Central
Nervous System (CNS) -
Adverse Effects
Fluorinated and Fluoride Pesticides
The Nervous System is divided
into:
The Central Nervous System and the Peripheral Nervous System.
The central nervous system is divided into two parts: the
brain and the spinal cord. The brain contains
about 100 billion nerve cells (neurons) and trillons of
"support cells" called glia. The spinal cord is
about 43 cm long in adult women and 45 cm long in adult
men and weighs about 35-40 grams. The vertebral column,
the collection of bones (back bone) that houses the spinal
cord, is about 70 cm long. Therefore, the spinal cord is
much shorter than the vertebral column.
The Peripheral Nervous System
is divided into two major parts:
the somatic nervous system and the
autonomic nervous system.
1. Somatic Nervous System
The somatic nervous system consists of peripheral nerve
fibers that send sensory information to the central nervous
system AND motor nerve fibers that project to skeletal muscle.
2. Autonomic Nervous System
The autonomic nervous system is divided into three parts:
the sympathetic nervous system, the parasympathetic nervous
system and the enteric nervous system. The autonomic nervous
system controls smooth muscle of the viscera (internal organs)
and glands.
Some differences between
the Peripheral Nervous System (PNS) and the Central Nervous
System (CNS):
1. In the CNS, collections of neurons are called nuclei.
In the PNS, collections of neurons are called ganglia.
2. In the CNS, collections of axons are called tracts.
In the PNS, collections of axons are called nerves.
From the excellent
website: Neuroscience
for Kids
What
is Cholinesterase?
An enzyme produced by the body Essential to the Central
Nervous System (CNS) Lack of Cholinesterase can cause CNS
confusion. Symptoms of decreased cholinesterase: Headaches Dizziness
Nausea Abdominal pain Anxiety Constricted pupils Muscle
twitch or weakness Shortness of breath Diarrhea Convulsions
Coma:
The
use of high doses increases the likelihood that potentially
significant toxic effects will be identified. Findings of
adverse effects in any one species do not necessarily indicate
such effects might be generated in humans. From a conservative
risk assessment perspective however, adverse findings in
animal species are assumed to represent potential effects
in humans, unless convincing evidence of species specificity
is available.
--
Food and Agricultural Organization of the United Nations
Note:
This is not an exhaustive list.
As time allows more information will be added.
Potential
Health Effects: If inhaled or swallowed, this compound
can cause fluoride poisoning. Early symptoms include nausea, vomiting,
diarrhea, and weakness. Later effects include central
nervous system effects, cardiovascular
effects and death.
Ref:
Analytyka. Material Safety Data Sheet. Online as of September
15, 2003. http://www.analytyka.com.mx/tabla%20periodica/MSDS/N/AMMONIUM%20BIFLUORIDE.htm
If inhaled or swallowed,
this compound can cause fluoride poisoning. Early symptoms include
nausea, vomiting, diarrhea, and weakness. Later effects include
central nervous system effects, cardiovascular
effects and death.
Ingestion: May cause salivation, nausea, vomiting, diarrhea, and
abdominal pain, followed by weakness, tremors, shallow respiration,
cardopedal spasm, convulsions, and coma. May cause brain and kidney
damage. Death may be caused by respiratory paralysis. Affects
heart and circulatory system.
Ref: 1999 Material Safety Data Sheet prepared
by Mallinckrodt Baker, Inc. http://www.fluoridealert.org/pesticides/Ammonium.F.MSDS.htm
Ammonium
fluosilicate-
Insecticide, Miticide Wood Preservative,
EPA List 3 Inert-
CAS No. 16919-19-0
LD50 ranges of sodium,
potassium, or ammonium fluorosilicates administered intragastrically
in rats and mice were 89-128 and 45-64 mg fluoride ion/kg, respectively.
Severe cornea damage was observed 3 hr after the administration
of 50 mg of any of the salts into rabbits' eyes. Min toxic dose
(intragastric) of fluorosilicic acid in rats was 8 mg/kg. Min
toxic concn in 4 hr inhalation of the salt aerosols were 7.4-9.6
mg/cu m; nontoxic concn was 0.8 mg/cu m. Main toxic effects were
decreased activities of cholinesterase and
lactate dehydrogenase in blood serum. The intragastric effects
of the fluorosilicates were similar to and additive with those
of sodium fluoride. [Rumyantser GI et al; Oig Sanit (11): 80-2
(1988)]
Ref: TOXNET profile from Hazardous Substances
Data Bank for AMMONIUM SILICOFLUORIDE. http://www.fluoridealert.org/pesticides/Ammonium.Silicofluor.TOXNET.htm
Ammonium
silicofluoride -
Insecticide, Miticide Wood Preservative,
EPA List 3 Inert-
CAS No. 16919-19-0
-- Human Toxicity Excerpts:
SYMPTOMATOLOGY: A. Ingestion of soluble fluoride salts. 1. Salty
or soapy taste, salivation, nausea. Repeated small doses (as in
drinking water) may produce no other symptoms, but polyuria and
polydipsia have also been reported. 2. Large doses lead promptly
to burning or crampy abdominal pain, intense vomiting and diarrhea,
often with hematemesis and melena. Dehydration and thirst. 3.
Muscle weakness, tremors, and rarely transient
epileptiform convulsions, preceded or followed by progressive
central nervous depression (lethargy,
coma and respiratory arrest, even in the absence of circulatory
failure).
-- LD50 ranges of sodium, potassium, or ammonium fluorosilicates
administered intragastrically in rats and mice were 89-128 and
45-64 mg fluoride ion/kg, respectively. Severe cornea damage was
observed 3 hr after the administration of 50 mg of any of the
salts into rabbits' eyes. Min toxic dose (intragastric) of fluorosilicic
acid in rats was 8 mg/kg. Min toxic concn in 4 hr inhalation of
the salt aerosols were 7.4-9.6 mg/cu m; nontoxic concn was 0.8
mg/cu m. Main toxic effects were decreased
activities of cholinesterase and lactate dehydrogenase
in blood serum. The intragastric effects of the fluorosilicates
were similar to and additive with those of sodium fluoride. [Rumyantser
GI et al; Oig Sanit (11): 80-2 (1988)]
Ref: TOXNET profile from Hazardous Substances
Data Bank for AMMONIUM SILICOFLUORIDE
http://www.fluoridealert.org/pesticides/Ammonium.Silicofluor.TOXNET.htm
-- TARGET ORGANS: Central
Nervous System, Eyes, Skin, Respiratory Tract.
-- SHORT-TERM EXPOSURE (ACUTE) INHALATION: May produce symptoms
of central nervous system depression including
headache, dizziness, nausea, loss of balance and drowsiness.
Ref: BENZOTRIFLUORIDE Material Safety Data
Sheet. OxyChem. Issue Date: 07-08-98 http://www.oxychem.com/products/msds/m7644.pdf
-- Animal Toxicity
Studies Non-Human Toxicity Excerpts: Moderate toxic by animal-experiment;
effective to central nervous system.
[ITII. Toxic and Hazardous Industrial Chemicals Safety Manual.
Tokyo, Japan: The International Technical Information Institute,
1988. 68]
Ref: TOXNET profile from Hazardous Substances
Data Base. http://www.fluoridealert.org/pesticides/Benzotrifluoride.TOXNET.HSD.htm
-- Short term toxicity.
Target / critical effect: CNS / General
behavioural disturbances; axonal degeneration.
Lowest relevant oral NOAEL / NOEL: 90-d dog: 60 ppm (1.5 mg/kg
bw/d. ) Lowest relevant dermal NOAEL / NOEL: 3-wk rabbit: 340
mg/kg bw/d * Lowest relevant inhalation NOAEL / NOEL: 3-mo rat:
0.09 µg/l (0.0243 mg/kg bw/d)*
-- Neurotoxicity / Delayed neurotoxicity. Critical effects: Clinical
signs indicative of a neurological disorder and a
reversible axonal degeneration. No evidence of delayed
neurotoxicity in hens. NOAEL (acute oral neurotoxicity, rat) 2
mg/kg bw/d (aqueous vehicle) NOAEL (90-d oral neurotoxicity, rat)
30 ppm (2 mg/kg bw/d)
Ref: December 2002 - Beta-cyflutrin: Review
report for the active substance beta-cyfluthrin Finalised in the
Standing Committee on the Food Chain and Animal Health at its
meeting on 3 December 2002 in view of the inclusion of beta-cyfluthrin
in Annex I of Directive 91/414/EEC. EUROPEAN COMMISSION HEALTH
& CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate E Ü Food
Safety: plant health, animal health and welfare, international
questions E1 - Plant health.
http://www.fluorideaction.org/pesticides/cyfluthrin.beta.eu.dec.2002.pdf
Animal Toxicity Studies:
Non-Human Toxicity Excerpts: The principal feature in acute action
... is the irritation of mucous membranes of respiratory tract
& eyes. In animal acute experiments, a concn of 42 mg/cu m proved
fatal in some cases. Exam revealed a fall in inorg phosphorus
level in blood & autopsy showed pneumonia & degenerative changes
in renal tubules. Long-term (4 mo) exposure to 3 & 10 mg/cu m
... produced irritation of resp tract, dysproteinemia, reduction
in cholinesterase activity &
increased nervous system lability.
Exposure to high concn results in reduction of acetyl carbonic
acid & inorg phosphorus levels in blood, & dental fluorosis. [International
Labour Office. Encyclopedia of Occupational Health and Safety.
Vols. I&II. Geneva, Switzerland: International Labour Office,
1983. 320]
Ref: TOXNET profile from Hazardous Substances
Data Bank for BORON TRIFLUORIDE. http://www.fluoridealert.org/pesticides/Boron.Trifluoride.TOXNET.htm
Bromethalin, a diphenylamine,
is a neurotoxicant that causes respiratory arrest from inadequate
nerve impulse transmission after fluid build-up and demyelination
inside the central nervous system
(Spaulding and Spannring 1988, Hyngstrom et al. 1994).
Ref: Potential
Risks of Nine Rodenticides to Birds and Nontarget Mammals: a Comparative
Approach. December 19, 2002. US EPA
Office of Prevention, Pesticices, and Toxic Substances.
-- TARGET
ORGANS: Respiratory system, cardio-vascular system, central nervous
system.
-- ACUTE: The most significant hazard associated with Tetrafluoromethane
[carbon tetrafluoride] is inhalation of high concentrations of
Tetrafluoromethane. Such overexposure can cause oxygen deficiency.
Symptoms of such exposures include respiratory difficulty, ringing
in ears, headaches, dizziness, indigestion, nausea, and possible
death...
-- INHALATION: Exposures to high concentrations of this gas may
cause sensitization of the heart
to adrenaline and nor-adrenaline. Effects of such overexposure
can include light-headedness, giddiness, shortness of breath and
in extreme cases, irregular heartbeats, cardiac arrest, and death.
High concentrations of this gas can cause an oxygen-deficient
environment. Individuals breathing such an atmosphere may experience
symptoms which include headaches, ringing in ears, dizziness,
drowsiness, unconsciousness, nausea, vomiting, and depression
of all the senses. The skin of a victim of overexposure may have
a blue color. Under some circumstances of overexposure, death
may occur. The effects associated with various levels of oxygen
are as follows:
CONCENTRATION SYMPTOMS OF EXPOSURE
12-16% Oxygen: Breathing and pulse rate increased, muscular coordination
slightly disturbed.
10-14% Oxygen: Emotional upset, abnormal fatigue, disturbed respiration.
6-10% Oxygen: Nausea and vomiting, collapse or loss of consciousness.
Below 6%: Convulsive movements, possible respiratory collapse,
and death.
Ref: Material Safety Data Sheet: TETRAFLUOROMETHANE
- CF4 MSDS (Document # 001051). Airgas. http://www.airgas.com/documents/pdf/1051.pdf
HUMAN HEALTH
EFFECTS.
-- Overexposure by
inhalation may include temporary central nervous system
depression with such effects as dizziness,
headache, confusion, incoordination, and loss of consciousness;
or with gross overexposure (>20%), temporary alteration of the
heart's electrical activity with irregular pulse, palpitations
or inadequate circulation. Eye or skin contact with the liquid
may cause frostbite.
-- Individuals
with preexisting diseases of the central nervous or
cardiovascular systems may have increased susceptibility
to the toxicity of excessive exposures.
Ref:
UndatedDuPont's Material Safety Data Sheet. http://www.fluorideaction.org/pesticides/carbon.tetrafluoride.MSDS.pdf
Chlorfenapyr
-
Acaricide, Insecticide - CAS No. 122453-73-0
-- MRID No. 43492833
(1994). Chronic neurotoxicity rat.
NOAEL = 2.6/3.4 mg/kg/day, M/F. LOAEL = 13.6/18 mg/kg/ day, M/F,
based on the presence of myelinopathic alterations
in the central nervous system (CNS) in male rats and
decreased average body weights/body weight gains,
food efficiency,
absolute food consumption (females) and water consumption (males)
-- Chronic neurotoxicity study - rat.
LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic
alterations in the CNS in male rats and
decreased average body weights, body weigh gains,
food efficiency, absolute food consumption
(F), and water
consumption (M). Supporting this endpoint are similar CNS
lesions and skin lesions observed
in the mouse carcinogenicity study (NOAEL = 2.8).
-- Conditions: A developmental neurotoxicity study to determine
the cause/relationship of potential central
nervous system/myelinopathic alterations to neurotoxicity in the
developing young.
Ref:
Federal Register: September 26, 2003. Chlorfenapyr; Pesticide
Tolerance. Final Rule. http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm
The substance may cause
effects on the cardiovascular system
and central nervous system, resulting
in cardiac disorders and central
nervous system depression.
Ref: ICSC: 0049. March 2002. International
Programme on Chemical Safety (IPCS). http://www.inchem.org/documents/icsc/icsc/eics0049.htm
Potential Health Effects
- Inhalation of high concentrations of vapor is harmful and may
cause heart irregularities, unconsciousness or death. .. Human
Health Effects: Higher exposures may lead to temporary alteration
of the heart's electrical activity with irregular pulse, palpitations,
or inadequate circulation. Fatality may occur from gross overexposure.
Individuals with preexisting diseases of
the central nervous or cardiovascular system may have increased
susceptibility to the toxicity of excessive exposures.
Animal
Data - INHALATION: 4 hour, LC50, rat: 220,000 ppm. The
compound is a skin irritant and a slight eye irritant, but is
not a skin sensitizer in animals. Effects from single high exposures
include central nervous
system depression, anesthesia, rapid breathing, lung congestion
and microscopic
liver changes...
Ref: Material Safety Data Sheet for Freon
22. DuPont. 1996. http://www.fluoridealert.org/pesticides/Chlorodifluoromethane.MSDS.pdf.
Cyhalothrin
- Acaricide,
Insecticide
- CAS No.
68085-85-8
Rationale
for US EPA to add Cyhalothrin to the Toxic Release Inventory.
Cyhalothrin administered orally (in capsules) to dogs at 10 mg/kg/day
for 26 weeks produced occasional disturbances of the nervous
system (unsteadiness and/or muscular trembling). The NOEL
for these effects was not defined. In a 1-year dog study, ataxia,
muscle tremors, and convulsions were observed following oral administration
at 3.5 mg/kg/day. Abnormal gait and convulsions were observed
at 0.5 mg/kg/day. The LOEL of the study was 0.5 mg/kg/day and
the NOEL was 0.1 mg/kg/day. EPA believes that there is sufficient
evidence for listing cyhalothrin on EPCRA section 313 pursuant
to EPCRA section 313(d)(2)(B) based on the available neurological
toxicity data.
Ref:
USEPA/OPP. Support Document for the Addition of Chemicals from
Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active
Ingredients to EPCRA Section 313. U. S. Environmental Protection
Agency, Washington, DC (1993).
As cited by US EPA in:
Federal
Register: January 12, 1994. Part IV.
40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical
Release Reporting; Community Right-to-Know; Proposed Rule.
-- Cyhalothrin. 28-Day
feeding - rat. 00153029. NOAEL: 2 mg/kg/day LOAEL: 10 mg/kg/day
clinical signs of neurotoxicity. At higher doses,
decreases in body weight gain and food consumption and
changes in organ weights.
-- cyhalothrin. 28-Day feeding - rat.
00154806. NOAEL: 1.0 mg/kg/day LOAEL: 2.0 mg/kg/day decreases
in mean body weight gain in females.
-- cyhalothrin. 26-Week feeding - dog.
00154795. NOAEL: 1.0 mg/kg/day LOAEL: 2.5 mg/kg/day increase in
liquid feces. At 10.0 mg/kg/ day, clinical
signs of neurotoxicity.
-- cyhalothrin. 28-Day feeding - rat.
00153029. NOAEL: 2 mg/kg/day 1984/Acceptable LOAEL: 10 mg/kg/day
nonguideline. clinical signs of 0, 2, 10, 25, 50, 75 mg/ neurotoxicity.
At kg/day. higher doses, decreases in body
weight gain and food consumption and changes in organ weights.
-- cyhalothrin. Developmental toxicity -
rat. 00154800. Maternal NOAEL: 10 mg/kg/day. Maternal LOAEL:
15 mg/ kg/day. uncoordinated limbs, reduced
body weight gain and food consumption. Developmental NOAEL:
15 mg/kg/day, the highest dose tested (HDT) Developmental LOAEL:
>15 mg/kg/day
Ref: Federal Register: September 27, 2002.
Lambda-cyhalothrin; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Lambda.Cyhalot.FR.Sept27.02.htm
-- Short term toxicity.
Target / critical effect: Organs Liver,
CNS. Lowest relevant oral NOAEL /
NOEL: 0.5 mg/kg bw/d, oral, 1 y dog.
Ref: European Commission. Review report
for the active substance lambda-cyhalothrin. Finalised in the
Standing Committee on Plant Health at its meeting on 19 October
2000 in view of the inclusion of lambda-cyhalothrin in Annex I
of Directive 91/414/EEC. 7572/VI/97-final. 25 January 2001. http://europa.eu.int/comm/food/fs/ph_ps/pro/eva/existing/list1-24_en.pdf
--
lambda-cyhalothrin. 21-Day inhalation toxicity
- rat. 41387702. NOAEL: 0.08 mg/kg/day. LOAEL: 0.90 mg/kg/day.
clinical signs of neurotoxicity,
decreased body weight gains, increased incidence of punctuate
foci in cornea, slight reductions in cholesterol in females, slight
changes in selected urinalysis parameters
-- lambda-cyhalothrin.
1- Year
oral - dog. 40027902. NOAEL: 0.1 mg/kg/day. LOAEL: 0.5 mg/kg/day.
clinical signs of neurotoxicity.
--
lambda-cyhalothrin. Acute
neurotoxicity - rat. 44861510.
NOAEL: 10 mg/kg. LOAEL: 35 mg/kg. clinical
observations indicative of neurotoxicity and changes in
functional observational battery (FOB) parameters
Ref: Federal Register: September 27, 2002.
Lambda-cyhalothrin; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Lambda.Cyhalot.FR.Sept27.02.htm
Abstract (2003).
Synthetic pyrethroids such as cyhalothrin are extensively used
in agriculture for the control of a broad range of ectoparasites
in farm animals. It has been suggested that type II pyrethroids
might induce anxiogenic-like effects in laboratory animals. The
present study was undertaken to investigate a possible anxiogenic-like
outcome of cyhalothrin in rats. Adult male
rats were orally dosed for 7 days with 1.0, 3.0, or 7.0 mg/kg/day
of cyhalothrin, present in a commercial formulation (Grenade Coopers
do Brazil S.A.). The neurobehavioral changes induced by
cyhalothrin as well as those produced on corticosterone serum
levels were measured 24 h after the last treatment. Picrotoxin
(1.0 mg/kg) was also acutely used as a positive control for anxiety.
Results showed that cyhalothrin:
(1) induced some signs and symptoms of intoxication that included
salivation, tremors, and liquid feces;
(2) reduced total locomotor activity in
the open-field;
(3) reduced the percentage of time spent in open-field central
zones;
(4) increased immobility time in the open-field;
(5) reduced the percentage of time spent
in plus-maze open arms exploration;
(6) reduced the time spent in social interactions, and
(7) increased the levels of serum corticosterone.
The behavioral changes reported for cyhalothrin (3.0 mg/kg/day)
were similar of those induced by picrotoxin.
The no effect level dose obtained for cyhalothrin in this study
was 1.0 mg/kg/day. These results provide experimental evidence
that cyhalothrin induces anxiety-like symptoms, with this effect
being dose-related. Thus, anxiety must be included among
the several signs and symptoms of pesticide intoxication.
Ref:
Behavioral effects of type II pyrethroid cyhalothrin in rats;
by Righi DA, Palermo-Neto J. Toxicol Appl Pharmacol. 2003 Sep
1;191(2):167-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12946652
Organophosphate insecticides
such as ... DFP are potent cholinesterase
enzyme inhibitors that act by interfering
with the metabolism of acetylcholine, resulting in the accumulation
of acetylcholine at neuroreceptor transmission sites. [Klaassen,
C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology.
The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill,
1995. 979]
-- MUSCARINIC (PARASYMPATHETIC) EFFECTS may include bradycardia,
bronchospasm, bronchorrhea, salivation, lacrimation, diaphoresis,
vomiting, diarrhea, and miosis. NICOTINIC (SYMPATHETIC AND MOTOR)
EFFECTS may include tachycardia, hypertension, fasciculations,
muscle cramps, weakness, and RESPIRATORY PARALYSIS. CENTRAL EFFECTS
may include CNS depression, agitation,
confusion, delirium, coma, and seizures.
-- Children may have different predominant signs and symptoms
than adults: CNS depression, stupor,
flaccidity, dyspnea, and coma are the most common signs in children.
-- ... Its high lipid solubility, low molecular weight, and volatility
facilitate inhalation and transdermal absorption. DFP
also readily penetrates the central nervous system. [Hardman,
J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.).
Goodman and Gilman's The Pharmacological Basis of Therapeutics.
9th ed. New York, NY: McGraw-Hill, 1996. 167]
Ref: TOXNET Hazardous Substances Data Base
for DIISOPROPYL FLUOROPHOSPHATE. http://www.fluoridealert.org/pesticides/Isofluorphate-TOXNET.htm
Abstract:
Diisopropyl phosphorofluoridate (DFP) produces organophosphorus-ester
induced delayed neurotoxicity (OPIDN) in the hen, human and other
sensitive species. We studied the effect of a single dose of DFP
(1.7 mg/kg/sc) on the expression of c-jun, which is one of the
heterodimerizing ITFs (Inducible Transcriptional Factors) of the
AP-1 family. The hens were sacrificed at different time points
ie 0.25,.0.50, 1 and 2 hrs. Total RNA was extracted from the following
brain regions: cerebrum, cerebellum, brainstem, midbrain and as
well as spinal cord. Northern blots prepared using standard protocols
were hybridized with c-jun as well as b-actin and 18S RNA cDNA
(control) probes. The results indicate differential regulation
of c-jun levels which may be due to the activation of both cholinergic
and non-cholinergic pathways of CNS,
besides changing roles of c-jun (as mediator of degeneration or
regeneration) depending on heterodimerization with other ITFs.
In the highly susceptible tissues like brainstem and spinal cord
c-jun transcript levels increased at 15 minutes and continued
to increase gradually till it reached the maximum at 2 hrs. Overall
spinal cord showed the maximum levels of c-jun induction (207%)
at 2 hrs time point of all the CNS tissues. The enhancement
of cholinergic transmisson by the inhibition of cholinestrase
may be responsible for the gradual increase mediated by neural
and vascular factors. In contrast, less susceptible tissue, cerebellum
showed almost immediate induction to high level of (179%) at 15
minutes and the levels stayed more or less the same until it peaked
to 185% at 2 hrs. Relatively low abundance of cholinergic neurons
and high number of sensitized specialized cell types like Bergman
glia and Purkinje cells may be responsible for the immediate higher
induction. Non-susceptible tissue cerebrum did not show any changes
in the c-jun levels. In midbrain the induction pattern was very
similar to that of brainstem. This differential
induction pattern of c-jun encomposing the differences in the
quantity and time course was directly proportionate to the degree
of susceptibility and cellular heterogeneity of different regions
of CNS. The significant increase
in c-jun levels along with our earlier observation on the increased
c-fos levels indicate that AP-1 family of genes may be one of
the IEGs involved in the long term changes which eventually lead
to OPIDN.
Ref:
Early Differential Induction of C-jun
in the Central Nervous System of
Hens Treated with Diisopropylphosphorofluoridate (DFP) by TV
Damodaran et al. Neurochemical Research 25 (12): 1579-1586, December
2000.
Abstract:
A single dose of diisopropyl phosphorofluoridate (DFP), an organophosphorus
ester, produces delayed neurotoxicity (OPIDN) in hen. DFP
produces mild ataxia in hens in 7–14 days, which develops
into severe ataxia or paralysis as the disease progresses.
Since, OPIDN is associated with alteration in the expression of
several proteins (e.g., Ca2+/calmodulin-dependent protein kinase
II (CaM kinase II) [alpha]-subunit, tau, tubulin, neurofilament
(NF) protein, vimentin, GFAP) as well as their mRNAs (e.g., NF,
CaM kinase II [alpha]-subunit), we determined the effect of a
single dose of DFP on the expression of one of the best known
immediate-early gene (IEG), c-fos. C-fos expression was measured
by Northern hybridization in cerebrum, cerebellum, brainstem,
midbrain, spinal cord, and the sciatic nerves of hens at 0.5 hr,
1 hr, 2 hr, 1 day, 5 days, 10 days, and 20 days after a single
1.7 mg/kg, sc. injection of DFP. All the
tissues (cerebrum, 52%; cerebellum, 55%; brainstem, 49%; midbrain,
23%; spinal cord, 80%; sciatic nerve, 157%;) showed significant
increase in c-fos expression in 30 min and this elevated level
persisted at least up to 2 hr. Expressions of [beta]-actin
mRNA and 18S RNA were used as internal controls.
The significant increase in c-fos expression
in DFP-treated hens suggests that c-fos may be one of the IEGs
involved in the development of OPIDN.
Ref:
C-fos
mRNA Induction in the Central and Peripheral
Nervous Systems of Diisopropyl Phosphorofluoridate (DFP)-Treated
Hens; by RP
Gupta et al. Neurochemical Research 25 (3): 327-334, March 2000.
Daily
subcutaneous (s.c) injections of the organophosphate diisopropylfluorophosphate
caused prolonged inhibition of cholinesterase (ChE) activity in
whole blood and brain and downregulation of muscarinic receptors
in the central nervous system; these changes were accompanied
by progressive, persistent deterioration of working memory and
motor function.
Ref: 1994
- Repeated Inhibition of Cholinesterase by Chlorpyrifos in Rats:
Behavioral, Neurochemical and Pharmacological Indices of Tolerance;
by Bushnell PJ, Kelly KL, Ward TR. NTIS report no.NTIS/PB95-148979
[The National Technical Information Service).
Abstract:
Behavioral effects of organophosphates (OPs) typically decrease
with repeated exposure, despite persistence of OP-induced inhibition
of acetylcholinesterase (AChE) and downregulation of muscarinic
acetylcholine (ACh) receptors. To characterize this tolerance
phenomenon, rats were trained to perform an appetitive operant
task which allowed daily quantification of working memory (delayed
matching-to-position), reference memory (visual discrimination)
and motor function (choice response latencies and inter-response
times (IRTs) during delay). Findings indicate that animals showing
a definitive sign of tolerance to OP administration (subsensitivity
to a cholinergic agonist) were also functionally
impaired on both the motoric and mnemonic demands of a working
memory task. The nature of this impairment suggests further
that it results from compensatory changes in the CNS, e.g., muscarinic
receptor downregulation, considered to produce 'tolerance' to
OPs in exposed animals.
Ref: 1991 - Behavioral and Neurochemical Changes in Rats Dosed
Repeatedly with Diisopropylfluorophosphate; by Bushnell PJ, Padilla
SS, Ward T, Pope CN, Olszyk VB. Report No. NTIS/PB91-200238 from
Tge National Technical Information Service.
The Morris
water task was used to measure the effects of chronic diisopropylfluorophosphate
(DFP) treatment on C57BL/6Ibg mice. Control mice showed good task
acquisition and searched accurately for the platform after it
was removed from the pool, suggesting that they had formed a spatial
map of the platform's location relative to distal cues.
In contrast, mice chronically treated with DFP prior to training
showed a marked deficit in spatial learning. Chronic DFP
treatment did not affect ability to locate a visible platform
and did not impair task retention in mice trained to find the
hidden platform prior to DFP treatment. The
chronic DFP treatment decreased muscarinic binding in cortex,
hippocampus, and striatum. These results indicate that
C57BL mice are capable of spatial learning in the water task.
The ability of chronic DFP treatment to
impair place but not cue learning suggests that the cholinergic
dysfunction produced by DFP is similar to those produced by lesions
of central cholinergic s [abstract truncated]
Ref:
1987 - Effects of Chronic Diisopropylfluorophosphate Treatment
on Spatial Learning in Mice; by Upchurch M, Wehner JM. Report
No. NTIS/AD-A188 368/5 from The National Technical Information
Service.
--
IN HIGH CONCN, IT MAY CAUSE CENTRAL NERVOUS
DEPRESSION. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical
Toxicology of Commercial Products. 5th ed. Baltimore: Williams
and Wilkins, 1984.,p. II-159]
-- Exposure to 100,000 ppm killed
rats and guinea pigs within an hour. Clinical signs included loss
of coordination, tremors ... /CNS depression/
and prostration; limited pathologic examination, partly obscured
by post-mortem change, revealed lung and liver changes. [American
Conference of Governmental Industrial Hygienists, Inc. Documentation
of the Threshold Limit Values and Biological Exposure Indices.
6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 434]
Ref: TOXNET profile from Hazardous Substances Data Base for DICHLOROFLUOROMETHANE
http://www.fluoridealert.org/pesticides/Dichlorofluoromethan.TOXNET.htm
Dichlorodifluoromethane(Freon
12 or CFC 12)-
Insecticide, Fungicide Propellant, EPA List 2 Inert -
CAS No. 75-71-8
-- Health
Hazards - General. ...At high concentrations, Freon vapor
may cause pulmonary edema and neurological problems such as
central nervous system depression, dizziness, headache,
drowsiness, tremors, seizures, confusion, in-coordination, loss
of consciousness, and paralysis (Hazardtext, 2003B; Dupont, 1996A;
OSHA, 1998; NIOSH, 2003C).
-- Predisposing Conditions. Individuals
with pre-existing diseases of the central
nervous or cardiovascular system may have increased susceptibility
to the effects of Freons (Dupont, 1996A; OSHA, 1998; Dupont, 1996B;
Dupont, 1996D). Persons exposed to epinephrine or other sympathomimetic
amines, e.g., bronchodilators and nasal decongestants (e.g., Sudafed
¥), might be at increased risk for the cardiotoxic effects of
Freons (Reprotext, 2003).
-- Special Concerns for Children.
Children may inhale relatively larger doses of Freon because,
relative to their body weight, they have a greater lung surface
area and larger minute volume than adults. Since Freon has a high
vapor density, children could also receive high doses due to their
short stature and the higher levels of Freon vapor that may be
present near the ground when Freon is spilled.
Ref:
September 24, 2003 (Revised)
- FREON [11, 12, 113].
Technical Support Document: Toxicology. Clandestine
Drug Labs/ Methamphetamine. Volume 1, Number 11. California EPA,
Office of Environmental Health Hazard Assessment (OEHHA), Department
of Toxic Substances Control.
-- SUMMARY TOXICITY
STATEMENT: MILD IRRITANT ... /CNS DEPRESSANT/
IN HIGH CONCN. ASPHYXIANT. [Sax, N.I. Dangerous Properties of
Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold,
1979. 567]
-- Chlorinated hydrocarbons may cause systemic toxicity through
percutaneous absorption. Systemic toxicity includes convulsion,
delirium, and central nervous system depression
/From table/. /Chlorinated hydrocarbons/ [Zenz, C. Occupational
Medicine-Principles and Practical Applications. 2nd ed. St. Louis,
MO: Mosby-Yearbook, Inc, 1988. 160]
Ref:
1,2-DICHLORO-1,1,2,2-TETRAFLUOROETHANE. CASRN: 76-14-2. TOXNET
profile from Hazardous Substances Data Base.
http://www.fluorideaction.org/pesticides/dichlorotetrafluoroe.toxnet.htm
Dimefox
- Acaricide, Insecticide -
CAS No. 115-26-4
Abstract: The neurobehavioral
toxicity of three organophosphate pesticides, sumithion, dimefox
and trichlorphon, was evaluated in rats using measures of open
field activity, rotorod performance, conditioned escape from shock,
and nerve conduction velocity. These measures were correlated
with blood and brain cholinesterase level determinations. All
three chemicals disrupted behavior ranging from transient disruptions
accompanied by alterations in nerve conduction to disruption throughout
the exposure. Even in the case of prolonged behavioral
disruption, however, some recovery of performance occurred. Cholinesterase
in both blood and brain decreased with initial dosing and remained
low with continued dosing regardless of changes in the behavioral
measures. The results are discussed in terms of the necessity
of using mammalian behavioral tests to determine the toxicity
of organophosphorous compounds in order to safeguard the health
of the human population.
Ref: Lehotzky K (1982). Effect
of pesticides on central and peripheral nervous system function
in rats. Neurobehav Toxicol Teratol. Nov-Dec;4(6):665-9.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7170026&dopt=Abstract
Fipronil
- Acaricide,
Insecticide
- CAS No. 120068-37-3
•
Acute neurotoxicity. The
NOEL was 2 mg/kg, based on decreases in
body weight gain and food consumption
in males and
females during the week following treatment, decreases
in locomotor activity, hind-limb splay and
rectal temperature 6-hour
post dosing in males and females, and decreases
in the proportion of males with an immediate righting reflex
on days 7 and 14, at 12 mg/kg/day.
•
Subchronic toxicity. The
NOAEL in the rat was 3 ppm (0.18
and 0.21 mg/kg/day in males and females, respectively), based
on clinical signs of toxicity in both sexes and decreased body
weight and body weight gain in males at 10 ppm. The NOEL
for the mouse was 0.5 ppm (0.08
mg/kg/day), based on the aggressive and
irritable behavior with increased motor activity in males at 2
ppm. The
NOEL for the dog was 9.5 ppm
(0.29 mg/kg/day), based on behavioral changes
in females at 35 ppm (1.05 mg/kg/day).
• Subchronic
neurotoxicity study in
rats,
the NOEL was 5 ppm (0.301 and 0.351 mg/kg/day for males and females,
respectively), based on results of the functional
observational battery (FOB) at 150 ppm (8.89 and 10.8 mg/kg/day
for males and females, respectively).
•
Chronic toxicity. The
NOAEL for systemic toxicity in a 1-year feeding study in the
dog was 0.3 mg/kg/day in females and 1 mg/kg/day in males,
based on clinical signs of neurotoxicity at 1 and 2 mg/kg/day
in females and males, respectively.
• In
a developmental neurotoxicity study in the rat,
the NOAEL for maternal toxicity was 10 ppm
(0.91 mg/kg/day), based on decreased body weights and body weight
gain at 200 ppm (HDT; 15 mg/kg/day). Considerable maternal
toxicity at the HDT prevented adequate neurotoxicity evaluation
of pups at this dose level. There was no evidence of neurotoxicity
at 10 ppm (0.91 mg/kg/day), which was the NOAEL for developmental
neurotoxicity.
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
on Food. http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html
(pages 127-128) - Diagnosis of
poisoning. The applicant [Aventis] submits the following
proposal (shown by italic text). (The ACP advised that some amendments
should be made, these are indicated by struckthrough/bold font
for deleted/new text respectively).
Fipronil is a reversible gamma-aminobutyric acid (GABA)
receptor inhibitor. During intoxication, it
will induce neurological stimulation with possible convulsions.
Signs and symptoms which appear the most relevant for humans
may be observed after acute or repeated over-exposure.
These signs mainly consist of central nervous system (CNS) hyperexcitability:
over-activity, irritability, tremors, and, at a more severe
state, lethargy or convulsions. These symptoms are reversible
after termination of exposure.
In the rat, clear signs of toxicity were observed following
a single oral administation of fipronil at a dose of 50 mg/kg/body
weight while minimal symptoms were observed at 5 mg/kg bodyweight.
Due to slow absorption through the gut, symptoms of intoxication
may be delayed for several hours to one day. Fipronil does not
readily penetrate skin. Therefore absorption should be minimal
following dermal exposure. Symptoms are expected only after
repeated excessive exposure.
Measurement of fipronil and its metabolites in the blood (or
in the gastric lavage) is the only way to definitively
confirm exposure. In cases of suspected intoxication evidenced
by symptoms, a blood sample should be taken as soon after the
alleged exposure as possible and may be sent
to: AventisRhone-Poulenc Agro
Toxicology Department
Centre de Recherche
355, Rue Dostoievski
B.P. 153
F-06903 Sophia Antipolis Cedex
FRANCE
Attention: Dr Pierre-Gerard Pontal
Ref:
April 204. Evaluation
on : Fipronil (Horticultural Uses).
No. 212.
UK Dept. for Environment, Food and Rural Affairs, Pesticides
Safety Directory. http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf
Human
Toxicity Excerpts: SYMPTOMATOLOGY
INDICATES OVERDOSING MAY PRODUCE /CNS DEPRESSION/
AND OTHER GENERAL CNS INVOLVEMENT. [Weed Science Society
of America. Herbicide Handbook. 5th ed. Champaign, Illinois: Weed
Science Society of America, 1983. 238]
Ref: Hazardous Substance Data Bank for FLUCHLORALIN
CASRN: 33245-39-5 from Toxnet.
Abstract.
Male Swiss mice, 25-30 g, were utilized to define some of the
behavioral effects of the herbicides Lasso [alachlor 43%; (A)],
Basalin [fluchloralin 45%; (F)],
Premerge 3 [dinoseb 51%; (D)], and the fungicide Maneb-80 [maneb
80%; (M)]. These compounds were tested for their effects on locomotor
activity and for their ability to establish a conditioned taste
aversion following oral or dermal exposure. Individual and grouped
(N = 5) activity measures were assessed immediately following
the dermal administration of the commercially available pesticide
formulations. Grouped activity measures were also assessed following
the oral administration of the compounds. Total
activity was significantly (p less than 0.05) increased over vehicle
controls in both grouped and individual subjects by A, F, and
D following dermal administration. Grouped activity measures were
also increased by A, F, D, and M following the oral administration
of the compounds...
Ref: The behavioral effects of pesticides in male mice; by Mitchell
JA, Long SF, Wilson MC, Kallman MJ. Neurotoxicol Teratol 1989
Jan-Feb;11(1):45-50.
Abstract.
Basalin, a formulation of fluchloralin (N-(2-chloroethyl)-2-6-dinitro-N-propyl-4-(trifluoromethyl)-aniline),
is being very widely used as herbicide in large number of important
crops. But very limited data on its toxicological profile is available.
Its adverse effects on central nervous system and locomotor alterations
in sheep given 5 mg/kg orally have been reported. Preliminary
studies in our laboratory indicated alteration in gait in chicken
given Basalin orally @ 200-500 mg/kg followed by ataxia at higher
doses. Since chicken is a suitable model for neurotoxicity assay,
present studies were conducted on one week old broiler chicks
given Basalin daily for four weeks through feed at different dose
levels of 50 mg/kg (Gr I), 100 mg/kg (Gr II) and 150 mg/kg (Gr
III). Each group contained ten chicks. The control chicks (Gr
C) were given equal amount of normal feed. Activities of brain,
liver and plasma acetylcholinesterase (ACHE), carboxylesterase
(CE) and brain neurotoxicesterase (NTE) were estimated, the tissue
esterases after four weeks treatment and
plasma esterases at weekly intervals. The locomoter activity was
determined using inclined plane at alternate days. Histopathological
examinations of brains and spinal cords of four birds from each
group were conducted after four weeks treatment. The
data on all these experiments indicated inhibition of all tissue
and plasma esterases in a dose dependent manner, which were significant
in chicks of Gr III receiving maximum dose for four weeks. (Brain
NTE 70%, brain and liver ACHE 85.71 and 85.45% respectively and
liver CE 85.58% of control activity). The plasma ACHE and CE activities
were significantly inhibited in this group after two weeks onwards
(ACHE90.8-90.3%, CE 84.9-84.5% of control). Alteration
in gait in Gr III chicks was observed after three weeks treatment
and was correlated with NTE inhibition. Histopathological
examinations of brain and spinal cords of chicks receiving maximum
dose revealed increased number of Schwann cells in brain and small
numbers of myelinated nerve fibers in spinal cord. The
studies thus indicated possibility of neuropathic effects of Basalin
on prolonged exposure or at higher doses.
Ref: Basalin induced neurotoxic effects
in broiler chicks; by Sushma Rishi and Uma Arora. Toxicology Letters;
Volume 95, Supplement 1 , July 1998, Pages 144-145.
Fluoroacetamine
-
- Insecticide, Rodenticide - CAS No.
640-19-7
(also known as Fluoroacetamide or Compound
1081)
EPILEPTIFORM
CONVULSIONS ALTERNATE WITH COMA & DEPRESSION; DEATH MAY RESULT
FROM ASPHYXIA DURING CONVULSION OR FROM RESP FAILURE. MOST PROMINENT
FEATURES ... ARE CARDIAC IRREGULARITIES, NOTABLY VENTRICULAR FIBRILLATION
& SUDDEN CARDIAC ARREST. [International Labour Office. Encyclopedia
of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland:
International Labour Office, 1983. 895]
-- Moderately fast-acting rodenticide which is less likely to
lead to poison shyness because of sublethal dosing. It acts chiefly
on the heart, with secondary effects on
CNS. [Tomlin, C.D.S. (ed.). The Pesticide Manual - World
Compendium. 10th ed. Surrey, UK: The British Crop Protection Council,
1994. 492]
-- Mechanism of Action: FLUOROACETATE PRODUCES ITS TOXIC ACTION
BY INHIBITING THE CITRIC ACID CYCLE. THE FLUORINE SUBSTITUTED
ACETATE BECOMES INCORPORATED, AS A NORMAL ACETATE, INTO FLUOROACETYL
COENZYME A, WHICH CONDENSES WITH OXALOACETATE TO FORM FLUOROCITRATE.
FLUOROCITRATE INHIBITS THE ENZYME ACONITASE & THEREBY INHIBITS
THE CONVERSION OF CITRATE TO ISOCITRATE. AS A RESULT THERE IS
AN ACCUMULATION OF LARGE QUANTITIES OF CITRATE IN THE TISSUE,
& THE CYCLE IS BLOCKED. ... THE HEART
& CNS ARE THE MOST CRITICAL TISSUES INVOLVED IN POISONING
BY GENERAL INHIBITION OF OXIDATIVE ENERGY METABOLISM. /FLUOROACETATE/
[Doull, J., C.D.Klassen, and M.D. Amdur (eds.).
Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan
Co., Inc., 1986. 565] Ref:
FLUOROACETAMIDE CASRN: 640-19-7. Hazardous Substances Data Bank. http://www.fluorideaction.org/pesticides/fluoroacetamide.hsdb.htm
--
ACUTE TOXICITY. ... It may be fatal if inhaled, swallowed, or
absorbed through skin, as it is irritating to the mucous membrane
lining the skin, gastrointestinal tract, and respiratory system
(2). While there have been no reports of cases of fluometuron
poisoning in humans, this herbicide is considered a
mild
inhibitor of cholinesterase. Cholinesterase
is an essential enzyme of the nervous system. Cholinesterase inhibition
was observed in guinea pigs exposed by inhalation to 588 mg/m3
for 2 hours (18)... Fluometuron caused an increased white blood
cell count in agricultural workers (3).
Ref: Flumeturon. EXTOXNET. Pesticide Information
Profile. March 1994. http://pmep.cce.cornell.edu/profiles/extoxnet/dienochlor-glyphosate/fluometuron-ext.html
Human
Toxicity Excerpts:
... /MAJOR EFFECTS/ INVOLVE CNS
& CARDIOVASCULAR
SYSTEM. SEVERE EPILEPTIFORM CONVULSIONS ALTERNATE WITH COMA &
DEPRESSION; DEATH MAY RESULT FROM ASPHYXIA DURING CONVULSION OR
FROM RESP FAILURE. MOST PROMINENT FEATURES ... ARE CARDIAC IRREGULARITIES,
NOTABLY VENTRICULAR FIBRILLATION & SUDDEN CARDIAC ARREST.
[International Labour Office. Encyclopedia of Occupational Health
and Safety. Vols. I&II. Geneva, Switzerland: International
Labour Office, 1983. 895]
Ref: TOXNET profile from Hazardous Substances
Data Bank. http://www.fluoridealert.org/pesticides/Fluoroacetic.Acid.TOXNET.htm
Gliftor -
Rodenticide - Rodenticide - CAS No. 8065-71-2
Abstract. Acute poisoning with gliftor, a pesticide composed
of 30% glycerol chlorofluorohydrin and 70% glycerol difluorohydrin,
was studied in three tractor drivers who, mistaking it for alcohol,
ingested 30 ml each of this liquid. Motor
disorders comprising complex chloreiform hyperkinesis (Kulenkampff-Tarnow
syndrome) due to lesions in the cortical
and subcortical structures of the corpus striatum and of the limbicoreticular
portion of the brain, were the principal poisoning symptoms. There
were no symptoms of fluorine poisoning. One patient, who
presented the first symptoms 48 hr after ingestion of the poison,
died in respiratory collapse 6 days later. Leukocytosis (up to
20% rod neutrophilis) hyperglycemia, a serum potassium level of
2.7 mEq/liter, proteinuria, pyuria, and hematuria were observed.
Histopathological examination revealed acute
circulatory disturbances in the internal organs, parenchymatous
dystrophy, and dystrophic changes in the central nervous system.
Ref: Three cases of gliftor poisoning;
by Kovalenko LI, Bulkina VA, Panteleev RI. Gig. Tr. Prof. Zabol.
(12): 53-54; 1975. [Abstract from Toxline at Toxnet.]
Abstract. Under conditions of the acute inhalation effect of
the vapors of gliftor (I) the LD50 for rats was 580 plus or minus
65 and for mice 1260 plus or minus 15 mg/m-3. The threshold concentration
(TC) for rats with respect to brief disturbance of the functional
state of the CNS was 50 and the subthreshold 10 mg/m-3; for mice
the TC was 190 mg/m-3. Chronic (4 mo.) inhalation
by rats of I in a concentration of 110 and 64 mg/m-3 disturbed
the functional state of the CNS and antitoxic and
protein-forming functions of the liver and reduced oxidation-reduction
processes. I in a concentration of 1.0 mg/m-3 increased the concent
of eosinophils and reduced the number of lymphocytes by the end
of the poisoning period. I is a hazardous compound.
A maximum allowable concentration of I of 0.05 mg/m-3 in the air
of production shops is recommended for worker exposure.
Ref: Effect of gliftor on certain metabolic
processes of experimental animals under inhalation poisoning conditions;
by TKACH NZ, KNYSH VS, MILOVANOVA VI, SHISHKOVA NK, SLEPOVA LI.
TR INST KRAEV PATOL AKAD NAUK KAZ SSR; 22 1971 5-12. [Abstract
from Toxline at Toxnet.]
52425-040
162205 "Oncogenicity Study with DPX-JW062-106 (50% DPX-KN128,
50% DPX-KN127) Eighteen-Month Feeding Study in Mice" (Frame,
S. 832-E. I. du Pont de Nemours and Company, Haskell Laboratory,
Elkton Road, Newark, Delaware, Study HLR 799-96, 3/24/97). DPX-JW062-106
technical (Batch DPX-JW062-106, approximately 48% DPX-KN128)
was given in the diet daily to 70 Crl:CD ¨ -1(ICR)BR mice/sex/dose
at 0, 20, 100, or 125/150/200 ppm for 18 months (200 ppm level
reduced to 150 ppm on day 126 and to 125 ppm on day 287 due to
excessive mortality). The cause of death was either central
nervous system disorder (determined from clinical signs
of abnormal gait/mobility and head tilt) or heart inflammation/
necrosis (males only). Non-neoplastic changes were noted in the
brain of both sexes and in the heart of males only of mice that
died or were sacrificed in extremis. Neuronal necrosis was reported
in two high-dose males and two females and in one female at 100
ppm. Both high-dose males were sacrificed in extremis, one while
receiving the 150 ppm diet (day 133) and the other while receiving
the 125 ppm diet (test day 302). The two affected females died
or were killed in extremis (day 83 and 108, respectively) while
receiving 200 ppm. Residual vacuolation of the piriform cortex
was observed in 2 female high-dose mice that survived to the 18-month
scheduled sacrifice.
Ref: March
11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch. http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
Neurotoxicity was present in both rats
and mice; however, it did not occur in the absence of other
signs of toxicity. Neurotoxicity was characterized by one or more
of the following symptoms in both male and female rats and mice:
weakness, head tilting, and abnormal gait
or mobility with inability to stand, ataxia. Acute and
subchronic neurotoxicity screening batteries were performed using
DPX-MP062 in rats. Neurotoxicity was characterized by clinical
signs (depression, abnormal gait, head shake,
salivation) and functional-observation battery (FOB) (circling
behavior, incoordination, slow righting reflex, decreased forelimb
grip strength, decreased foot splay, decreased motor activity).
However, there was no evidence of neurohistopathology in any study.
Learning and memory parameters were affected
in the pups in the developmental neurotoxicity study in
rats with DPX-KN128.
Ref: USEPA. May 23,
2007. Indoxacarb. Health Effects Division (HED) Risk Assessment
for Grapes; Vegetable, Brassica, Leafy, Group 5; Turnip Greens;
Vegetable, Leafy, Except Brassica (Group 4); Pome Fruits (Group
11, except pear); Tuberous and Corm Vegetables (Subgroup 1C);
Cucurbit Vegetables (Group 9); Stone Fruits (Group 12); Cranberry;
Mint; Okra; Southern Pea; and Fire Ant Bait. http://www.fluoridealert.org/pesticides/EPA-HQ-OPP-2005-0149-0005.pdf
Range of Toxicity:
-- Minimum lethal human exposure is unknown. In rats exposed by
inhalation to a concentration of 2.2 ppm for 1 hour, only minimal
salivation was seen; at 5 ppm for the same duration, copious salivation,
eye and nose exudates, diarrhea, depression,
ataxia, and tremors were observed.
-- Only subclinical alterations of blood glucose, serum creatinine,
total bilirubin, and depression of acetylcholinesterase
were noted in rats exposed by inhalation to 19 or 91 ppb of methanesulfonyl
fluoride for 61 exposures, each lasting 7 hours.
-- ACUTE EXPOSURE. Methanesulfonyl fluoride is an irreversible
inhibitor of acetylcholinesterase in vitro. It also inhibits
butyrylcholinesterase and trypsinogen in vitro.
-- NEUROLOGIC. ACUTE EXPOSURE. Symptoms noted in experimental
animals included CNS depression,
tremors, ataxia, and convulsions. ANTICHOLINESTERASE COMPOUNDS
can affect the CENTRAL NERVOUS SYSTEM, producing restlessness,
anxiety, headaches, convulsions, and coma.
Ref: TOXNET profile from Hazardous Substances
Data Base. http://www.fluoridealert.org/pesticides/Methanesulfonyl.fluo.TOXNET.htm
Mipafox
-
Acaricide, Insecticide -
CAS No. 371-86-8
CHOLINESTERASE
INHIBITOR. [The
Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983.
889]
Ref:
TOXNET profile for Mipafox from Hazardous Substances Data Base.
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB
Abstract: Chick embryo dorsal root ganglia (DRG) cultures were
used to explore early pathological events associated with exposure
to neuropathy-inducing organophosphorus (OP) compounds. This approach
used an in vitro neuronal system from the species that provides
the animal model for OP-induced delayed neuropathy (OPIDN). DRG
were obtained from 9-day-old chick embryos, and grown for 14 days
in minimal essential medium (MEM) supplemented with bovine and
human placental sera and growth factors. Cultures were then exposed
to 1 microM of the OP compounds phenyl saligenin phosphate (PSP)
or mipafox, which readily elicit
OPIDN in hens, paraoxon, which does not cause OPIDN, or the DMSO
vehicle. The medium containing these toxicants was removed after
12 h, and cultures maintained for 4-7 days post-exposure. Morphometric
analysis of neurites was performed by inverted microscopy, which
demonstrated that neurites of cells treated with mipafox or PSP
but not with paraoxon had decreased length-to-diameter ratios
at day 4 post-exposure. Ultrastructural alterations of neurons
treated with PSP and mipafox included dissolution of microtubules
and neurofilaments and degrading mitochondria. Paraoxon-treated
and DMSO control neuronal cell cultures did not show such evident
ultrastructural changes. This study demonstrates that chick DRG
show pathological changes following exposure to neuropathy-inducing
OP compounds.
Ref: Morphological effects of neuropathy-inducing
organophosphorus compounds in primary dorsal root ganglia cell
cultures; by Massicotte C, Jortner BS, Ehrich M. Neurotoxicology.
2003 Dec;24(6):787-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14637373
Abstract:
Short term clinical and neuropathological effects induced by tri-ortho-tolyl-phosphate
(78308) (TOTP), diisopropyl-fluorophosphate (55914) (DFP), phenyl-saligenin-phosphate
(4081236) (PSP), mipafox (371868),
malathion (121755), dichlorvos (62737), and carbaryl (63252) were
studied in rats. Male Long-Evans-rats were administered 300 to
1000mg/kg TOTP or 300 to 2000mg/kg malathion orally, injected
intramuscularly with 5 to 24mg/kg PSP, injected subcutaneously
with 1 to 3mg/kg DFP, or injected intraperitoneally with 3 to
30mg/kg mipafox or dichlorvos or 30 to 160mg/kg carbaryl. The
rats were also treated with atropine-sulfate to protect against
cholinergic symptoms. Selected rats were killed 4 hours after
DFP, PSP, mipafox, dichlorvos, and carbaryl or 48 hours after
TOTP and malathion and the brains and spinal cords were removed
and assayed for acetylcholinesterase (AChE) and neurotoxic-esterase
(NTE) activity. The remaining rats were weighed and evaluated
on a functional observational battery (FOB) that measured motor
activity and responses to being handled or approached 1, 7, 14,
and 21 days after dosing. The rats were then killed and the brains,
spinal cords, and tibial nerve branches leading to the gastrocnemius
muscle were examined for histopathological changes. The highest
doses of all compounds except PSP induced transient cholinergic
symptoms and caused 8.3 to 61% mortality within 48 hours. The
highest doses of TOTP, DFP, and malathion significantly decreased
body weight after 14 days. All compounds
caused dose related inhibitions of brain and spinal cord AChE
and NTE activity. DFP was the most potent and PSP the least
potent. All compounds induced significant
changes in FOB parameters related to behavioral and central nervous
system excitability 21 days after dosing. Mipafox, PSP, dichlorvos,
and carbaryl induced these changes 1 day after dosing. TOTP,
DFP, PSP, and mipafox caused mild to moderate
myelinated fiber degeneration in the rostral fasciculus gracilis
21 days after dosing. Mipafox was the most potent. DFP
also induced Wallerian like degeneration in the tibial nerve branches.
Dichlorvos, malathion, and carbaryl did not cause any neurological
changes. The authors conclude that some cholinesterase inhibitors
cause behavioral changes even after cholinergic signs are no longer
evident.
Ref: Short-Term Clinical and Neuropathologic Effects of Cholinesterase
Inhibitors in Rats; by Ehrich M, Shell L, Rozum M, Jortner BS.
Journal of the American College of Toxicology, Vol. 12, No. 1,
pages 55-68, 1993.
Abstract: Various structurally
unrelated chemicals [2,5 hexandione, acrylamide, organophosphates
like mipafox, beta,beta iminodipropionnitrile
(IDPN), 3-nitropropionic acid (3-NP), potassium cyanide (KCN),
paraquat, and NMDA (N-methyl-D-apartic acid)] are known to cause
degenerative damage of the peripheral or central nervous system.
Differentiated neuronal cell cultures obtained from fetal rats
have been used to differentiate the mechanisms underlying this
type of neurotoxicity. Cytotoxicity as measured by a viability
assay was not sensitive enough and had to be supplemented by further
endpoints covering effects on cytoskeleton and on the energy state
of the cells [glucose consumption, mitochondrial membrane potential
and adenosine 5'-triphosphate (ATP) concentration]. Compounds
like the delayed neurotoxic organophosphates, exert a selective
direct effect on cytoskeleton elements in this model at concentrations
distinctly below cytotoxic concentrations. Other compounds, like
KCN, paraquat, and 3-NP selectively disrupt the balance between
energy supply and demand of the neurons either by interacting
with mitochondrial respiration or glycolysis. For these compounds
cytoskeletal damage seemed to be secondary to the energy depletion.
For NMDA, 2,5 hexandione and acrylamide, both mechanisms may contribute
to the neuronal damage. In conclusion, primary cortical neuronal
cultures of the rat are well suited to detect a neurotoxic potential
and to differentiate its underlying mechanisms. Damage of the
cytoskeleton may be considered as an endpoint mechanistically
related to degenerative neuropathic effects.
Ref: Schmuck G et al. (2000). Rat cortical
neuron cultures: an in vitro model for differentiating mechanisms
of chemically induced neurotoxicity. In Vitr Mol Toxicol; Spring;13(1):37-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10900406&dopt=Abstract
Abstract:
This study compares two direct-acting neuropathy
target esterase (NTE) inhibitors (mipafox and 2-octyl-4H-1,3,2-benzodioxophosphorin
2-oxide (OBDPO)), a metabolic precursor to an NTE inhibitor (tri-o-cresyl
phosphate or TOCP) and a potent acetylcholinesterase inhibitor
(chlorpyrifos oxon or CPO) for their effects on outgrowth of neurite-like
and cell processes and on viability in differentiated cultured
cells (rat adrenal pheochromocytoma (PC-12) and brain glial tumor
(C6)). The direct-acting NTE inhibitors block process outgrowth
by 50% or more at 50-100 microM for OBDPO and 100-200 microM for
mipafox, well below their cytotoxic levels (EC50 values, 445-474
microM for OBDPO and 1021-1613 microM for mipafox). In contrast,
the effects on process development for TOCP and CPO parallel their
cytotoxicity. These findings suggest that inhibition of neurite-like
and cell process outgrowth by OBDPO and mipafox may be associated
with NTE inhibition.
Ref: Li W et al. (2000). Organophosphorus
neuropathy target esterase inhibitors selectively block outgrowth
of neurite-like and cell processes in cultured cells. Toxicol
Lett; Sep 15;98(3):139-46 http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9788582&dopt=Abstract
Novaluron
-
Insecticide, Insect growth
regulator - CAS No.
116714-46-6
52846-001; 174426;
"'Rimon' Technical: Neurotoxicity Study by a Single Oral
Gavage Administration to CD Rats Followed by a 14-Day Observation
Period"; (A. Broadmeadow, W.D. Harvey and M.J. Collier; Huntingdon
Life Sciences Ltd, Huntingdon, Cambridgeshire, PE18 6ES, England;
Report No. MAK 480/983207; 2/3/99); Ten CD rats/sex/group were
dosed orally by gavage with 0, 200, 650 or 2000 mg/kg of Rimon
Technical (Novaluron Technical) (batch no. 970211/4; purity: 99.3%).
The animals were examined in the functional observational battery
(FOB) and motor activity assessments prior to dosing, on day 1
(at one hour post-dose) and on days 8 and 15. Five animals/sex/group
in the control and high dose group were chosen for histological
evaluation of the nervous system and muscle. No mortality resulted
from the treatment. The incidence of the clinical signs, piloerection
and irregular or fast breathing occurred in a dose-related manner
for all of the treatment groups between days 3 and 5 post-dose.
Among the parameters evaluated in the FOB and the motor activity
measurements, only the forelimb grip strength was apparently affected
by the treatment. The mean forelimb grip strength of the 2000
mg/kg males was less than that of the control animals at 1 hour
post-dose (p<0.05). There was an increased
incidence of degenerated fibers (minimal) in the peripheral nerves
of the high dose group (M: (0) 0/5 vs. (2000) 2/5, F: (0) 1/5
vs. (2000) 3/5). Possible adverse effect: increased incidence
of degenerated fibers in the peripheral nerves. The study
data were insufficient to establish a NOEL for neurotoxicity.
Acute NOEL: < 200 mg/kg (based upon the incidence of clinical
signs in the 200 mg/kg group). Study unacceptable, possibly upgradeable
to acceptable with the submission of histopathology data for the
200 and 650 mg/kg treatment groups. (Moore, 11/2/00)
Ref:
2001. Summary of Toxicology Data for Novaluron. California Environmental
Protection Agency, Department of Pesticide Regulation, Medical
Toxicology Branch. Chemical Code # 5754, Tolerance # 52846 3/23/01.
http://www.fluoridealert.org/pesticides/Novaluron.CAepa.ToxTst.2001.pdf
LD50 ranges of sodium, potassium, or ammonium fluorosilicates
administered intragastrically in rats and mice were 89-128 and
45-64 mg fluoride ion/kg, respectively. Severe cornea damage was
observed 3 hr after the administration of 50 mg of any of the
salts into rabbits' eyes. Min toxic dose (intragastric) of fluorosilicic
acid in rats was 8 mg/kg. Min toxic concn in 4 hr inhalation of
the salt aerosols were 7.4-9.6 mg/cu m; nontoxic concn was 0.8
mg/cu m. Main toxic effects were decreased
activities of cholinesterase and lactate dehydrogenase
in blood serum. The intragastric effects of the fluorosilicates
were similar to and additive with those of sodium fluoride. [Rumyantser
GI et al; Oig Sanit (11): 80-2 (1988)]
Ref: TOXNET profile from Hazardous Substances
Data Bank for AMMONIUM SILICOFLUORIDE. http://www.fluoridealert.org/pesticides/Ammonium.Silicofluor.TOXNET.htm
Sodium
fluoride-
Wood
preservative, EPA List 4B Inert - CAS No. 7681-49-4
Abstract:
In an attempt to elucidate the mechanism by which excessive fluoride
damages the central nervous system, the effects of exposure
of PC12 cells to different concentrations of fluoride for 48 h
on nicotinic acetylcholine receptors (nAChRs) were characterized
here. Significant reductions in the number of binding sites for
both [3H]epibatidine and [125I]alpha-bungarotoxin, as well as
a significant decrease in the B(max) value for the high-affinity
of epibatidine binding site were observed in PC12 cells subjected
to high levels of fluoride. On the protein level, the alpha3 and
alpha7 subunits of nAChRs were also significantly decreased in
the cells exposed to high concentrations of fluoride. In contrast,
such exposure had no significant effect on the level of the beta2
subunit. These findings suggest that selective
decreases in the number of nAChRs may play an important role in
the mechanism(s) by which fluoride causes dysfunction of the central
nervous system.
Ref: Toxicology 2003 Feb 1;183(1-3):235-42.
Selective
decreases of nicotinic acetylcholine receptors in PC12 cells exposed
to fluoride by Chen J, Shan KR, Long YG, Wang YN, Nordberg
A, Guan ZZ.
Sodium
fluoroacetate
(also known as Sodium monofluoroacetate, Compound 1080)
- Insecticide, Rodenticide - CAS No.
62-74-8
Effects of Short-Term Exposure: The substance
may cause effects on the cardiovascular
system and central
nervous system, resulting in cardiac disorders
and respiratory failure. Exposure may result in death.
Ref: IPSCS INCHEM. ICSC: 0484. Date of Peer
Review: April 1997. Prepared in the context of cooperation between
the International Programme on Chemical Safety (IPCS) and the
Commission of the European Communities. http://www.inchem.org/documents/icsc/icsc/eics0484.htm
Abstract: A TLV-TWA
of 0.05 mg/m3 is recommended for occupational exposure to highly
toxic sodium fluoroacetate. This value is intended to minimize
the potential for progressive central nervous
system and cardiovascular system effects.
These may include nausea, womiting, apprehension, nystagmus,
facial twitching, and convulsions that are usually followed or
accompanied by tachycardia, ventricular fibrillation, and death
due to cardiac failure or respiratory arrest. Rapid absorption
through intact and abraded or cut skin warrants a Skin notation.
Sublethal sodium fluoroacetate is reported to cause changes in
testicular morphology in exposed rodents. Sufficient data were
not available to recommend SEN or carcinogenicity notations or
a TLV-STEL.
Ref: Anon (2001). Sodium Fluoroacetate.
TA:ACGIH. Documentation of the threshold limit values and biological
exposure indices PG:4 p YR:2001 IP: VI:7th Ed
Abstract: IPA COPYRIGHT:
ASHP A case is described of poisoning in a boy who ingested wheat
previously impregnated with 1080 (sodium fluoroacetate) to poison
rabbits. The product causes vomiting, convulsions, coma, respiratory
depression and cardiac irregularities. The boy was treated for
convulsions with I.V. thiopentone sodium and diazepam. He was
resuscitated from cardiac arrest but was left with severe
neurological impairment. 1080 is a widely used agricultural
poison with cardiotoxic and neurotoxic effects and stingent precautions
exist to control its use.
Ref: McTaggart DR (1970). Poisoning due
to sodium fluoroacetate (1080). Med. J. Aust.; VOL 2 ISS Oct 3
1970, P641-642,
PubMed abstract:
This study assessed
the health effects associated with occupational exposure to methyl
bromide and sulfuryl fluoride among
structural fumigation workers... Sulfuryl
fluoride exposure over the year preceding examination was associated
with significantly reduced performance
on the Pattern Memory Test and on olfactory
testing...
Occupational sulfuryl fluoride exposures may be associated with
subclinical effects on the central nervous system, including effects
on olfactory and some cognitive functions.
Ref: Am J Public Health 1998 Dec;88(12):1774-80.
Health
effects associated with sulfuryl fluoride and methyl bromide exposure
among structural fumigation workers by
Calvert GM et al.
"Sulphuryl fluoride
induces CNS depression."
Ref: Pesticide Policies in Zimbabwe. Status
and Implications for Change. Godfrey D. Mudimu Hermann Waibel
Gerd Fleischer (eds). A Publication of the Pesticide Policy Project
Hannover, September 1999 Special Issue Publication Series, No.
1. http://www.ifgb.uni-hannover.de/ppp/ppp_s01.pdf
A review of unpublished
reports of animal experiments apparently ... /indicated/ that
dosages sufficient to produce illness from a single exposure produce
respiratory irritation, CNS depression,
and possible liver and kidney injury. [Hayes, W.J., Jr., E.R.
Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2.
Classes of Pesticides. New York, NY: Academic Press, Inc., 1991.
564]
Ref:
Hazardous Substances Data Bank for SULFURYL FLUORIDE CASRN: 2699-79-8.
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB
The
primary effects of sulfuryl fluoride in humans are respiratory
irritation and central nervous system depression,
followed by excitation and possibly convulsions. Rabbits
exposed via inhalation (6 hours/day, 5 days/week, for 2 weeks)
to sulfuryl fluoride showed hyperactivity, convulsions and vacuolation
of the cerebrum at 600 ppm (2.5 mg/L). Renal lesions were present
in all rats exposed by inhalation (6 hours/day, 5 days/week, for
2 weeks) to 600 ppm (2.5 mg/ L) sulfuryl fluoride. Minimal renal
changes were noted in rats exposed to 300 ppm (1252 mg/L), whereas
no effects occurred at 100 ppm (4.2 mg/ L). Convulsions at near
lethal concentrations were reported in rabbits, mice, and rats.
In a 30-day inhalation study, loss of control, tremors of the
hind quarters, and histopathological changes in the lung, liver,
and kidney were reported in rabbits exposed to 400 ppm (1.6 mg/L)
for 7 hours/day, 5 days/week for 5 weeks. The NOEL was 200 ppm
(0.83 mg/L). Cerebral vacuolation and/or malacia and inflammation
of nasal tissues were observed in rabbits exposed by inhalation
to 100 or 300 ppm (0.4 or 1.25 mg/L) for 13 weeks. The NOEL was
30 ppm (0.125 mg/L). Rats exposed by inhalation to 100 to 600
ppm (0.4 to 0.25 mg/L) sulfuryl fluoride for 13 weeks developed
mottled teeth (indicative of fluoride toxicity), renal and respiratory
effects, and cerebral vacuolation. EPA believes that there is
sufficient evidence for listing sulfuryl fluoride on EPCRA section
313 pursuant to EPCRA section 313(d)(2)(B) based on the available
neurological, renal, and respiratory toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the
Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide
Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental
Protection Agency, Washington, DC (1993). As cited by US EPA in:
Federal Register: January 12, 1994. Part IV. 40 CFR Part 372.
Addition of Certain Chemicals; Toxic Chemical Release Reporting;
Community Right-to-Know; Proposed Rule. http://www.epa.gov/tri/frnotices/59fr1788.htm
-- NEUROLOGIC 0.2.7.1.
ACUTE EXPOSURE - Headache, dizziness, and disorientation are common.
Cerebral edema may be found on autopsy.
A syndrome of impaired psychomotor speed, impaired memory and
learning, and emotional lability has been described in workers
with chronic occupational exposure to fluorinated hydrocarbons.
-- THERE IS A SIGNIFICANT
ACCUMULATION OF FLUOROCARBONS IN BRAIN, LIVER & LUNG COMPARED
TO BLOOD LEVELS, SIGNIFYING A TISSUE DISTRIBUTION OF FLUOROCARBONS
SIMILAR TO THAT OF CHLOROFORM. /FLUOROCARBONS/ [Clayton, G. D.
and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology:
Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons,
1981-1982. 3076]
Ref: Hazardous Substances Data Bank for
1,1,1,2-TETRAFLUOROETHANE CASRN: 811-97-2. http://www.fluorideaction.org/pesticides/1,1,1,2-tetrafluoroe.toxnet.htm
3.2.5.1.2 Rabbit. In
an adequately conducted teratology study, pregnant Himalayan rabbits
(15/group) were administered transfluthrin (94% purity) in 0.5%
(v/v) aqueous Cremophor EM emulsion by gavage at doses of 0, 15,
50 and 150 mg kg d during days of 6-18 of gestation. Control animals
received vehicle alone... Dams were necropsied on day 29 of gestation
following delivery of the foetuses by caesarean section. Two deaths
occurred, one on day 18 at 50 mg kg d and one on day 19 at 150
mg kg d. Immediately prior to death both animals displayed symptoms
consistent with CNS involvement inclusing
spasms, severe tremor and prostration (animals found lying on
their side). Autopsy of these animals revealed an enlarged lobulated
liver and pale lobulated lungs at 50 mg kg d whereas no
pathological fingings were observed at 150 mg kg d.
Ref: Evaluation on: Transfluthrin Use as
a Public Hygiene Insecticide. September 1997. Prepared by: the
UK Health and Safety Executive, Biocides & Pesticides Assessment
Unit, Magdalen House, Stanley Precinct, Bootle, Merseyside L20
3QZ. Available from: Department for Environment, Food and Rural
Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool,
3 Peasholme Green, York YO1 7PX. UK. Also at http://www.pesticides.gov.uk/citizen/evaluations/165_confirm-box.htm
• Note:
This was transcribed from the copy available on the web. While
one can easily read this report on the web, the report is inaccessible,
or locked, to any attempt to copy it. Any errors are mine. EC.
Trichlorofluoromethane
- Insecticide, Fungicide, Propellant, US EPA List 2 Inert
- CAS No. 75-69-4
-- Health
Hazards - General. ...At high concentrations, Freon vapor
may cause pulmonary edema and neurological problems such as
central nervous system depression, dizziness, headache,
drowsiness, tremors, seizures, confusion, in-coordination, loss
of consciousness, and paralysis (Hazardtext, 2003B; Dupont, 1996A;
OSHA, 1998; NIOSH, 2003C).
-- Chronic effects ... Chronic Effects
Chronic use of Freon 11 has been linked to diseases of the mucous
membranes, lungs, and central nervous system
(Hazardtext, 2003B). In the occupational setting, chronic fluorocarbon
exposure has been associated with a syndrome of impaired psychomotor
speed, impaired memory and learning, and emotional
instability (Reprotext, 2003). Repeated or prolonged skin
contact may cause dermatitis (NIOSH, 2001E; NIOSH, 2001D).
-- Predisposing Conditions. Individuals
with pre-existing diseases of the central
nervous or cardiovascular system may have increased susceptibility
to the effects of Freons (Dupont, 1996A; OSHA, 1998; Dupont, 1996B;
Dupont, 1996D). Persons exposed to epinephrine or other sympathomimetic
amines, e.g., bronchodilators and nasal decongestants (e.g., Sudafed
¥), might be at increased risk for the cardiotoxic effects of
Freons (Reprotext, 2003).
-- Special Concerns for Children.
Children may inhale relatively larger doses of Freon because,
relative to their body weight, they have a greater lung surface
area and larger minute volume than adults. Since Freon has a high
vapor density, children could also receive high doses due to their
short stature and the higher levels of Freon vapor that may be
present near the ground when Freon is spilled.
Ref:
September 24, 2003 (Revised)
- FREON [11, 12, 113].
Technical Support Document: Toxicology. Clandestine
Drug Labs/ Methamphetamine. Volume 1, Number 11. California EPA,
Office of Environmental Health Hazard Assessment (OEHHA), Department
of Toxic Substances Control.
-- MAY BE /CENTRAL
NERVOUS SYSTEM DEPRESSANT/ ... IN HIGH CONCN. [Budavari, S. (ed.).
The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals.
Rahway, NJ: Merck and Co., Inc., 1989. 1517]
-- Workers ... /involved in a spill of/ large volume of CFC-11
were exposed to high concentrations and developed /CNS depressant/
effects. In one case, unconsciousness occurred, and in another,
potentiation of the endogenous adrenaline effect and tachycardia.
[WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons
p.93 (1990)]
-- Freons are toxic to humans by several mechanisms. Inhaled fluorocarbons
sensitized the myocardium to catecholamines,
frequently resulting in lethal ventricular arrhythmias. Because
they are gases heavier than air, fluorocarbons can displace atmospheric
oxygen, thus resulting in asphyxiation. These
compounds also have a central nervous system (CNS) anesthetic
effect analogous to a structurally similar general anesthetic,
halothane. Pressurized refrigerant or liquid fluorocarbons
with a low boiling point have a cyrogenic effect on exposed tissues,
causing frostbite, laryngeal or pulmonary edema, and gastrointestinal
perforation. Certain fluorocarbons degrade at high temperatures
into toxic products of chlorine, hydrofluoric acid, or phosgene
gases. /Freons/ [Haddad, L.M., Clinical Management of Poisoning
and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co.,
1990. 1281]
-- Non-occupational exposure and accidental or abusive inhalation
of aerosols /due to Fluorocarbon propellants/ have also been documented,
the main symptoms being CNS depression and
cardiovascular reactions. Cardiac
arrhythmia, possibly aggravated by elevated levels of catecholamines
due to stress or by moderate hypercapnia, is suggested as the
cause of these adverse response, which may lead to death. /Aerosols/
[WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons
p.20 (1990)]
Ref:
Hazardous Substances Data Base for TRICHLOROFLUOROMETHANE. http://www.fluoridealert.org/pesticides/Trichlorofluorometha.TOXNET.htm
-- Human Toxicity Values:
TCLO HUMAN INHALATION 4500 PPM; TOXIC EFFECT: CNS
EFFECTS [Sax, N.I. Dangerous Properties of Industrial Materials.
6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1458]
-- Animal Toxicity Studies: Non-Human Toxicity Excerpts: THE CHIEF
EFFECTS OF EXPOSURE TO ... /TRICHLOROTRIFLUOROETHANE/
ARE DEPRESSION OF THE CENTRAL NERVOUS SYSTEM
AND IRRITATION OF THE RESPIRATORY TRACT. SUCH EFFECTS OCCUR
IN ANIMALS AT CONCENTRATIONS ABOVE 12000 PPM. MILD LIVER CHANGES
HAVE BEEN NOTICED AT LEVELS SOMEWHAT BELOW THIS. [American Conference
of Governmental Industrial Hygienists. Documentation of the Threshold
Limit Values for Substances in Workroom Air. Third Edition, 1971.
Cincinnati, Ohio: American Conference of Governmental Industrial
Hygienists, 1971. (Plus supplements to 1979)267]
-- Psychomotor performance was evaluated using CFC-113
at concentrations of 0.15% (12 g/cu m), 0.25% (19 g/cu m), 0.35%
(27 g/cu m) or 0.45% (35 g/cu m) for 165 min. There was no effect
at the lowest concentration, but there was difficulty
in mental concentration and some decrease in test scores
beginning at 0.35% (27 g/cu m). [WHO; Environmental Health Criteria
113: Fully Halogenated Chlorofluorocarbons p.19 (1990)]
-- GUINEA PIGS EXPOSED ... FOR PERIODS OF 5 MINUTES TO 2 HOURS
SHOWED INCREASING SIGNS OF IRRITATION AND /CNS
DEPRESSION/; NASAL IRRITATION WAS APPARENT IN 5 MINUTES
AT 25000 PPM, AND LOSS OF COORDINATION AT 50000 PPM AFTER 30 MINUTES;
DEATHS OCCURRED AFTER 1 HOUR AT THIS LEVEL. [American Conference
of Governmental Industrial Hygienists. Documentation of the Threshold
Limit Values for Substances in Workroom Air. Third Edition, 1971.
Cincinnati, Ohio: American Conference of Governmental Industrial
Hygienists, 1971. (Plus supplements to 1979)267]
Ref:
Hazardous Substances Data Bank for 1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE
CASRN: 76-13-1. http://www.fluorideaction.org/pesticides/trichlorotrifluorome.toxnet.htm
-- Health
Hazards - General. ...At high concentrations, Freon vapor
may cause pulmonary edema and neurological problems such as
central nervous system depression, dizziness, headache,
drowsiness, tremors, seizures, confusion, in-coordination, loss
of consciousness, and paralysis (Hazardtext, 2003B; Dupont, 1996A;
OSHA, 1998; NIOSH, 2003C).
-- Predisposing Conditions. Individuals
with pre-existing diseases of the central
nervous or cardiovascular system may have increased susceptibility
to the effects of Freons (Dupont, 1996A; OSHA, 1998; Dupont, 1996B;
Dupont, 1996D). Persons exposed to epinephrine or other sympathomimetic
amines, e.g., bronchodilators and nasal decongestants (e.g., Sudafed
¥), might be at increased risk for the cardiotoxic effects of
Freons (Reprotext, 2003).
-- Special Concerns for Children.
Children may inhale relatively larger doses of Freon because,
relative to their body weight, they have a greater lung surface
area and larger minute volume than adults. Since Freon has a high
vapor density, children could also receive high doses due to their
short stature and the higher levels of Freon vapor that may be
present near the ground when Freon is spilled.
Ref:
September 24, 2003 (Revised)
- FREON [11, 12, 113].
Technical Support Document: Toxicology. Clandestine
Drug Labs/ Methamphetamine. Volume 1, Number 11. California EPA,
Office of Environmental Health Hazard Assessment (OEHHA), Department
of Toxic Substances Control.
Note
from FAN: We are including this under CNS even though no information
was presented to clarify the lesions.
Acute dietary (general
population) NOAEL = 600 mg/kg UF = 100. Acute RfD =6.0 mg/kg...
Special FQPA SF = 1 aPAD = acute RfD/Special FQPA SF = 6.0 mg/kg.
Acute Neurotoxicity Studies in Rats.
LOAEL = 2,000 mg/kg based on decreased motor activity on day 1
and histopathological lesions in nervous
system tissues of males and females.
Ref:
Federal Register: September 17, 2003 (Volume 68, Number 180)]
Rules and Regulations. Trifloxysulfuron; Pesticide Tolerance.
Final Rule. http://www.fluorideaction.org/pesticides/trifloxysulfuron.fr.sept.03.htm