIPHOS
PROPOSED: November 2009
( *** The model parameters) -background have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
intercept slope
intercept 1 -1
slope -1 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
background 0 NA
intercept -15.2331 3.24344 -21.5901 -8.87605
slope 3.30866 0.704182 1.92849 4.68883
NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -13.4331 6
Fitted model -14.1051 2 1.34385 4 0.8539
Reduced model -40.7516 1 54.6369 5 <.0001
AIC: 32.2101
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0.000
10
0.000
57.0000
0.0317
0.317
0.000
10
-0.572
62.0000
0.0573
0.573
1.000
10
0.581
100.0000
0.5015
5.015
5.000
10
-0.010
155.0000
0.9270
9.270
9.000
10
-0.328
191.0000
0.9840
9.840
10.000
10
0.403
ChiA2 = 0.94 d.f. =
4 P-value = 0.9194
Benchmark Dose Computation
Specified effect = 0.05 0.01
Risk Type = Extra risk Extra Risk
Confidence level = 0.95 0.95
BMC = 60.7558 49.4464
BMCL= 46.6337 34.904
52
-------
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
LogProbit
1
0.8
0.6
0.4
0.2
0
BMDL
BMD
0
50
100
150
200
dose
1 11:43 09/28 2009
2 Female BMCL05 graph
3
53
-------
FENAMIPHOS
PROPOSED: November 2009
LogProbit Model with 0.95 Confidence Level
1
2
3
4
5
T3
0)
O
,
------- |