Variation in red cell size. Normal red blood cells are 7
to 8 micrometers, and have an average volume of 90 fl, with
a normal range of 80-100 fl. RBCs which are smaller than
normal are termed microcytic (MCV 100). Macrocytic anemia
has many causes, including folate/vitamin B12 deficiency
and some drugs (e.g., methotrexate, Zidovudine (AZT), and
A mature red blood cell. SYN. haemacyte, hemacyte, red
blood cell, red corpuscle.•
is the process of red blood cell production (which occurs
in red bone marrow).•
(also known as a strawberry birthmark) is a type of birthmark
caused by an abnormal collection of abnormal blood vessels
just below the skin. http://www.heros.org.uk/health/health.ihtml?step=4&Healthpid=818
bodies Small irregular, deep purple granules in red
blood cells due to damage of the haemoglobin molecules.
Seen in premature infants, in certain forms of drug sensitivity,
characteristically in glucose-6-phosphate dehydrogenase
deficiency following administration of oxidant drugs, e.g.
primaquin. Also in certain type of hereditary haemolytic
anaemia, especially in patients with thalassaemia. The bodies
are best seen when the blood is stained with crystal violet.
Heinz reported these bodies in the blood of guinea pigs
treated with acetylphenylhydrazine. Also known as: Ehrlich's
bodies Ehrlich Innenkrper (German) Ehrlich hşmoglobinşmische
Innenkrper (German) Heinz-Ehrlich bodies http://www.whonamedit.com/synd.cfm/658.html
SYN hemopoietic (see below).
Pertaining to or relted to
the formation of blood cells. SYN haemoplastic, hematogenic
(1), hematogenous, hematoplastic, hematopoietic, hemogenic,hemoplastic,
system. the blood making organs;
in the embryo at different ages these are the yolk sac,
liver, thymus, spleen, lymph nodes, and bone marrow; after
birth they are principally the bone marrow, spleen, thymus,
and lymph nodes.•
Decrease in hemoglobin concentration per red cell. Morphologically,
this is reflected by increased size of the central pallor
of the RBC when observed on a peripheral blood smear. http://www.kumc.edu/instruction/medicine/pathology/ed/keywords/kw_hypochro.html
Histology ¥ a white or colorless cell of the blood, having
a nucleus and either granular or nongranular cytoplasm;
leukocytes function as bacterial or viral phagocytes, as
detoxifiers of toxic proteins, and in the development of
immunities. Also, WHITE BLOOD CELL. http://www.academicpress.com/inscight/10011998/leukocy1.htm
This brownish pigment is left over from the breakdown and
absorption of damaged blood cells. Lipofuscin is found in
heart muscle and smooth muscles and is also called the "aging"
A condition in which the iron in the hemoglobin molecule
(the red blood pigment) is defective, making it unable to
carry oxygen effectively to the tissues. http://www.nlm.nih.gov/medlineplus/ency/article/000562.htm
Anemia These are associated with an inability to
produce hemoglobin. Hemoglobin consists of iron inserted
into the prtoporphyrin ring complex to form heme which in
turn is inserted into the globin chain. Hence these anemias
are seen in: iron deficiency - absence of iron chronic disease
- iron unavailable thalassemia - inability to produce globin
chains sideroblastic anemia- inability to produce heme.
Blue-gray coloration of young (anucleate) red cells when
observed on a Wright-stained peripheral smear, due to the
presence of residual RNA in the cytosol of the immature
red cell. Polychromatic cells which are macrocytic suggest
that this cell is a reticulocyte. Increased polychromasia
occurs when the bone marrow releases immature RBC's into
the peripheral blood in response to stress such as a hemolytic
A morbid condition due to the presence of sulfmethemoglobin
in the blood; it is marked by a persistent cyanosis, but
the blood count does not reveal any special abnormality
in blood cells; it is thought to be caused by the action
of hydrogen sulfide absorbed from the intestine.•
Stedman's Concise Medical Dictionary
for the Health Professions. Illustrated, 4th ed
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
Food and Agricultural Organization of the United Nations
This is not an exhaustive list.
When time allows more information will be added.
- Fungicide - CAS No. 124495-18-7
-- 034 -
181176 ÒXDE-795: "One Year Chronic Dietary Toxicity Study
in Beagle Dogs," (Cosse, P.F., Stebbins,
K.E., Redmond, J.M., Ormand, J.R.; The Toxicology Research Laboratory,
Health and Environmental Sciences Ğ The Dow
Chemical Company, Midland, MI; Laboratory ID#: DR-0325-7474-011;
4/21/95). XDE-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline;
97.4% pure) was fed in diet to Beagle dogs (4/sex/dose) at 0,
5, 20 or 200 mg/kg/day for 1year. NOEL = 20 mg/kg (A male at 200
mg/kg was killed moribund, due to a severe
weight decrease (2 kg), decreased
hemoglobin and RBC counts. Both sexes had significantly
decreased body weights and food consumption
at 200 mg/kg. The report stated it was due to unpalatability of
diet at the high dose, which persisted throughout the majority
of the study. A treatment-related hematological
effect was observed in 1/sex at 200 mg/kg. Alkaline
phosphatase in both sexes at 200 mg/kg was statistically significantly
increased. Liver weights (absolute
& relative) were significantly increased in both sexes at 200
mg/kg. Statistically significantly increased relative organ
weights were observed in both sexes at 200 mg/kg (brain, kidney,
pituitary). Liver histopathology was observed
in 3/sex at 200 mg/kg, primarily in the midzonal region (diffuse,
increased size in hepatocytes, enlarged nuclei and prominent nucleoli).
At 200 mg/kg, 1/sex had increased hepatocyte size, increased bile
in centrilobular canaliculi. Possible adverse effect: At 200 mg/kg,
1/sex showed erythroid proliferation in spleen and liver, due
to treatment-related anemia.) Acceptable. M. Silva, 8/15/01
-- (90-day feeding
study) 031; 181173; "XR-795: 13-Week Dietary Toxicity Study
with 4-Week Study in Fischer 344 Rats" (Szabo,
R.A. et al., Health and Environmental Sciences-Texas, Lake Jackson
Research Center, The Dow Chemical
Company, Freeport, TX, Laboratory Project Study ID TXT: DR-0325-7474-005,
12/21/92). 821. XR-795 (TSN100010, DECO-104-116, purity
= 99.0%) was admixed to the diet at dose levels of 0 (untreated
diet), 10, 100, or 250 mg/kg/day and fed to 10 Fischer 344 rats
per sex per dose for 13 weeks (an additional 10 rats per sex per
dose at the control and high dose levels were included to test
for recovery for 4 weeks following dosing). No treatment-related
clinical signs were observed. A treatment-related increase in
mean relative liver weight was observed
at 100 and 250 mg/kg/day in animals of both sexes sacrificed after
13 weeks of treatment; in recovery group animals at 250 mg/kg/day,
a treatment-related increase in mean relative liver weight was
observed in males but not females. Microscopic examination revealed
treatment-related hepatocellular hypertrophy with
increased basophilia at 100 and 250 mg/kg/day in animals
of both sexes sacrificed after 13 weeks of treatment persisting
in recovery group males but not in recovery group females. No
adverse effects. NOEL (M/F) = 10 mg/kg/day (based on increased
mean relative liver weights and hepatocellular hypertrophy).
Unacceptable and not upgradeable because no ophthalmological examinations
were conducted. (Corlett, 9/5/01)
Ref: October 4, 2001. SUMMARY OF TOXICOLOGY
DATA QUINOXYFEN (XDE-795 & XR-795). California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
bifluoride - Insecticide, Former US EPA
List 3 Inert -
CHRONIC EXPOSURE -
Hydrogen fluoride and hydrofluoric acid are extreme irritants
to any part of the body that they contact. The main route of exposure
to hydrogen fluoride is inhalation, followed by dermal contact
for acute exposure and ingestion for chronic exposure. Symptoms
of the chronic effects of hydrofluoric acid include weight loss,
malaise, anemia, leukopenia, discoloration
of teeth, and osteosclerosis.
Definition of Leukopenia: an abnormal lowering of the white blood
Hazardous Substances Data Bank for SODIUM HYDROGEN DIFLUORIDE CASRN:
(Sodium Hexafluorosilicate) - Insecticiide;
Wood Preservative; EPA List 3 Inert - CAS No. 16893-85-9
-- Rats, oral; 248
mg/ kg (1.32 mmol/ kg) for 30 days intermittent; Toxic effects
in the kidney, ureter, and/ or bladder (other
changes in urine composition) were observed. Musculoskeletal (other
changes) and biochemical (enzyme inhibition, induction,
or changes in blood or tissue [phosphatases]
levels) effects were seen. RTECS* (1997)
-- Sheep, Awassi breed, 1- to 3- yr- old, 5F technical sodium
hexafluorosilicate, 25, 50, 200, 1500, and 2000 mg/ kg (0.13,
0.27, 1.06, 7.976, and 10.63 mmol/ kg) suspended in water; duration
and observation period n. p. With the 25- and 50- mg/ kg doses,
animals exhibited grinding of teeth (an indication of pain), dullness,
and mild diarrhea. At 200 mg/ kg, additional symptoms were experienced
and included staggering and severe diarrhea. Animals died on day
6. With the two higher doses, licking of the lips, kicking of
the belly, grinding of the teeth, falling down (after 1.5 h),
frothing at the mouth, congested conjunctiva,
protrudation of the tongue, forced and labored breathing, fever,
and increased respiration and heart rates were observed. Animals
died 3 h after administration of 1500 mg/
kg and 2.5 h after administration of 2000 mg/ kg. Post- mortem
examination showed serous pericardial fluid (few milliliters),
a slightly friable liver, mild edema in the lungs, and froth in
the trachea. Hemorrhages occurred on the spleen and mucosal folds
of the abomasum, and a gelatinous fluid was present in
the colon. For the 1500 mg/ kg- dose group, the change
in GOT went from 132% (of pretreatment activity) at 1.5 hours
to 230% at 2.5 hours. For LDH, the
change was 158% at death. The serum ICDH [isocitrate dehydrogenase]
change increased from 168% after one hour to 984% at death.
Egyed and Shlosberg (1975)
Ref: Review of Toxicological Literature.
October 2001. Sodium Hexafluorosilicate [CASRN 16893-85-9] and
Fluorosilicic Acid [CASRN 16961-83-4]. Prepared for Scott Masten,
Ph.D. National Institute of Environmental Health Sciences P.O.
Box 12233 Research Triangle Park, North Carolina 27709. Contract
No. N01-ES-65402. Submitted by Karen E. Haneke, M.S. (Principal
Investigator) Bonnie L. Carson, M.S. (Co-Principal Investigator)
Integrated Laboratory Systems P.O. Box 13501 Research Triangle
Park, North Carolina 27709.
- CAS No. 122836-35-5
-- A 1-year feeding
oral study was performed on dogs. The induction of normochromic
microcytosis in animals fed diets containing 1800 ppm test material,
although compensated by increased red cell production, reflects
an adverse treatment-related effect. The microcytosis may
have arisen from the inhibition of heme synthesis as indicated
by the presence of brown to yellow/brown pigmentation in hepatocytes
and reticuloendothelial cells of the liver. The microcytosis induced
by sulfentrazone justifies an oral LOEL of 61.2 mg/kg/day for
males and 61.9 mg/kg/day for females. The NOEL is 24.9 mg/kg/day
for males and 29.6 mg/kg/day for females.
-- A 18-month feeding/carcinogenicity study in mice resulted a
LOEL of 160.5 mg/kg/day in males and 198.0 mg/kg/day in females,
based upon treatment-related decreases in
hemoglobin and hematocrit. The NOEL is 93.9 mg/kg/day in
males and 116.9 mg/kg/day in females.
-- A developmental toxicity study in rats resulted in a maternal
(systemic) LOEL of 50.0 mg/kg/day based upon increased relative
spleen weight and splenic extramedullary hematopoiesis. The
maternal (systemic) NOEL is 25.00 mg/kg/day...
Ref: US EPA. Pesticide Fact Sheet. Sulfentrazone
Reason for Issuance: Registration of a New Chemical Date Issued:
February 27, l997.
-- 90-Day oral toxicity
rodents (mice) - [870.3100] NOAEL = 60 mg/kg/day for males and
79.8 mg/kg/day for females LOAEL = 108.4 mg/ kg/day for males
and 143.6 mg/kg/ day for females based on decreased body weights,
body weight gains, red blood cells, hemoglobin,
hematocrit, and severity of splenic micropathology (increased
incidence and severity of extramedullary hematopoiesis)
-- 90-Day oral toxicity in nonrodents (dogs) - [870.3150] NOAEL
= 28 mg/kg/day LOAEL = 57 mg/kg/ day for males and 73 mg/kg/day
for females based on decreased body weights (7-10%) and body weight
gains during first 5 weeks of study; decreased
hemoglobin, hematocrit, mean cell volume, mean cell hemoglobin
and mean cell hemoglobin concentration, and increased absolute
liver weights and alkaline phosphatase levels, and microscopic
changes in the liver and spleen (pigmented sinusoidal microphages
in the liver, swollen centrilobular hepatocytes and pigmented
reticuloendotheli al cells in the spleen)
-- Carcinogenicity mice - [870.4200] NOAEL = 93.9 mg/kg/ day for
males and 116.9 mg/kg/day for females LOAEL = 160.5 mg/ kg/day
for males and 198.0 mg/kg/ day for females
based on dose- related decreases in hemoglobin and hematocrit
by study termination. No evidence of carcinogenicity
-- Combined chronic toxicity/carcinogenicity rats - [870.4300]
NOAEL = 40 mg/kg/day for males and 36.4 mg/kg/day in females LOAEL
= 82.2 mg/kg/ day for males and 67 mg/kg/day for females based
on dose-related decreased body weights (11 and 19%), body weight
gains (13 and 26%), food consumption (13 and 19%), hemoglobin,
hematocrit, mean cell volume, and mean cell hemoglobin. Increased
nucleated red blood cells and reticulocytes in bone of females
at 124.7 mg/kg/ day. No evidence of carcinogenicity
Federal Register: September 24, 2003. Sulfentrazone; Pesticide
Tolerances. Final Rule.
insecticide - CAS No. 2699-79-8
Poisonings and fatalities have been reported in humans following
inhalation exposure to sulfuryl fluoride... A second person died
of cardiac arrest after sleeping
in the house overnight following fumigation. A
plasma fluoride level of 0.5 mg/L (10 times normal) was found
in this person following exposure. Prolonged chronic inhalation
exposure to concentrations of sulfuryl fluoride gas significantly
above the TLV of 5 ppm have caused fluorosis in humans because
sulfuryl fluoride is converted to fluoride anion in the body.
Fluorosis is characterized by binding of
fluoride anion to teeth (causing mottling of the teeth) and to
Federal Register: September 5, 2001 (Volume 66, Number 172). Sulfuryl
Fluoride; Proposed Pesticide Temporary Tolerances.
-- 2-Week inhalation study--dog
NOAEL = 26/27 (M/F) mg/kg/day
LOAEL = 79/80 (M/F) mg/kg/day based on intermittant tremors and
tetany during exposure, minimal inflammatory changes in upper
respiratory tract, decreased body weight (F only).
Note: Increased serum fluoride at >=
-- 90-Day inhalation
toxicity--mouse NOAEL = 38/36 (M/F) mg/kg/day
LOAEL = 125/121 (M/F) mg/kg/day
based on miscroscopic lesions in caudate-putamen nucleus and external
capsule of the brain, decreased body weight, decreased body weight
gain, follicular cell hypertrophy in thyroid.
Note: Increased serum fluoride at >=
23, 2004. Sulfuryl Fluoride; Pesticide Tolerance.
40 CFR Part 180 [OPP-2003-0373; FRL-7342-1]. Final Rule. Federal
(PTFE: polytetrafluoroethylene) - EPA List 3 Inert -
CAS No. 9002-84-0
Abstract: The cases of three patients with acute pulmonary oedema
caused by inhalation of fumes from heated polytetrafluoroethylene
(PTFE) in a plastic factory are described.
One patient died from profound hypoxemia
and shock shortly after admission, and the other two patients
survived after medical treatment. This is the first report of
fatal pulmonary oedema in a worker exposed
to PTFE heated in a plastic extruding operation. From
this observation, it appears that inhalation exposure to pyrolytic
products from polytetrafluoroethylene can cause fatal respiratory
complications. Special precautions are warranted in this kind
of operation to prevent workers from being exposed to these substances.
Ref: Fatal acute pulmonary oedema after
inhalation of fumes from polytetrafluoroethylene (PTFE) by LEE
CH, GUO YL, TSAI PJ, CHANG HY, CHEN CR, CHEN CW, HSIUE T-R. EUROPEAN
RESPIRATORY JOURNAL; 10 (6). 1997. 1408-1411.
Definition of hypoxemia: low blood oxygen: inadequate oxygen
in the blood
Abstract: A case of marked progression
of chronic obstructive pulmonary disease after several
episodes of occupational inhalation fever in a carding machine
operator was reported. The patient was a 45 year old male with
a history of exertional dyspnea who experienced recurrent episodes
of flu like symptoms beginning 2 weeks after starting work at
a synthetic textile plant. After approximately 9 months on the
job the patient was hospitalized with fever, chills, chest pain,
productive cough, and malaise that had not responded to antibiotic
treatment. A decreased white cell count
was seen along with evidence of moderately severe obstructive
disease. The patient returned to work after the acute symptoms
resolved; however, he experienced dyspnea
with mild exertion at this time. The flu like illnesses continued
to recur over the next 18 months at which time the patient stopped
working on the advice of his physician. He was hospitalized 1
month later with chest pain and diaphoresis. Severe obstruction
with a significant bronchodilator response was seen and he was
placed on disability leave. Polymer fume
fever due to exposure to polytetrafluoroethylene (9002-84-0) was
suspected as the cause of his illness. A subsequent
examination of the patient's workplace demonstrated that major
renovations had been done since his departure to improve chemical
contamination and air quality; however, potential for significant
exposures to formaldehyde (50000) were still evident. The authors
conclude that polymer fume fever may not always be a benign, self
limiting disease and may result in permanent airways damage. Long
term follow up is recommended.
Ref: Progression of Chronic Obstructive
Pulmonary Disease after Multiple Episodes of an Occupational Inhalation
Fever by Kales SN, Christiani DC. Journal of Occupational Medicine,
Vol. 36, No. 1, Grant No. T15-OH-07096, pages 75-78, 10 references,
at a polytetrafluoroethylene (9002-84-0) (PTFE) plastic production
plant were investigated to ascertain whether chronic exposure
to this chemical was correlated with changes in biochemical indicators
of toxicity. The exposed group comprised 129 workers (47 male
and 82 female), of mean age 33.5 years (yr) and mean exposure
period 8 months. A group removed from exposure was comprised of
32 workers (mean age 32.1yr) who had been exposed for a mean duration
of 2.2yr, but had left the workplace and had been unexposed for
more than 1yr (mean duration 1.8yr). A control group of 74 subjects
had been employed in nonproduction work at the factory for more
than 1yr and had never been exposed to the chemical. Urine and
blood samples were collected at the start of the workday. Inorganic
fluorides in urine were detected using an ion selective electrode
method, and blood cholinesterase (ChE) levels were determined
by colorimetry, using acetylthiocholine-iodide as substrate. Results
showed that the urinary inorganic fluorides in the exposed group
were significantly higher than in the controls. The group
removed from exposure was not tested. ChE activities of whole
blood, erythrocytes and plasma in the exposed group were higher
than those of the group removed from exposure group, and both
were significantly higher than those of the control group (23.2%,
17.5%, and 33.7% above control levels, respectively, in the exposed
group and 11.2%, 11.2% and 8.7% above control levels, respectively,
in the formerly exposed group). ChE activities
in males of the exposed group were much higher than in females;
whole blood, erythrocyte and plasma activities were enhanced by
22%, 22.5%, and 47.9%, respectively, in males, as opposed to 21.1%,
17.5% and 35.2%, respectively, in females. The authors
conclude that exposure to organic fluorides during PTFE production
results in a reversible increase in ChE activity in whole blood,
erythrocytes, and plasma, which may indicate a protective response
in the exposed worker. An increase in urinary
inorganic fluoride may be used as an indicator of exposure.
Ref: ELEVATED CHOLINESTERASE ACTIVITY
AND INCREASED URINARY EXCRETION OF INORGANIC FLUORIDES IN THE
WORKERS PRODUCING FLUORINE-CONTAINING PLASTIC POLYTETRAFLUOROETHYLENE
by XU B, ZHANG J, MAO G, YANG G, CHEN A, AOYAMA K, MATSUSHITA
T, UEDA A. BULL ENVIRON CONTAM TOXICOL; 49 (1). 1992. 44-50.
- Insecticide - CAS No. 79538-32-2
In a 3-month rat study,
dietary administration of 10 mg/kg/day produced plasma,
red blood cell, and brain cholinesterase inhibition.
The NOEL was 5 mg/kg/day. In a 6-month dog study, dietary administration
of 10 mg/kg/day (LOEL) produced plasma cholinesterase
inhibition. The NOEL was 1 mg/kg/day. In a 21-day rat dietary
study, administration of 20 mg/kg/day (LOEL for females) produced
decreased platelet counts, increased white
blood cell, lymphocyte, and neutrophil counts in males
and females. The NOEL for females was 5 mg/kg/day... EPA believes
that there is sufficient evidence for listing tefluthrin on EPCRA
section 313 pursuant to EPCRA section 313(d)(2)(B) based on the
available developmental, neurological, hepatic, and hematological
toxicity data for this chemical.
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
Tembotrione - Herbicide - CAS No. 335104-84-2
• This non-guideline study (MRID 46695732)  was performed to evaluate the effects of AE 0172747 on blood tyrosine levels in pregnant rabbits following administration by gavage from GD 6-28. AE 0172747 (Tembotrione) has been shown to inhibit 4- hydroxyphenylpyruvate dioxygenase (HPPDase). HPPDase is involved in L-tyrosine catabolism, and inhibition of this enzyme leads to an increase in systemic L-tyrosine concentrations. In this study, AE 0172747 (95.0% a.i.; Bacth # PFI 0195) in aqueous 0.5PFI 0195) in aqueous 0.5% methylcellulose was administered daily via oral gavage at a dose volume of 4 mL/kg to groups of 6 presumed pregnant New Zealand White (KBL [NZW]) rabbits/dose at dose levels of 0 or 10 mg/kg bw/day on gestation days (GD) 6-28. Clinical observations, body weights, and food consumption were recorded at regular intervals during treatment. Blood samples were taken from each animal on GD 4, 10, 15, 22, and 29, and the levels of tyrosine were determined. All surviving does were killed on GD 29 for examination of their uterine contents. Pre-treatment (GD 4) L-tyrosine levels were similar between the treated and control groups. Control group tyrosine levels also remained relatively constant throughout the study (GD 4-29). Animals treated with AE 0172747 displayed marked increases in blood tyrosine levels at all time points examined (39.33-98.93 mg/L) compared to controls (10.00-15.32 mg/L), and the changes in blood tyrosine levels relative to GD 4 were significantly (p≤0.01) higher than controls for all intervals measured during treatment (page 92).
• The dog appeared to be more sensitive to hematological effects. In the subchronic and chronic dog toxicity studies hematological changes indicative of anemia were seen [decreased mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV)]. Similar hematological effects were also observed in the chronic toxicity study in the mouse (page 6).
• Chronic/carcinogenicity mouse study. MRID 46695706 (2005). 0, 30, 300, 1000, or 3000 ppm. M: 0, 4, 43, 146, 440 mg/kg/day. F: 0, 5, 54, 179, 552 mg/kg/day. NOAEL was not established. LOAEL =M/F: 4/5 mg/kg/day based on based on gallstones, eosinophilic cytoplasmic alteration, subepithelial mixed cell infiltrate, and dilatation in/of the gallbladder; hepatocellular vacuolation, hepatocellular hypertrophy, and increased liver weight in males and females; and papillary mineralization of the kidney and changes in hematological parameters indicative of anemia in females (page 49).
• Inhibition of 4- Hydroxyphenylpyruvate Dioxygenase in Rats and In Vitro study. MRID 46695733 and 46695734 (2005). In vivo: 0, 10 mg/kg. AE0172747 (Tembotrione) increased plasma tyrosine levels by 20-fold. In vivo: AE1417286 increased plasma tyrosine levels by 5-fold.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.
NOTE ON TYROSINE: Tembotrione [FLUORINATED], mesotrione, pyrasulfotole [FLUORINATED], isoxaflutole [FLUORINATED] and topramezone belongs to a class of herbicides that inhibit the liver enzyme HPPD, which is involved in the catabolism (metabolic breakdown) of tyrosine (an amino acid derived from proteins in the diet). Inhibition of HPPD can result in elevated tyrosine levels in the blood, a condition called tyrosinemia (see Note 2 below). HPPD- inhibiting herbicides have been found to cause a number of toxicities in laboratory animal studies including ocular, developmental, liver and kidney effects. Of these toxicities, it is the ocular effect (corneal opacity) that is highly correlated with the elevated blood tyrosine levels. In fact, rats dosed with tyrosine alone show ocular opacities similar to those seen with HPPD inhibitors. Although the other toxicities may be associated with chemically-induced tyrosinemia, other mechanisms may also be involved.
There are marked differences among species in the ocular toxicity associated with inhibition of HPPD. Ocular effects following treatment with HPPD-inhibitor herbicides are seen in the rat, but not in the mouse. Monkeys also seem to be recalcitrant to the ocular toxicity induced by HPPD inhibition. The explanation of this species-specific response in ocular opacity is related to the species differences in the clearance of tyrosine. A metabolic pathway exists to remove tyrosine from the blood that involves a liver enzyme called tyrosine aminotransferase (TAT). In contrast to rats where ocular toxicity is observed following exposure to HPPD-inhibiting
herbicides, mice and humans are unlikely to achieve the levels of plasma tyrosine necessary to produce ocular opacities because the activity of TAT in these species is much greater compared to rats. Thus, humans and mice have a highly effective metabolic process for handling excess tyrosine. (page 37 )
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.
NOTE 2: TYROSINEMIA. Elevated blood tyrosine levels are associated with several clinical entities. The term tyrosinemia was first given to a clinical entity based on observations (eg, elevated blood tyrosine levels) that have proven to be common to various disorders, including transient tyrosinemia of the newborn (TTN), hereditary infantile tyrosinemia (tyrosinemia I), Richner-Hanhart syndrome (tyrosinemia II), and tyrosinemia III. In addition, a mysterious entity called tyrosinosis has been described once in the literature. This designation was chosen at a time when specific enzymatic diagnosis was unavailable, leaving a clinical description that has not been duplicated in the 50 years since its publication.
Transient tyrosinemia is believed to result from delayed enzyme maturation in the tyrosine catabolic pathway. This condition is essentially benign and spontaneously disappears with no sequelae. Transient tyrosinemia is not categorized as an inborn error of metabolism because it is not caused by a genetic mutation.
Hereditary infantile tyrosinemia, or tyrosinemia I, is a completely different disease. Patients have a peculiar (cabbagelike) odor, renal tubular dysfunction (Fanconi syndrome), and survival of less than 12 months of life if untreated. Fulminant onset of liver failure occurs in the first few months of life. Some patients have a later onset, usually before age 6 months, with a somewhat protracted course.
For many years, the diagnosis was based on the observation that plasma tyrosine and methionine levels were significantly elevated. Postmortem examination revealed that both the liver and the kidney had a highly unusual pattern of nodular cirrhosis, the histopathologic hallmark of the disease. In the early 1970s, researchers discovered that most severe liver diseases caused such findings regardless of etiology, and, in the late 1970s, the biochemical and enzymatic causes of the disease were reported.
Tyrosinemia II is a disease with a clinical presentation distinctly different from that described above. This presentation includes herpetiform corneal ulcers and hyperkeratotic lesions of the digits, palms, and soles, as well as mental retardation. The biochemical and enzymatic basis for the disease bears no relationship to that of tyrosinemia I, and tyrosinemia II is not discussed further in this article.
Tyrosinemia III is an extremely rare cause of intermittent ataxia, without hepatorenal involvement or skin lesions, and is also not discussed further in this article.
Reference: Tyrosinemia by Karl S. Roth, MD. http://www.emedicine.com/ped/topic2339.htm
- Fungicide - CAS No. 112281-77-3
• Chronic & Carcinogenicity Studies.
Dogs received 0, 22.5, 90 or 360 ppm of tetraconazole in the diet
for 1 year. Some dogs of each group including control suffered
body weight loss which was more pronounced at 360 ppm. In dogs
at 360 ppm, prolonged activated partial
thromboplastin times, lower albumin and higher globulin and cholesterol
levels, and increased AP, ALT, gamma glutamyl transferase and
ornithine carbamoyl transferase activities, as well as increased
inorganic phosphorus were observed.
-- Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to
males only) of tetraconazole in the diet for 2 years; Mortality
and body weight gain were lower at 640 and 1280 ppm. Slight
anemia at 640 and erythrocyte counts. (page 5)
• Sub-chronic studies. Rats
received 0, 10, 60 or 360 ppm of tetraconazole in the diet for
13 weeks. Slightly lower AP, ALT and AST,
and slightly higher cholesterol and calcium levels (males) were
observed at 360 ppm, and some of these changes
also occurred at 60 ppm.
-- Mice received 0, 5, 25,
125 or 625 ppm of tetraconazole in the diet for 13 weeks. In males
at 625 ppm and females at 125 and 625 ppm, decreased
BUN was detected, and elevated alanine aminotransferase (ALT)
and AST activities were associated
with increased liver weights. (page 4)
Short Term Studies. Male rats received 0, 2, 5, 15 or 40 ppm of
tetraconazole in the diet for 4 weeks. No treatment-induced changes
were observed except for increased plasma
aspartate aminotransferase (AST) and glutamate dehydrogenase at
40 ppm. (page 4)
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
Hematological changes, including slightly decreased hemoglobin
and/or hematocrit, have also been seen in multiple studies and
species (in rats at doses of 33 mg/kg/day and above, and in mice
at doses of 487 mg/kg/day and above). Studies depicting the effects
of chronic exposure to free triazole or its conjugates are not
Health Aggregate Risk Assessment for Triazole-derivative Fungicide
Compounds (1,2,4-Triazole, Triazole Alanine, Triazole Acetic
Acid). US EPA, February 7, 2006.
(HFC-134a) - Propellant, US
EPA List 4B Inert - CAS No. 811-97-2
Subject #3 was the first volunteer exposed to HFC-134a.
The exposure concentration was 4000 ppm (0.4% v/v) and was scheduled
to last for 30 minutes with a 5-minute postexposure evaluation
period as was accomplished in the Halon 1301 portion of the study.
Approximately 4.5 minutes into the exposure,
the subject lost consciousness and both pulse and blood pressure
dropped to zero. The exposure was immediately aborted and
the subject was removed from the exposure apparatus. Medical personnel
intervened and after pulse and blood pressure
were restored the subject was administered 100% oxygen. Blood
pressure and pulse remained low (approximately 1/2 of baseline)
and the subject could not maintain consciousness in a seated position.
The subject was reclined and moved to an operating room recovery
area where he rested for approximately 1 hour after which the
subject's vital signs had returned to pre-exposure values.
Subject #3 displayed a rapid rise in blood concentration of HFC-134a
which reached 1.29 mg/L at the 2.5 minute point in the exposure
(Figure 3). The blood sample scheduled for 3 minutes was not collected.
The medical representative had considerable difficulty getting
blood from the cannula at the 3-minute point and significant manipulation
of the indwelling cannula was noted. No further blood samples
were taken. Subject #5 was also exposed
to 4000 ppm (0.4% v/v) HFC-134a. There was some difficulty
with blood collection and manipulation of the cannula was noted,
but exposure was uneventful through the first 10 minutes of exposure.
Breathing effort and rate appeared normal.
At approximately 10.5 minutes into the exposure the subject's
blood pressure and pulse began to rise rapidly and the subject
gave the hand signal for possible trouble. His
pulse rose rapidly until it was double the pre-exposure value,
at which time the subject gave the hand signal to terminate the
exposure. The exposure
was aborted and the subject began breathing room air, but the
in-dwelling cannula was not removed from the subject. After 30
seconds, the subject's blood pressure and pulse were at pre-exposure
levels. The HFC-134a concentration in blood reached 0.70 mg/L
at the point where the exposure was terminated (Figure 3).
Subject #5 breathed room air for 1 hour and was then re-exposed
to 2000 ppm (0.2% v/v) HFC-134a. After 2.5 minutes of exposure,
the subject's blood pressure and pulse again
rose rapidly, the subject signaled trouble and the exposure was
terminated. The subject's
vital signs returned to pre-exposure levels within 30 seconds
after the exposure was terminated. The in-dwelling cannula remained
attached to the subject and blood was drawn for an additional
10 minutes at 1-minute intervals. The venous blood concentration
of HFC-134a was 0.16 mg/L at the start of the 2000 ppm exposure
and reached 0.38 mg/L at the time of exposure termination (Figure
3). The HFC-134a concentration was still at 0.2 mg/L 10 minutes
after the exposure was terminated. No further human HFC-134a exposures
were conducted. In addition to the monitored effects, there were
several subjective effects associated with the inhalation exposures
to HFC-134a. Subject #3 reported problems
with dizziness and balance following the exposure. At the time
of this report (6 weeks post exposure), both the dizziness and
balance problems still persisted.
Subject #5 reported chest tightness and a headache with associated
dizziness immediately following the exposure. The headache subsided
by the time the subject woke up the day following the exposure.
The day following the exposure, subject #5 reported unusual feelings
in the chest resembling "flutters". The chest tightness was reported
to subside within 3 days of the exposure and the "flutters" within
2 weeks of the exposure. As with subject #3, subject #5 was still
experiencing dizziness and balance problems at the time of this
report (6 weeks post exposure). Subject #5 also reported persistent
ringing in the ears which was still present at the time of this
report. The adverse events observed during the exposures
to HFC-134a and HFC-227ea were unexpected and inconsistent with
the published data. Based on the published
data on HFC-134a and HFC-227ea, no adverse effects should have
been observed at the 0.4% v/v and 0.6% levels, respectively, used
in this study. Both HFC-134a and HFC-227ea have been considered
to be inert compounds which exert toxic effects only after their
concentrations are so high that oxygen depravation effects prevail
(Graepel and Alexander, 1991)...
Rats and mice have shown no acute toxicity during or after a 1-hour
inhalation exposure to 810,000 ppm HFC-134a and dogs were essentially
unaffected following an 80,000 ppm exposure (Alexander,
1995). Based on the laboratory animal data, Alexander,
1995, concluded that HFA-134a is devoid of acute and long
term toxicity, is poorly absorbed and is rapidly excreted. In
addition to the claims of inertness, the chemicals of interest
have been reported to rapidly leave the human system with an apparent
half-life of only 5.1 minutes (Harrison,
1996). Similarly, another report states that only 10% of
the administered dose of HFC-134a remained 10 minutes after termination
of the exposure (Woodcock, 1995).
The 5.1 minute half-life for HFC-134a and extremely rapid elimination
is in contrast to the 31 minute apparent half-life reported as
part of a clinical pharmacology study (Ventresca,
1995). While the sample size was extremely small in our
study due to unplanned termination, the apparent half-lives of
HFC-134a and HFC-227ea are estimated to be 12.6 and 7.5 minutes,
respectively (Figures 2 and 3). This probably represents only
the rapid elimination phase since data were not available to assess
any slower elimination phases that may be present. As such, the
half-life estimates could be quite low especially since
measurable levels of HFC-134a were present 1 hour after
the exposure was terminated (Figure 2). The
presence of HFC-134a in the blood 1 hour after exposure was unexpected.
Alexander, 1995, reported that there was no carry over in blood
after 30 minutes. Halon 1301 cleared more rapidly with an estimated
half-life of 3.6 minutes. Based on published
work, regulatory approval and commercial use of Halon 1301, HFC-134a
and HFC-227ea, the exposure levels selected for the 30-minute
inhalation exposures were expected to be without adverse effects
in humans. Since the study was designed to collect only
kinetic information for use in PBPK model validation and only
at "no effect" concentration levels, clinical type experimental
design was not adopted. Additionally, the subjects participating
in the study were scientists or technicians and they were knowledgeable
about the study results as they occurred... In summary, all 7
human volunteers completed the Halon 1301 exposures without incident
while both the HFC-134a and HFC-227ea exposures were terminated
due to the adverse effects described in this report. Additionally,
no adverse effects were reported during "blank" exposures where
all conditions were the same as in chemical exposures except the
test material was air. Based on the chemical similarity between
HFC-134a and HFC-227ea and the similar human responses during
the exposures, it became the opinion of the investigators that
further exposures would constitute a study of human effects rather
than simply of kinetics. Given this opinion, the study was terminated.
In view of the sample size and experimental design, no conclusion
or speculation about cause and effect is offered at this time.
Rather, the purpose of this document is to report the unexpected
events that occurred during human inhalation of HFC-134a and HFC-227ea
under controlled conditions.
Human Inhalation of Halon 1301, HFC-134a and HFC-227ea for Collection
of Pharmacokinetic Data.
- also available at http://www.autofrost.com/r134atox.txt
- Herbicide - CAS No. 117718-60-2
-- Thiazopyr technical
produced organ toxicity following multiple exposures at high doses.
The primary target organs for thiazopyr toxicity in the rat, mouse
and dog were the liver, thyroid, kidney
and blood, with the
liver being the most sensitive indicator of toxicity. In
chronic dietary feeding studies, the dog was the most sensitive
species. An RfD for thiazopyr of 0.008 mg/kg/day was established
by the RfD Committee of the USEPA Health Effects Division, based
on the NOEL of 0.8 mg a.i./kg/day (20 ppm) from the chronic dog
study and a 100-fold safety factor to account for intraspecies
extrapolation and intraspecies variability.
-- 90-day Oral (Rat): NOEL (systemic) =100 ppm (6.60 mg /kg/day
and 7.99 mg/kg/day for males and females, respectively). The LOEL
was 1000 ppm (68 - 79 mg/kg/day in males and females, respectively)
based on increased liver, thyroid and kidney
weights, changes in clinical chemistry and hematological
parameters and on gross and microscopic
changes observed in the liver and thyroid at does levels of 68
mg/kg/day and higher. At the 201 mg/kg/day dose diffused thyroid
follicular cell hypertrophy/ hyperplasia was observed.
-- 90-day Oral (Dog): NOEL (systemic) =10 ppm. (0.2 mg/kg/day(m);
0.3 mg/kg/day(f)), based on decreased body
weight gain and increased SGPT [serum
glutamic-oxaloacetic transaminase] levels at 3 and 6 m/kg/day
for males and females, respectively and above; decreased total
protein and albumin concentration and albumin/globulin ratio,
increased AP, hepatocytic hypertrophy, oval cell proliferation
and increased hepatocytic fatty content at 35 mg/kg/day and above;
and decreased calcium concentration which is thought to be related
to hypoalbuminemia, decreased cholesterol
and triglyceride concentrations, slightly increased GGT and SGPT,
follicular hyperplasia of thyroid, increased colloid content in
follicles and increased relative thyroid weight at 175 mg/kg/day.
-- A 1 year feeding study in dogs at 0, 0.8, 7.8, 86.0 with males,
and 0.8, 8.8, and 78.0 with females with a NOEL of 0.8 mg/kg/day.
The Loel was based on hepatocellular hypertrophy and hyperplasia.
A 10% increase in prothrombin time and several and several
changes in blood chemistry: increased
SGOT, SGPT, GGT and ALK levels and
decreased cholesterol, albumin and total protein and calcium were
observed in high- dose dogs. There were increases in absolute
weights, liver and body weight and liver to brain weight,
heptotoxicity characterized by enlargement and/or discoloration
in some high dose animals and by hepatocellular hypertrophy/hyperplasia
in the 0.8 and 7.8 mg/kg/day dogs. The NOEL was based on hepatocellular
hypertrophy and hyperplasia.
-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4,
44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1
mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were
protruding eyes, evidence of mild anemia, increased
GGT and cholesterol,
increased absolute and relative liver, kidney
and thyroid weights and significant increase in microscopic lesions
in the liver (hypertrophy and vacuolar changes), kidney (nephropathy)
and thyroid (hypertrophy and hyperplasia); decreased mean body
weight and body weight gain and food consumption. A statistically
significant increase in thyroid follicular cell adenomas/cystadenomas
were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant
increase in renal tubular adenomas in high-dose females
was considered to be equivocal.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr
Reason for Issuance: Registration of a New Chemical Date Issued:
February 20, l997.
- Herbicide - CAS No. 199119-58-9
The main hazards associated with repeat exposure to product are
systemic effects (effects on liver, haematopoietic
system and testes). No worker exposure data were available
for trifloxysulfuron sodium or ENVOKE HERBICIDE. NOHSC used UK
POEM to estimate mixer/loader and applicator exposure. The repeat
dose risk assessment indicated that workers should wear elbow-
length PVC gloves when preparing spray.
-- Dogs were given trifloxysulfuron at doses of 0, 50, 200 or
500 mg/kg bw/day in gelatin capsules for 28 days. There were no
mortalities, changes in food consumption, clinical signs of toxicity
or effects on body weight gain. A white material in the faeces
of animals at 500 mg/kg bw/day was confirmed by analysis to be
the test material. Red blood cell count,
haematocrit, haemoglobin, platelet counts and clotting times,
plasma bilirubin, protein and albumin were lower and globulin
and chloride were higher in both sexes at 500 mg/kg bw/day. Plasma
bilirubin was also lower in females at 200 mg/kg bw/day and plasma
potassium and calcium were lower in males at 500 mg/kg bw/day...
Ref: August 2002 -
Evaluation of the new active Trifloxysulfuron-sodium in the product
ENVOKE HERBICIDE. Public Release Summary.
National Registration Authority for Agricultural and Veterinary
Chemicals 2002 ISSN1443-1335.
-- Subchronic toxicity.
Trifloxysulfuron-sodium technical was evaluated in a number of
subchronic studies. In a 3-month rat
feeding study the NOAEL was 65.7 mg/kg with
hematologic and liver effects noted. In a 3-month
mouse feeding study, the NOAEL was 67.9 mg/kg. Effects seen were
adaptive liver effects. In a 3-month feeding study in dogs
the NOAEL was 19.6 mg/kg and
hematopoietic and liver effects were seen. In a 28-day
dermal (rat) study, the NOAEL was 100 mg/kg. In this study only
body weight effects were noted, and only occurred at 1,000 mg/kg.
-- Chronic toxicity. Trifloxysulfuron-sodium technical was not
oncogenic in rats or mice. In a 12-month feeding study in dogs
fed diets containing trifloxysulfuron-sodium that resulted in
average (sexes combined) daily test substance intakes of 0, 1.67,
6.71, 15.0, 48.2 or 122 mg/kg/day, all animals survived...
There was a tendency for a decrease
in the erythrocyte count, hemoglobin concentration and hematocrit
for both sexes at 122 mg/kg/day at the end of treatment, and for
males throughout the treatment period... Administration
of trifloxysulfuron-sodium to dogs for 12
months caused a tendency for decrease
in red blood cell parameters in both sexes at 122 mg/kg/day.
There was neither histopathological nor functional evidence for
compound related neurotoxicity. Based on the effects at 48.2 and
122 mg/kg/day, the NOAEL was established
at 15.0 mg/kg/day for males and 14.9 mg/kg/day for females.
Federal Register: March 21, 2003. Trifloxysulfuron-sodium; Notice
of Filing a Pesticide Petition to Establish a Tolerance for a
Certain Pesticide Chemical in or on Food.
- Insecticide - CAS No. 64628-44-0
effects of five benzoylphenylurea insecticides, diflubenzuron
(35367385), flufenoxuron (101463698), hexaflumuron (86479063),
teflubenzuron (83121180), and triflumuron
(64628440) were comparatively evaluated on hematological
parameters in rats. Sixty adult Wistar-rats were divided into
five dose groups and a control group. Daily doses of 100mg/kg
of each tested insecticide were administered by gavage for 28
days, after which rats were sacrificed and blood was taken for
examination. Parameters measured were red blood cell count, hemoglobin
(Hb), hematocrit, mean corpuscular volume, mean corpuscular Hb
concentration, methemoglobin (metHb), and reticulocyte counts.
Results showed that treatment with insecticides at the dose given
did not produce any overt signs of toxicity. However, with regard
to hematological parameters, both diflubenzuron and triflumuron
induced elevated metHb levels. The no observed effect level for
metHb was 45mg/kg. The reticulocyte level was increased in all
treated groups, even at dose levels of 50mg/kg. The authors conclude
that the metHb level increase and reticulocyte increase are the
most sensitive parameters, but that one might be independent of
1993. J Appl Toxicol; Jan-Feb;13(1):67-8. Comparative study on
the effects of five benzoylphenylurea insecticides on haematological
parameters in rats, by Tasheva M, Hristeva V.
- Herbicide - CAS No. 1582-09-8
excretion and metabolism in mammals (Annex IIA, point 5.1). Widely
distributed; highest concentration in adrenals, fat, kidneys,
liver, skin and blood (page 45)
March 14, 2005. European
Food Safety Authority:
Conclusion regarding the peer review
of the pesticide risk assessment of the active substance trifluralin.
EFSA Scientific Report (2005) 28, 1-77.
of trifluralin are associated with increases in kidney, bladder,
and thyroid tumors. Dogs chronically exposed to trifluralin in
their diet showed decreased weight gain, changes in hematological
parameters, and increased liver weight.
Skeletal abnormalities were observed in the offspring of
mice exposed via gavage (experimentally introducing trifluralin
into the stomach). The RfD for trifluralin is based on increased
liver weights and an increase in methemoglobinemia
Ref: March 2000.
Health Assessment Cenex Supply and Marketing, Inc. Quincy, Washington.
CERCLIS #WAD058619255. Draft for Public Comment.. Prepared by:
Washington State Department of Health Under Cooperative Agreement
with the Agency for Toxic Substances and Disease Registry. Also
available at http://www.doh.wa.gov/ehp/oehas/Cenex%20PHA%20Draft%20Public%20Review.pdf
Teratology - rat: Maternal
NOEL=100 mg/kg/day; Maternal LEL=500 mg/kg/day (decreased food
consumption and increased liver and spleen weights); Developmental
NOEL=none; LEL=20 mg/kg/day (reduced skeletal
maturity and increased vascular
fragility); core grade supplementary (Hoechst Aktiengesellschaft,
Ref: US EPA IRIS for Trifluralin CASRN: 1582-09-8.
• Vascular: pertaining to blood
aniline - Intermediate
for herbicides (eg, Fluometron & Norflurazon),
and pharmaceuticals, Breakdown product - CAS No. 98-16-8
HEMATOLOGIC. ACUTE EXPOSURE. Methemoglobinemia
is a possibility with exposure to m-trifluoroaniline.
-- CHRONIC EXPOSURE. Methemoglobin
was evident in rats exposed to m-trifluoromethylaniline for five
months... No reproductive studies were found. Methemoglobin inducers
are considered especially dangerous to the fetus.
-- ACUTE EXPOSURE. m-Trifluoromethylaniline is toxic by the oral,
inhalation, dermal, or IP routes.
Ref: TOXNET profile from Hazardous Substances
of this criteria document: 3-trifluoromethylaniline has been show
to irritate the skin and mucous membranes.
Animal experiments show it to be a strong, indirect methaemoglobin-forming
title: 3-Trifluoromethylaniline (3-trifluoromethylbenzeneamine).
Name: Gesellschaft Deutscher Chemiker (GDCh) - Advisory Committee
on Existing chemicals of Environmental Relevance (BUA).
Source: VCH Verlagsgesellschaft mbH, D-W-6940 Weinheim, Germany,
1991. 43p. Bibl.ref.Language: English.
As cited on Toxline at Toxnet.
- CAS No. 126535-15-7
NOAEL = 2.44 mg/kg/day LOAEL = 30.6 mg/kg/day based on decreased
body weight and body weight gain, alteration
in hematology (mainly males) and increased
incidences of interstitial cell hyperplasia in the testes. (Possible)
evidence of carcinogenicity
Ref: Federal Register: June 12, 2002 (Volume
67, Number 113). Triflusulfuron Methyl; Pesticide Tolerance. Final
CHRONIC STUDIES: Triflusulfuron
methyl Chronic Feeding Study in Rats - Non-oncogenic in female
rats. Increased incidence of Leydig cell adenomas were observed
in males following chronic and excessive exposures at 750 and
1500 ppm. The NOELs for male
and female rats were 100 and 750
ppm, respectively. These were based on increased adenomas
and reduced circulating red cell mass among
higher-dosed males and reduced body weights and increased
incidence or severity of species- and age-specific effects among
male and female rats at higher doses...
Nov 2001 - Material Safety Data Sheet for DuPont "UPBEET" HERBICIDE.
In another 90-day subchronic
study, dogs were fed dosages of 3.87, 146.1, or 267.6 mg/kg/day
(males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron
methyl was found to be hepatotoxic at 4,000 ppm (146.1 mg/kg/day
males and 159.9 mg/kg/day females), and greater elevated hepatic
enzyme levels and postmortem evidence, including elevation in
liver weights and microscopic evidence of bile stasis. Other microscopic
findings considered to be treatment related were testicular atrophy
and decreased testicular weights and hypercellularity
of the sternal and femoral bone marrow, with a corresponding increase
in reticulocyte and leukocyte counts seen in the high-dose
males and females. Based on the microscopic findings in the liver
and testes of the 4,000 ppm and greater treated animals, the NOAEL
was 3.87 mg/kg/day (males) and 3.72 mg/kg/day (females).
Ref: Federal Register. August 8, 2001. [PF-1036;
- Antifoulant, Algaecide, Herbicide - CAS No.
Abstract: Recent work in our laboratory has shown that oral administration
of triphenyltin fluoride (TPTF) evokes hypertriglyceridemia
in rabbits. The present experiments were conducted to elucidate
the mechanism of TPTF-induced hypertriglyceridemia in rabbits
by a combined biochemical and ultrastructural approach. After
a single TPTF administration, fasting blood glucose and plasma
triglyceride levels increased significantly (P less than 0.02)
for about 20 days. On the other hand, both plasma and adipose
tissue lipoprotein lipase (LPL) activity was markedly decreased
(P less than 0.001) during this period, and triglyceride production
rates on day 2 after TPTF administration was significantly decreased
(P less than 0.01). Density-gradient ultracentrifugation showed
a remarkable accumulation of chylomicron and VLDL in the composition
of plasma lipoproteins. Insulin injection to the hypertriglyceridemic
rabbits induced a significant recovery of the decreased plasma
LPL activity with a concomitant decrease of plasma triglyceride
levels, while abeyance of insulin injection resulted in a decrease
of LPL activity again. A significant inhibition of insulin release
in response to the loading of glucose, glucagon, or arginine was
observed in the TPTF rabbits (P less than 0.02). Inhibition of
glucagon release was also observed in the arginine-loading test
(P less than 0.01). Electron microscopic studies showed small
abnormalities in the pancreatic islets of TPTF-treated rabbits.
These findings suggest that TPTF inhibits
insulin release from rabbit islets, subsequently inducing diabetic
lipemia due to the insulin deficiency. Furthermore, it is possible
to provide a new animal model for diabetes and diabetic lipemia
by administration of TPTF to rabbits.
Ref: Diabetes 1981 Dec;30(12):1013-21.
fluoride (TPTF) as a diabetogenic agent. TPTF induces diabetic
lipemia by inhibiting insulin secretion from morphologically intact
rabbit B-cell. Manabe S, Wada O.
of hypertriglyceridemia: Condition of elevated triglyceride
concentration in the blood; an inherited form occurs in familial
hyperlipoproteinaemia IIb and hyperlipoproteinaemia type IV.
It has been linked to higher risk of heart disease and arteriosclerosis.
•• see National
Institutes of Health Consensus Development Conference Statement
on Hypertriglyceridemia, September 27-29, 1983
Recent studies have demonstrated
that triphenyltin fluoride (TPTF)
inhibits collagen-induced aggregation and ATP secretion of rabbit
platelets in vivo [S. Manabe and O. Wada, J. Toxic. Sci. 6, 236
(1981)]. The aim of the present investigation was to test the
effects in vitro of TPTF on platelet aggregation and to elucidate
the mechanism of the inhibitory action by studying the release
and metabolism of arachidonic acid and the cyclic AMP contents
of rabbit platelets treated in vitro with TPTF. Although no inhibitory
effect of TPTF was found on sodium arachidonate-induced platelet
aggregation and ATP secretion, TPTF inhibited both reactions induced
by collagen. Triphenylarsine and triphenylantimony did not inhibit,
even at a concentration of 10(-3) M. The anti-aggregating concentration
(IC50) of TPTF was 6.0 x 10(-6) M against collagen. TPTF had no
inhibitory effect on the conversion of exogenous arachidonic acid
to malondialdehyde (MDA) by platelets, while the collagen-induced
production of arachidonate metabolites [MDA, 12-L-hydroxy-5,8,10-heptadecatrienoic
acid (HHT) and thromboxane B2] was remarkably inhibited by TPTF.
Furthermore, TPTF apparently inhibited the collagen-induced release
of arachidonic acid from platelets, although the formation of
phosphatidic acid was not inhibited. Total cyclic AMP content
after TPTF exposure was not changed significantly. These
results indicate that TPTF inhibited the collagen-induced arachidonic
acid release from platelet phospholipids, presumably by acting
on phospholipase A2. Furthermore, it seems unlikely that the inhibition
of arachidonic acid release by TPTF can be explained by the level
of cyclic AMP in platelets.
Ref: Triphenyltin fluoride
in vitro inhibition of rabbit platelet collagen-induced aggregation
and ATP secretion and blockade of arachidonic acid mobilization
from membrane phospholipids; by S Manabe et al. Biochem Pharmacol
1983 May 15;32(10):1627-34.
Recent studies have demonstrated that triphenyltin fluoride (TPTF),
widely used as an agricultural chemical and a marine antifoulant,
inhibits collagen-induced platelet aggregation and ATP secretion
in rabbits ex vivo. The aim of the present investigation was to
elucidate the mechanism of the inhibitory action of TPTF by investigating
platelet malondialdehyde (MDA) formation, aggregation and ATP
secretion following the stimulation by various stimuli of rabbit
platelets treated in vitro with TPTF, other triphenyl metals and
aspirin. Although no inhibitory effect of TPTF was found on sodium
arachidonate-induced platelet aggregation and ATP secretion, TPTF
inhibited dose-dependently both platelet aggregation and ATP secretion
induced by collagen. The antiaggregating (IC50) concentration
of TPTF was 6.0 X 10(-6) M against collagen. In addition, TPTF
prevented the collagen-, and thrombin-induced formation of MDA,
but had little inhibitory effect on the conversion of exogenous
arachidonic acid to MDA in platelets. In contrast, aspirin (10(-3)
M) inhibited platelet aggregation, ATP secretion and MDA formation
induced by all the stimuli tested. Other triphenyl metals did
not any inhibitory effect on collagen-, and sodium arachidonate-induced
platelet aggregation and ATP secretion even at a final concentration
at 10(-3) M. These results suggest that
TPTF has a specific inhibitory effect on platelet aggregation
and ATP secretion by acting at some step(s) of platelet membrane
between the binding site of collagen and thrombin and the release
of arachidonic acid.
Ref: [The effect of triphenyltin
fluoride on aggregation, ATP secretion and malondialdehyde formation
of rabbit platelets in vitro]. [Article in Japanese]; by S Manabe
S et al. Sangyo Igaku 1983 Jan;25(1):15-22.