See some background information and definitions on liver
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.
When time allows more information will be added.
Quinoxyfen
- Fungicide - CAS No. 124495-18-7
** 040 - 181140 "XDE-795:
"Two-Year Dietary Chronic Toxicity/Oncogenicity Study in
Fischer 344 Rats-Final Report," (Redmond,
J.M., Quast, J.F., Bond, D.M., Ormand, J.R.; The Toxicology Research
Laboratory, Health and Environmental Sciences Ð The Dow
Chemical Company, Midland, MI; Laboratory ID#: DR-0325-7474-007;
6/29/95). XDE-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline;
97.4% pure) was fed in diet to Fischer 344 rats at 0, 5, 20 or
80 mg/kg/day for 1 Ð 2 years. XDE-795 was administered for 2 years
to 50/sex/dose for chronic/oncogenicity assessment. A satellite
group (15/sex/dose) was sacrificed at 12 months (10/sex/dose for
interim assessment of chronic toxicity; 5/sex/dose to assess neurotoxicity).
NOEL = 20 mg/kg (Females at 80 mg/kg had increased perineal soiling
(satellite & main group). Both sexes had decreased
bodyweights and bodyweight gains
at 80 mg/kg throughout the study. Urea nitrogen was increased
in males at 80 mg/kg at 18 and 24 months. Alanine amino transferase
(80 mg/kg) was decreased in males at 24 months. Females had cholesterol
levels that were statistically significantly increased at 80 mg/kg
at 18 and 24 months. Liver and kidney
weights (absolute & relative) were statistically significantly
increased in both sexes at 80 mg/kg at 12 months. Relative
brain weights in both sexes were increased at 80 mg/kg by 24 months.
Males had increased absolute and relative testes weights at 80
mg/kg and females had decreased relative heart and increased relative
kidney weights at 80 mg/kg at 24 months. There was an
increased incidence in chronic progressive glomerulonephropathy
in males at 80 mg/kgÑ37 versus 19 in control, p < 0.05.)
No adverse effects. Acceptable. M. Silva, 8/21/01
-- 034 - 181176 "XDE-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 Ð 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
-- Subchronic Study: 029 - 181169 "XR-795: 13-Week Dietary
Toxicity Study in CD-1 Mice," (Grandjean,
M., Szabo, J.R.; Health and Environmental Sciences - Texas, Lake
Jackson Research Center, The Dow Chemical,
Freeport, TX; Laboratory ID#: DR-0325-7474-003; 10/12/92).
XR-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 98.7% pure)
was fed in diet to CD-1 mice (10/sex/dose) at 0, 10, 50, 100 or
500 mg/kg/day for 13 weeks. NOEL = 100 mg/kg (Relative
liver weights were significantly increased in both sexes
at 500 mg/kg. All animals (both sexes) had
hepatocellular hypertrophy (centrilobular & midzonal-diffuse)
at 500 mg/kg only. Hepatic inflammation (1/10-M) and hepatocellular
necrosis (3/10-M, 4/10-F) occurred only at 500 mg/kg.) No adverse
effects. Not acceptable but possibly upgradeable with submission
of results of ophthalmological examination. M. Silva, 8/15/01
-- ** 035 - 181177 "XDE-795: Potential Tumorigenic Effects
in Prolonged Dietary Administration to CD-1 Mice," (Bellringer,
M.E.; J.R.; Huntingdon Research Centre,
Ltd., Cambridgeshire, UK; HRC Project ID#: DWC/657; 6/5/95).
XR-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 97.4% pure)
was fed in diet to Crl:CD-1 (ICR)BR mice (50/sex/dose) at 0, 20,
80 and 250 mg/kg/day for 80 weeks. NOEL = 80 mg/kg (There was
a significantly decreased bodyweight gain
in both sexes at 250 mg/kg (primarily females). The effect
was intermittent in males throughout the study. Relative (to bodyweight)
liver and kidney weights were significantly
increased in females at 250 mg/kg.) There were no histological
(neoplastic or non-neoplastic) effects due to treatment. No adverse
effects. Acceptable. M. Silva, 8/24/01
-- ** 039 Ð 181139 "XDE-795: Two-Generation Dietary Reproduction
Study in Sprague-Dawley Rats," (Liberacki,
A.B., Breslin, W.J., Zwinker, G.M., Johnson, K.A., Freshour, N.L.;
The Toxicology Research Laboratory, Health and Environmental Sciences,
The Dow Chemical, Midland, MI; Laboratory ID#Õs: DR-0325- 7474-013
[P1, F0, W1, FB, WB, P2, F2 & W4]; 5/23/95). XDE-795 (97.4%
pure) was fed in diet to Sprague-Dawley rats (30/sex/dose) at
0, 5, 20 and 100 mg/kg/day, 7 days/week for 2 generations. Systemic
NOEL = 20 mg/kg (Kidney pathology was observed
in P1 and P2 females at 100 mg/kg. Males showed liver,
kidney and epididymal histopathology at 100 mg/kg in P1
and P2 adults.) Reproductive NOEL = 100 mg/kg/day (There were
no treatment-related reproductive effects in either sex.) Pup
NOEL = 20 mg/kg/ (F1a & F1b pups showed
decreased bodyweights at 21 days of lactation and this
was considered to be due to excessive dose and decreased food
consumption.) No adverse effect. Acceptable. M. Silva, 8/9/01
-- Rangefinding Study: 037 Ð 181136 "XDE-795: Oral Gavage
Teratology Probe Study in New Zealand White Rabbits,"
(Zablotny, C.L., Yano, B.L., Breslin, W.J.; The Toxicology Research
Laboratory, Health and Environmental Sciences, The Dow
Chemical, Midland, MI; Laboratory Project #: DR-0325-7474-014;
11/29/93). XDE-795 (96.2% pure) was administered by oral
gavage to time-mated New Zealand white rabbits (7/dose) at 0 (0.5%
METHOCEL A4M), 100, 300, 600 and 1000 mg/kg/day, days 7-19 of
gestation. Due to extreme maternal toxicity, treatment was discontinued
at 600 and 1000 mg/kg from gestation day 15. Effects included
decreased fecal output, weight loss,
extreme decrease in food consumption. Maternal NOEL = 100 mg/kg
(There were increased clinical observations, as well as decreased
body weight, body weight gain and food consumption at >
300 mg/kg. Liver weights were significantly
increased at 300 mg/kg.) Developmental NOEL > 300 mg/kg
(There were no treatment-related effects at 100 or 300 mg/kg.)
No adverse effect. These data are supplemental. M. Silva, 8/29/01
-- (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)
-- 030; 181170; "XR-795: Four Week Dietary Toxicity Study
in Fischer 344 Rats" (Szabo, J.R. and
Davis, N.L., Health and Environmental Sciences-Texas Lake Jackson
Research Center, The Dow Chemical Company,
Freeport, Texas, Laboratory Project Study ID TXT: DR-0325-7474-002,
10/12/92). XR-795 (TSN100003, DECO-36-106, purity = 97.6%)
was admixed to the diet at dose levels of 0 (untreated diet only),
250, 500, or 1000 mg/kg/day and fed continuously to 5 Fischer
344 rats per sex per dose for 4 weeks. No clinical signs were
observed. A treatment-related decrease in
mean body weight at all dose levels in both sexes was observed.
Treatment-related increases in mean
relative liver (in both sexes at all dose levels) and in
mean relative kidney (in males at all dose levels and in
females at 500 and 1000 mg/kg/day) weights and a treatment-related
decrease in mean relative testes weight at 1000 mg/kg/day were
observed. Macroscopic examination revealed
bilateral testicular atrophy in 3/5 animals at 1000 mg/kg/day.
Microscopic examination revealed a moderate to severe decrease
in spermatogenesis in 4/5 animals at 1000 mg/kg/day. Possible
adverse effect indicated: testicular atrophy with a decrease in
spermatogenesis. NOEL (M/F) < 250 mg/kg/day (based on body weight
and mean relative organ weight data). Supplemental (only
5 animals per sex per dose were used and the animals were only
dosed for 4 weeks). (Corlett, 8/27/01)
-- 030; 181172; "XDE-795: Four-Week Dietary Toxicity Study
in Beagle Dogs" (Szabo, J.R. and Davis,
N.L., Health and Environmental Sciences-Texas Lake Jackson Research
Center, The Dow Chemical Company,
Midland, MI, Texas, Laboratory Project Study ID: DR-0325-7474-008,
2/19/93). XDE-795 (TSN100010, Lot # DECO-104-116, purity
= 99.0%) was admixed to the diet at dose levels of 0 (untreated
diet only) or 250 mg/kg/day and fed continuously to 2 beagle dogs
per sex per dose for 4 weeks. No clinical signs were observed.
Treatment-related decreases in mean body
weight and in mean feed consumption were observed in both
males and females. Microscopic examination revealed treatment-related
vacuolation of midzonal and centrilobular
hepatocytes in both males and females. No adverse effects.
NOEL (M/F) < 250 mg/kg/day (based on body
weight and feed consumption data and microscopic findings).
Supplemental (only 2 animals per sex per dose were used, only
1 treatment level was used, and the animals were only dosed for
4 weeks). (Corlett, 8/29/01)
-- 029 - 181169 "XR-795: 13-Week Dietary Toxicity Study in
CD-1 Mice," (Grandjean, M., Szabo,
J.R.; Health and Environmental Sciences - Texas, Lake Jackson
Research Center, The Dow Chemical,
Freeport, TX; Laboratory ID#: DR-0325-7474-003; 10/12/92).
XR-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 98.7% pure)
was fed in diet to CD-1 mice (10/sex/dose) at 0, 10, 50, 100 or
500 mg/kg/day for 13 weeks. NOEL = 100 mg/kg (Relative liver
weights were significantly increased in both sexes at 500
mg/kg. All animals (both sexes) had hepatocellular
hypertrophy (centrilobular & midzonal-diffuse) at 500 mg/kg
only. Hepatic inflammation (1/10-M)
and hepatocellular necrosis (3/10-M,
4/10-F) occurred only at 500 mg/kg.) No adverse effects. Not acceptable
but possibly upgradeable with submission of results of ophthalmological
examination. M. Silva, 8/15/01
Ref: October 4, 2001. SUMMARY OF TOXICOLOGY
DATA QUINOXYFEN (XDE-795 & XR-795). California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/quinoxyfen.ca.epa.2001.pdf
Sodium
fluorosilicate
(Sodium Hexafluorosilicate) - Insecticiide;
Wood Preservative; EPA List 3 Inert - CAS No. 16893-85-9
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)
-- Toxicological Data. Human Data.
Chronic exposure to sodium hexafluorosilicate dust at levels above
the eight-hour TWA can result in severe
calcification of the ribs, pelvis, and spinal column ligaments;
effects on the enzyme system; pulmonary
fibrosis; stiffness; irritation of the eyes, skin, and mucous
membranes; weight loss; anorexia; anemia; cachexia; wasting; and
dental effects. Long-term or repeated exposure to the skin can
result in skin rash. A probable oral lethal dose of 50-500 mg/kg,
classified as very toxic, has been reported for a 150-pound (70-kg)
person receiving between 1 teaspoon and 1 ounce of sodium hexafluorosilicate.
Cases of sodium hexafluorosilicate ingestion reported symptoms
such as acute respiratory failure, ventricular tachycardia and
fibrillation, hypocalcemia, facial numbness, diarrhea, tachycardia,
enlarged liver, and cramps of the
palms, feet, and legs.
Ref: Sodium Hexafluorosilicate [CASRN 16893-85-9]
and Fluorosilicic Acid [CASRN 16961-83-4]. Review of Toxicological
Literature. October 2001. 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.
http://www.fluoridealert.org/pesticides/Fluorosilicates.NIH.2001.pdf
Sulfentrazone
- Herbicide
- CAS No. 122836-35-5
-- Chronic toxicity.
A 12-month feeding study in dogs was dosed at levels of 0.0, 24.9,
or 61.2 mg/kg/day for male dogs and 0.0, 10.4, 29.6, or 61.9 [[Page
11100]] mg/kg/day for female dogs in the control through high-dose
groups, respectively, with a NOAEL of 24.9 mg/kg/day for males
and 29.6 mg/kg/ day for females based on
hematology effects and microscopic
liver changes.
-- In a 90-day subchronic feeding study in dogs administered
by dietary admix at doses of 0, 10, 28, or 57 mg/kg/day for males
and 0, 10, 28, or 73 mg/kg/day for females, a NOAEL of 28 mg/kg/day
was determined for both males and females based on decreases
in Hgb and HCT, elevated alkaline phosphatase levels, increased
liver weights and microscopic liver as well as splenic changes.
Ref:
Federal Register, March 7, 2003 (Volume 68, Number 45)] [Notices]
[Page 11096-11100]. Notice of Filing Pesticide Petitions to Establish
Tolerances for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Sulfentrazone.FR.Mar.7.2003.htm
-- 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)
Ref:
Federal Register: September 24, 2003. Sulfentrazone; Pesticide
Tolerances. Final Rule.
http://www.fluorideaction.org/pesticides/sulfentrazone.fr.sept24.03.htm
Sulfuryl fluoride
- Fumigant
insecticide - CAS No. 2699-79-8
--
In a developmental toxicity inhalation study
in rats, no developmental toxicity was observed in the
pups. Although no maternal toxicity was observed in this study
at the highest dose tested (225 ppm), significant maternal toxicity
(decreased body weight, body weight gain and food consumption;
increased water consumption and kidney weights; and gross
pathological changes in the kidneys and liver) was observed
in a previously conducted range-finding study at a slightly higher
dose level (300 ppm)...
Ref:
Federal Register: September 5, 2001 (Volume 66, Number 172). Sulfuryl
Fluoride; Proposed Pesticide Temporary Tolerances.
http://www.fluorideaction.org/pesticides/sulfuryl.flu.fr.sept.5.2001.htm
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
Teflon
(PTFE: polytetrafluoroethylene) - EPA List 3 Inert -
CAS No. 9002-84-0
Abstract: Information
on potential occupational hazards from exposure to carbonyl fluoride
(353-50-4) was reviewed. Topics discussed included chemical and
physical properties, production, use, manufacturers and distributors,
manufacturing processes, occupational exposure, and biological
effects. Potential
exposure to carbonyl fluoride occurs as a result
of the thermal decomposition of polytetrafluoroethylene (PTFE)
in air. Effects of acute exposure in animal studies included
extreme malaise and weakness which preceded
death. Subchronic exposure
studies with PTFE pyrolysis products revealed pathologic
changes in the respiratory tracts and
livers of exposed animals. Protein, glucose, ketones, and
occult blood appeared in the urine following exposure. No information
was available concerning chronic exposures, carcinogenicity, mutagenicity,
teratogenicity, or reproductive effects.
Ref:
1987. Information Profiles on Potential Occupational Hazards:
Carbonyl Fluoride. Second Draft. Syracuse Research Corp., NY.
Center for Chemical Hazard Assessment. Sponsored by National Inst.
for Occupational Safety and Health, Rockville, MD. Report No.
NTIS/PB87-174330.
Teflubenzuron
- Insecticide - CAS No. 83121-18-0
-- Short term repeat
dose toxiciity tests in rats, mice and dogs revealed that the
major target organ for the toxic effect of teflubenzuron is the
liver. The main findings attributed to hepatoxiciity were
increased liver weights and liver lesions, such as
hepatocellular swellings, collapsed stroma, fatty changes, necrosis
and cell infilitration.
-- In a 18-month carcinogenicity study in mice, teflubenzuron
was given via the diet at concentrations of 0, 15, 75 or 375 mg/kg
feed, equal to 0, 2.1, 10.5 or 53.6 mg/kg
bw/day in males and 0, 3.1, 15.4 or 71.7 mg/kg bw/day in females...
Non-neoplastic dose-dependent hepatic changes were observed in
both sexes of all treated groups, such as hypertrophy,
hyperplasia, single cell necrosis, phagocytic cell foci, lipofuscin
accumulation and glycogen storage. The incidence of hepatocellular
adenomas at 18 months (terminal kill) was
significantly increased in males at
the two highest dose groups: 22%
in the mid-dose group and 32% in the high dose group versus 12%
in the concurrent control group and 16% in the historical control
group. There were no changes in the incidence of hepatocellular
carcinomas. Since the increased incidence of hepatocellular adenomas
is likely to be secondary to the hepatoxicity of teflubenzuron
and was of a type generally not considered to be of concern for
human health if not accompanied by other evidence for carcinogenicity,
the mouse study was considered not to provide evidence for carcinogenicity
of teflubenzuron.
-- The FAO/WHO Joint Meeting on Pesticides Residues (JMPR) evaluated
teflubenzuron in 1994 and established an ADI of 0.01 mg/kg bw/day,
based on the dose-related effects in the target tissue
liver in the mouse carcinogenicity study submitted.
January 1999 - Summary Report. Committee
for Veterinary Medicinal Products. The European Agency for the
Evaluation of Medicinal Products.
http://www.fluoridealert.org/pesticides/Teflubenzuron.Review.1999.pdf
Tefluthrin
- Insecticide - CAS No. 79538-32-2
-- In a chronic/oncogenicity
study, mice were dosed at 0, 25, 100, or 400 ppm (actual dose
levels were equivalent to 3.4, 13.5, or 54.4 mg/kg/day) for 104
weeks. The chronic LOEL is 13.5 mg/kg based on hemangiomatous
changes of the uterus and
liver necrosis observed in the mid- and high-dose females.
The chronic NOEL is 3.4 mg/kg. Under the conditions of this study,
there was no evidence of carcinogenic potential.
Ref: Federal Register: November 26, 1997.
Tefluthrin; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Tefluthrin.FR.Nov.1997.htm
Tetraconazole
-Fungicide - CAS No. 112281-77-3
Likely
to be Carcinogenic to Humans. Hepatocellular
adenomas, carcinomas and combined adenomas/carcinomas in both
sexes; Crl:CD-1 (ICR) mice.
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
Likely
to be carcinogenic to humans. Reviewed 1/
11/ 00.
Ref:
List of Chemicals Evaluated for Carcinogenic Potential. Science
Information Management Branch, Health Effects Division, Office
of Pesticide Programs, U. S. Environmental Protection Agency.
March 15, 2002.
http://www.biomuncie.org/chemicals_evaluated_for_carcinog.htm
• Metbolism nd Toxicokinetics. Tetraconazole
was broadly distributed to all organs and tissues tested, with
the highest level detected in the liver,
followed by kidneys, gonads, brain and bones.
Low residual levels were still detected in the liver and gastrointestinal
tract (sometimes bones) at 72 hr.
• Chronic & Carcinogenicity Studies.
Dogs received 0, 22.5, 90 or 360 ppm of tetraconazole in the diet
for 1 year. Histopathology detected apparent
hepatocyte enlargement, eosinophilic inclusions in hepatocytes,
centrilobular hepatocyte rarefaction, or centrilobular fat in
the liver at 90 and 360 ppm, and cortical tubular hypertrophy
and apoptotic bodies in the kidneys
at 360 and/or 90 ppm. The NOEL was 22.5 ppm (0.7 mg/kg
bw/day). (page 5)
-- In a carcinogenicity study, mice received 0, 10, 90, 800 or
1250 ppm of tetraconazole in the diet for 80 weeks. In the liver,
increased weight and masses and enlarged
and discoloured liver were noted at 90 ppm and above with a dose-related
increase in the incidence and degree of generalised hepatocyte
enlargement, vacuolation, fat deposition and bile duct hyperplasia
at 90 ppm (males) and higher doses. There were also
increased basophilic hepatocyte foci, eosinophilic hepatocytes,
pericholangitis, granulomatous inflammation and pigmented macrophages
in mice at 800 and 1250 ppm. Hepatocyte
necrosis was detected in some females
of each treated group (page 4) ... Benign and malignant
liver cell tumors were increased at 800 and 1250 ppm,
and resulted in the high mortality at 1250 ppm. The NOEL was 10
ppm (1.4 mg/kg bw/day). (page 5)
• Sub chronic studies. 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. Mice at 625 ppm exhibited
pale and enlarged liver with lobular markings
accentuated. Hepatocyte enlargement was
a major finding in the majority of mice at 25 ppm and above. Hepatocyte
necrosis, degeneration or congestion developed at 125 and
625 ppm, and a higher incidence of hepatocyte
vacuolation appeared at 625 ppm.
Some males at 625 ppm showed lymphocyte aggregation and foci in
the kidneys. The NOEL was 5 ppm (1 mg/kg bw/day). (page
4)
Ref: August
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf
-- Carcinogenicity.
Tetraconazole has not been classified with respect to carcinogenic
potential by EPA. However, based on the tumorigenic results in
the mouse carcinogenicity study, EPA has made an initial determination
that a Q1* should be determined based on the male mouse benign
liver tumors, excluding the highest dose. The Q1* is 0.037
(mg/kg/day)-1.
-- Aggregate cancer risk for U.S. population. Tetraconazole produced
statistically significant increases in male and female mouse liver
adenomas and carcinomas. Based on a determination of the
Q1* for this tolerance setting action only, the Q1* was determined
to be 3.7 x 10-2 based on benign tumors in males with the exclusion
of the high dose group. The cancer risk for the U.S. population
is, without adjustment, 2.5 x 10-6. Because this is an emergency
exemption use of tetraconazole, it is considered appropriate to
divide the cancer risk by a factor of 14 [5 years for potential
emergency exemption use/70 years lifetime = 1/14]. The adjusted
cancer risk for the U.S. population is 1.8 x 10-7 and this adjusted
cancer risk is below EPA's level of concern.
-- Reproductive toxicity study-- Rats. In the 2-generation reproductive
toxicity study in rats, the maternal (systemic) NOAEL was 0.7
mg/kg/day, based on dystocia, delayed vaginal
opening, and increased liver weight
at the LOAEL of 5.9 mg/kg/day. The developmental (pup) NOAEL was
0.7 mg/kg/day, based on increased time to observation of
balanopreputial skin fold and liver
weight at the LOAEL of 5.9 mg/ kg/day. At the high dose of 35.5
mg/kg/day, there was a decrease in the mean number of live pups
per litter on lactation days 0 and 4 (precull) in the presence
of significant maternal toxicity.
Ref: Federal Register: December 6, 1999.
Tetraconazole; Pesticide Tolerances for Emergency Exemptions.
Final Rule.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm
-- Subchronic toxicity.
A 90-day oral subchronic toxicity study was conducted with technical
grade tetraconazole in rats at 10, 60, and 360 ppm in the diet.
Treatment related increased liver weights and centrilobular
hepatocyte enlargement were observed at the two highest
dose levels. The NOAEL was 10 ppm (0.8 mg/kg/day), by comparison
with data from the zero-dose control group.
-- A 90-day oral subchronic toxicity study was conducted in mice
with dietary concentrations of technical grade tetraconazole at
5, 25, 125, and 625 ppm. The two highest dosages resulted in liver
enlargement, accentuated lobular markings and liver pallor. Microscopic
tissue alterations related to tetraconazole were liver
enlargement at the three highest doses and single
cell necrosis/degeneration and/or areas of necrosis at
the two highest doses. The NOAEL was 5 ppm (1 mg/kg/ day).
-- Chronic toxicity. A 12-month chronic oral toxicity study in
Beagle dogs was conducted with technical tetraconazole at dose
levels of 0.7, 2.8, and 5.6 mg/kg/day (22.5, 90, and 360 ppm dietary
concentrations, respectively). At the highest dose, liver
and kidney weights and cholesterol
levels were elevated, and liver injury
occurred based upon increased levels of GPT, -GT and
OCT. The no effect level was 0.7 mg/kg/day, as compared with zero-dose
control animals.
-- A chronic (full-lifetime) feeding/carcinogenicity study was
conducted with Crl:CD(SD)BR rats fed tetraconazole at dietary
levels of 10, 80, 640, and 1,280 ppm for 104 weeks in males and
10, 80, and 640 ppm for 104 weeks in females. In the liver,
changes such as hepatocyte enlargement
and increased incidence of eosinophilic
hepatocytes, seen at doses of 80, 640, or 1,280 ppm were
associated with hepatic enzyme induction.
-- At 90 ppm, non-neoplastic changes were detected in bone
and the epididymides in addition to
liver changes. No treatment-related findings were seen
in mice treated at 10 ppm (approximately 1.5 mg/kg/ day), and
this dose level was defined as the NOAEL. In this same study,
an increased incidence of benign liver
cell tumors was observed in males and females fed 800 ppm, and
an increased incidence of benign and malignant liver cell tumors
in males and females given 1,250 ppm. These tumors were associated
with increased signs of hepatotoxicity including hepatocyte vacuolation
and fat deposition at 90, 800, and 1,250 ppm; granulomatous inflammation,
pigmented macrophages, bile duct hyperplasia and pericholangitis
in mice given 800 and 1,250 ppm. In addition, there was evidence
of treatment-related hepatocellular enlargement and increased
numbers of altered foci of eosinophilic and basophilic hepatocytes
in both sexes given 800 and 1,250 ppm; eosinophilic
hepatocytes were noted in male (only) mice receiving 90
ppm.
-- Tetraconazole is a triazole, and this class of compounds is
known to induce liver microsomal
enzymes. A special mechanistic study was conducted in order to
more fully determine the potential role of microsomal enzyme induction
by tetraconazole administered in the diet upon the formation of
tumors in mouse. Dietary administration of tetraconazole to mice
for 4 weeks results in the induction of cytochrome P450-related
activities, as well as the concentrations of microsomal protein
and cytochrome P450, and of the phase II activity, and p-nitrophenol
UDP- [[Page 55720]] glucuronyl transferase activity. The effects
of tetraconazole on the cytochrome P450-dependent MFO system were
somewhat different from those of phenobarbital. Many of these
enzymes have not been as well- characterized in mice compared
to rats. However, the phase II enzyme activity increases were
similar to those of phenobarbital. It is concluded from these
studies that prolonged induction of liver
microsomal enzymes and/or production of sustained liver injury
can lead to the formation of liver
tumors in mice.
Ref: Federal Register: October 14, 1999.
Notice of Filing Pesticide Petitions to Establish a Tolerance
for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023,
and 7E4830.
http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Oct14.1999.htm
1,1,1,2-Tetrafluoroethane
(HFC-134a)
- Propellant, US EPA List 4B Inert - CAS No. 811-97-2
Comparative potency
studies showed that 1,1,1,2-tetrafluoroethane, dichlorodifluoromethane,
or 1,1,2,2-tetrafluoro-1,2-dichloroethane (25% gas phase) inhibited
gluconeogenesis about equally while as little as 300 ppm
halothane was effective and 1,1,1,2,2-pentafluoro-2-chloroethane
(25%) was without effect. Considering that the threshold for alteration
of the rate of glucose metabolism in this in vitro paradigm is
about 12.5% 1,1,1,2-tetrafluoroethane, it was concluded that toxicologically
significant alteration of glucose-linked bioenergetics is unlikely
at the levels of 1,1,1,2-tetrafluoroethane exposure anticipated
in workplace or environment. [Olson MJ et al; Fundam Appl Toxicol
15 (2): 270-80 (1990)]
Note from FAN: Definition
Gluconeogenesis: The process of making glucose (sugar) from its
own breakdown products or from the breakdown products of lipids
(fats) or proteins. Gluconeogenesis occurs mainly in cells of
the liver or kidney.
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
-- groups of 16 male
and 16 female rats were exposed at concentrations of 9, 1000,
10,000, or 50,000 ppm 6 h/d for 20 d of a 28-d period (Riley
et al. 1979). No treatment-related effects were observed
with regard to body weight, clinical signs, hematology, blood
chemistry, urine composition, or ophthalmoscopy.
Changes in liver, kidney, and gonad
weights of male rats in the group exposed to 50,000 ppm
were noted with a significant increase in
liver weight in the 10,000-ppm group also. In the absence
of pathological changes in these organs, Riley
et al. (1979) considered these changes physiological adaptations
to treatment.
-- 3.7 Subchronic and Chronic Toxicity and Carcinogenicity (pages
138 - 139)
... groups of 85 male and 85 female rats were exposed to concentrations
at 0, 2,500, 10,000, or 50,000 ppm for 6 h/d, 5 d/wk for 104 wk
(Collins et al. 1995). Exposure conditions
and analytical measurements were identical to procedures followed
in the 13 week study. Ten animals from each group were sacrificed
at 52 wk. At 52 and 104 wk there were no effects on clinical condition,
food consumption, growth, survival, hematology, clinical chemistry,
or urinary parameters. Absolute liver weights
of females were increased in the groups exposed at 2,500
and 50,000 ppm but not in the group exposed at 10,000 ppm. Males
in groups that received 10,000 or 50,000 ppm for 104 wk had an
increased incidence of enlarges testes (not
statistically significant), and males in the group that received
50,000 ppm for 104 wk had a statistically significant increase
in incidence of Leydig cell hyperplasia (40 vs. 27 in the concurrent
control group) and Leydig cell adenomas (23 vs. 9 in the
concurrent control group). There was no evidence of progression
to malignancy. As discussed earlier, these
tumors are not relevant to humans.
-- Collins
MA, Rusch GM, Sato F, Hext PM, Millischer RJ. 1995. 1,1,1,2-Tetrafluoroethane:
repeat exposure inhalation toxicity in the rat, developmental
toxicity in the rabbit, and genotoxicity in vitro and in
vivo. Fundam Appl Toxicol 25:271-280.
-- Riley
RA, Bennett IP, Chart IS, Gore CW, Robinson M, Weight TM. 1979.
Arcton-134a: Subacute toxicity to the rat by inhalation.
ICI Report No. CTL/P/463. Central Toxicology Laboratory,
Alderly Park, Macclesfield, Cheshire, UK.
Ref:
National Research Council. 2002. Acute Exposure Guideline Levels
for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute
Exposure Guideline Levels. Committee on Toxicology, Board of Environmental
Studies and Toxicology, Division of Earth and Life Studies. National
Academy Press, Washington DC. Available from: National Academy
Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055.
ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html
Thiazopyr
- 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.
-- 21-Day Dermal (Rat): NOEL =100 mg/kg/day. The LOEL was 500
mg/kg/day based on minimal hepatocellular
vacuolation in females.
-- 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 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-generation reproductive in rats at 0, 0.75, 7.5 and 75.0
mg/kg/day with a parental toxicity NOEL of 7.5 mg/kg/day. The
toxic effects were increased absolute and relative liver
weight, hepatic discoloration, histologic evidence of hepatic
hypertrophy and vacuolization in females in both generations.
No adverse efects were observed in adults or their offspring up
to 75 mg/kg/day, the highest dose tested.
-- A mouse carcinogenicity study at doses of 0, 0.17, 1.6, 16.9,
66.3 or 128.4 mg/kg/day (males) and 0,0.24, 2.6, 26.8, 108.1 or
215.9 mg/kg/day (female) with a systemic NOEL of 0.1 mg/kg/day.
The effects were hepatocellular hypertropy
and amyloid deposition. At 66.3 mg/kg/day
the same lesions plus increased liver
weights, random and periportal hepatocellular
vacuolation were observed. At 128.4 mg/kg/day the
same lesions plus distended abdonen, slight increase in
ALP, SGOT and SGPT, abnormal coloration
and enlargement of liver, decrease
in absolute and relative spleen weights,
increase in absolute and relative kidney
weights, increase in eosinophilia
in hepatocytes, kidney nephropathy and lymphocytic hyperplasia
of the nesenteric lymph nodes were observed. There was no evidence
of oncoenicity at any dose level.
-- 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.
-- The EPA Health Effects Division Carcinogenicity Peer Review
Committee classified thiazopyr as a Group
C, possible human carcinogen and recommended that for the
purpose of risk characterization a Margin of Exposure (M.O.E.)
approach should be used in evaluation of the consequences of human
exposure.
-- A second study on the effects of thiazopyr on the biochemical
mechanisms of thyroid toxicity in rats at doses of 0, 0.5, 1.5,
5, 15, 50 or 150 mg/kg/day was conducted. Dose response effects
on various biochemical parameters were observed. Two groups of
the rats in the study were observed for reversibility of effects
observed up to 56 and 112 days. Doses at 15, 50 and 150 mg/kg/day
significantly increased the liver weights.
Thyroid weights were increased at doses
of 50 and 150 mg/kg/day. There were no significant effect on body
weight or body weight gains during the study. The T4 UDPGT levels
were increased by 117 and 376% above controls at the 50 and 150
mg/kg/day dosages. Effects of 150 mg/kg/day were increases in
T3, TSH and rT3 serum concentrations, and increased incidence
of follicular cell hypertrophy/hyperplasia at the 150 mg/kg/day
dose. A NOEL of 1.5 mg/kg/day was determined based on liver weight
increases. Thyroid weight was the only parameter that did not
return to those similar to the controls. At the 56 and 112 day
recovery periods the thyroid weights were 120 and 123% of control
values, respectively.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr
Reason for Issuance: Registration of a New Chemical Date Issued:
February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf
Tolylfluanid
- Fungicide - CAS No. 731-27-1
Toxicity - General:
The skeletal system
(bones and teeth),
liver and thyroid were identified
as target organs in the animal studies.
Ref:
US EPA Pesticide Fact Sheet. Reason for Issuance: Import Tolerance.
September 2002.
http://www.fluorideaction.org/pesticides/tolylfluanid.epa.facts.2002.pdf
-- 90-Day oral toxicity
rodents (rat). NOAEL = 20.1 milligram/kilogram/ day (mg/kg/day)
male (M) LOAEL = 108 mg/kg/ day, based on changes
in clinical blood chemistry associated with the liver and thyroid
(M) NOAEL = 131 mg/kg/day female
(F) LOAEL = 736.1 mg/kg/
day, based on changes in clinical blood
chemistry associated with the liver and thyroid and
decreased body weights (F)
-- 90-Day oral toxicity in
nonrodents (dog). NOAEL
= 23.1/25 mg/kg/ day (F/M) LOAEL = 67.2/69.4 (F/ M) mg/kg/day,
based on decreased body weight gains and
changes in liver structure and function in both sexes
-- Prenatal developmental in nonrodents (rabbit). Maternal NOAEL
= 25 mg/kg/day LOAEL = 70 mg/kg/day, based on evidence of hepatotoxicity
(increased glutamate dehydrogenase (GLDH) and triglyceride levels
and gross and microscopic liver pathology) and
decreased food consumption and equivocal decreases in body weight
gain. Developmental NOAEL = 25 mg/kg/day LOAEL= 70 mg/kg/day,
based on increased malformations (arthrogryposis of front extremities
and small orbital cavity/folded retina) and variations (floating
rib and accelerated ossification).
-- 2-Generation reproduction and fertility effects (rat). Parental/systemic
NOAEL = 7.9-10.5 mg/ kg/day LOAEL = 57.5-78.0 mg/ kg/day, based
on decreased body weights, body weight
gains, and liver weights in the P
females Reproductive NOAEL
= 7.9-10.5 mg/kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on reduced
litter size Offspring NOAEL = 7.9- 10.5 mg/kg/day LOAEL = 57.5-78.0
mg/ kg/day, based on decreased pup weights,
increased pup deaths and related pup viability indices.
-- Carcinogenicity rodents (mouse). NOAEL
= 76.3/123.9 mg/ kg/day (M/F) LOAEL = 375.8/610.8 mg/kg/day (M/F),
based on skeletal, liver, and kidney changes
No evidence of carcinogenicity
Ref: Federal Register:
September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule.
Federal Register.
http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm
Transfluthrin
- Insecticide - CAS
No. 118712-89-3
-- The target organs
were the liver (rat,
mouse and dog) and kidney (rat).
There was evidence of liver hypertrophy
in the rat from 250 mg kg d (28 study) and after administration
for 90 d at 500 ppm (equivalent to 40 mg kg d), in the dog from
350 ppm (equivalent to 14 mg kg d) after 90 d administration and
from 30 ppm (equivalent to1 mg kg d) after 1 yr and in the mouse,
from 1000 pppm (equivalent to 280 mg kg d) after
2 yr administration. Increased kidney weights, proximal tubule
degeneration and regenertion and increases in protein in the urine
were observed in male rats from 50 ppm and in females from 500
ppm. Similar pathological findings were seen after 2 yr dietary
administrationwith focal hyperplasia in the urinary bladder in
both sexes at 2000 ppm in the rat and hepatocyte hypertrophy at
1000 ppm in the mouse. In the rat, increases in fluoride content
of teeth and bone were observed from 50 ppm in oral studies and
at 200 mg m3 following inhalation exposure in 90 d studies.
-- The NOEL's following 90 d oral administration were 10 ppm (equivalent
to 0.85 mg kg d) in the rat and 50
ppm (equivalent to 1.9 mg kg d) in the dog.
It was not possible to set a NOEL following dietary administration
for 1 yr in the dog as there was some slight evidence of
liver hypertrophy at the lowest dose (10 ppm)...
-- In 2 yr studies the NOEL for non-neoplastic findings in the
rat was 20 ppm (1 mg kg d) based on efffects in the kidney
(increased organ weight, pigment deposition and glomerulonephrosis)
at 200 ppm and above). In the mouse, the NOEL was 10 ppm in males
(based on increases in liver weight,
hepatocyte hypertrophy at 1000 ppm
and fluoride accumulation at 100 ppm). It
was not possible to set a NOEL for females as increases in serum
cholesterol, protein and albumin were reported at the lowest
dose.
-- Reproductive Toxicity. Developmental studies in both the rat
and rabbit provided no evidence of teratogenicity when
transfluthrin was administered at 125 and 150 mg kg d respectively.
One death occurred at 125 mg kg d in the rat study and 2 deaths
(1 each at 50 and 150 mg kg d) occurred in
the rabbit study. NOELs of 15 and 15 mg kg d were established
for maternal toxicity in the rat and rabbit respectively. These
were based tremors at 55 mg kg d in the rat and mortality (following
severe tremors) at 50 mg kg d in the rabbit. In a dietary multi-generation
reproductive toxicity study in the rat there was no evidence of
teratogenicity, foetotoxicity or maternal reproductive toxicity
in rats administered transfluthrin at doses up to 191 mg kg d.
NOELS of 62-191 and 9-38 mg kg d were established for maternal
reproductive and parental toxicity respectively. The NOEl
for parental toxicity was based on the following observations
at 1000 ppm: - decreased body weight and
body weight gain, increased absolute and relative liver
and kidney weights, increased
relative kidney weight, decreased hepatic triglyceride content,
increased incidence of tubular pigmentation, tubular casts and
pelvic calcinosis..
-- 3.2.2.1 Oral Route ... At 250 mg kg and 28 d, in both sexes,
there were absolute and body weight relative increases in
liver (15-20%) and kidney weights
(~ 10%). ... At necropsy there was evidence of effects
on the liver and kidney
at 500 and 5000 ppm. Relative and absolute liver
weights were increased by ~ 15% at 500 ppm, ~45% at 5000
ppm (males at 13 w) and up to ~55%
at 19 w. Histopathological examination showed centrilobular
hepatocyte hypertrophy in all males, 9/10 females at 5000
ppm and 8/10 males, 4/10 females at 500 ppm. In addition at 5000
ppm there was a significant increase (50%) in the numbers of animals
of both sexes with degenerated hepatocytes...
-- In 90 d study Beagles (4/sex/group)
were administered transfluthrin (94.5%0 pure via their food at
nominal concentrations of 0, 50, 350 or 2500 ppm. Haematological
and urine examinations were carried out on all grops pre study
and at 3, 6 and 13 w. Ophthalmological examinations were carried
out pre study, 6 and 13 w, and hearing tests were carried out
pre study and 13 w. ... The haematological and urine examinations
showed no treatment related changes. The clinical chemistry examination
indicated treatment related effects on the liver...
Histopathological examination showed centrilobular
hypertrophy in all animals at 2500 ppm and 1 female from
this group with minimal hepatocytic single
cell necrosis. The NOEL for this study was 50 ppm (1.9
kg d) based on the increase in N-demethylase activity in males
at 350 ppm (14 mg kg d).
-- 3.2.4 Carcinogenicity Studies. ... In a combined chronic toxicity
and carcinogenicity study, groups of 60 Wistar
rats (strain Bor:WISW (SPF Cpb) of both sexes were administered
transfluthrin (94.5-95% pure) in the diet at concentrations of
0, 20, 200 or 2000 ppm for 109 weeks. In addition, groups of 10
male and 10 female rats were treated identically for full interim
necropsy at 52 weeks.... Fluoride accumulation
occurred in both teeth and bone (femur) at 200 and 2000
ppm in males and females at 1 and 2 yr. The reported increases
were approximately 2 and 5 fold for teeth
(from 0.1 to 0.8 mg F/g ash) and 2 and 4 fold for bone (0.5-3
mg F/g ash). The main target organs
were the liver and kidney. ... Microscopic pathology showed
"ground galss cytoplasm" in the
liver in both sexes at 2000 ppm (approx. 9/60 for males
and females) and hepatocyte hyperplasia
in males (0, 2, 1, 1 at 0, 20, 200 and 2000 ppm)...
-- B6C3F1 mice (60/group/sex) received
0, 10, 100 or 1000 ppm mg kg transfluthrin (94.8-95%) pure in
the diet for up to 104 weeks with 10/sex/dose killed after one
yar. Two additional groups(10/sex) received 0 or 1000 ppm for
13 weeks... Serum
cholesterol levels were significantly raised from
13 weeks at 1000 ppm (20% in males and 54% in females) and from
100 ppm from week 53 (approximately 11 - 30%) and at week 103
from 10 ppm in females (approximately 50 - 70%) and at 1000 ppm
in males )~ 20%). ... Fluoride accumulation in bone and teeth
of both sexes were observed (in the 13 week study at 1000 ppm)
and at 53 and 104 weeks from 100 ppm (approximately 2 fold at
100 ppm and 4-5 fold at 1000 ppm with respect to controls).
... The only gross pathological findings considered to be treatment
related were nodules in the livers of females
at 1000 ppm (incidence 6/42, 4/39, 3/42 and 15/44). On histopathological
examination, at 1000 ppm, non neoplastic findings were periacinar
hepatocyte hypertropy was observed at 53 weeks (slight
to moderate in all males and minimal in 6/10 females) and more
marked but consistent with liver enzyme
induction at 104 weeks (38/50 males, 26/50 females). ...
Based on the chronic toxicity, in males the NOEL is 10 ppm (2
mg kg d based on increases in liver weight
and hepatocyte hypertrophy, at 1000 ppm and
increased fluoride accumulation at 100 ppm). It is not possible
to set a NOEL for females as increases in serum cholesterol, protein
and albumin were reported at the lowest dose.
-- 3.2.4.1 Promotion Studies ... 3.2.3.2 Summary. An increased
incidence of urinary bladder papillomas
and carcinomas was seen following dietary administration of 2000
ppm to the rat. The mechanism of tumourigenicity is considered
to be non genotoxic. Studies using
rat hepatocytes showed that transfluthrin does not cause cell
proliferation but acts as a weak promoter with a NOEL of 5 ppm.
Transfluthrin is not carcinogenic in the mouse. In the rat the
NOEL for non-neoplastic findings is 20 ppm (1 mg kg d), based
on effects in the kidney (increased organ
weight, pigment deposition and glomerulonephrosis) at 200 ppm
and above). In the male mouse the NOEL is 10 ppm (2 mg kg d, based
on increases in liver weight
and hepatocyte hypertrophy,
at 1000 ppm and increased fluoride accumulation
at 100 ppm). It is not possible to set a NOEL for females as increases
in serum cholesterol, protein and albumin were reported at the
lowest dose.
-- 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/evallist_alphabet.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.
Trichlorotrifluoromethane
- Solvent, US EPA List 2 Inert - CAS
No. 76-13-1
Studies of 4 to 6-weeks
duration, conducted at concn <25,000 ppm, reported variable findings.
After 19 seven-hr exposures at 5000 ppm, some rats developed slight,
diffuse, degenerative fatty infiltration; no such changes or other
pathological findings were observed in three subsequent similar
studies. No clinical, biochemical, or pathologic changes developed
after twenty 3.5 hr daily exposures of rats & guinea pigs, or
rats & dogs after 20 six-hr exposures at 5100 ppm or in rats after
30 seven-hr exposures at 2520 ppm; however, after inhaling 5000
ppm, 7 hr/day for 30 days, body-weight gain was depressed in the
rat. After 14 days of continuous exposure of monkeys, dogs, mice,
and rats at 2000 ppm, no adverse effects could be detected. The
only morphologic & biochemical changes noted in male Wistar rats
inhaling 1000 or 2000 ppm CFC-113,
6 hr/day, 5 days/week were proliferation of
hepatic smooth endoplasmic reticulum & induction of hepatic microsomal
enzymes. [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, 1991.1632]
-- 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]
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
Trifloxystrobin
- Fungicide - CAS No. 141517-21-7
-- Subchronic toxicity.
In subchronic studies, several mortality related changes were
reported for the top dose in dogs (500 mg/kg) and rats (800 mg/kg).
At these dose levels, excessive toxicity has resulted in body
weight loss and mortality with the associated and non-specific
changes in several organs (such as atrophy in the thymus, pancreas,
bone marrow, lymph node, and spleen) which are not considered
specific target organs for the test compound. In the dog, specific
effects were limited to hepatocellular hypertrophy
at 150 mg/kg and hyperplasia of the epithelium of the gall bladder
at 500 mg/kg. Target organ effects in the rat were noted as
hepatocellular hypertrophy (200 mg/kg) and the related
liver weight increase (50 mg/kg).
In the mouse, target organ effects included single cell necrosis
(300 mg/kg) and hypertrophy (1,050
mg/ kg) in the liver and extramedullary
hematopoiesis (300 mg/ kg) and hemosiderosis in the spleen (1,050
mg/kg). In general, definitive target organ toxicity, mostly in
the liver, was seen at high feeding
levels of over 100 mg/kg for an extended treatment period. At
the lowest observed adverse effect level (LOAEL), no serious toxicity
was observed other than mostly non-specific effects including
a reduction in body weight and food consumption or liver
hypertrophy.
-- Chronic toxicity. The liver appears
to be the major primary target organ based on the chronic studies
conducted in mice, rats, and dogs. It was identified as a target
organ in both the mouse and the dog studies with trifloxystrobin.
However, no liver effect was seen
in the chronic rat study which produced the lowest NOAEL of 2.5
mg/kg based on reduced body weight gain and food consumption seen
at higher dose levels.
Ref: Federal Register. November 14, 2001.
[PF-1048; FRL-6806-6]
http://www.fluoridealert.org/pesticides/Trifloxystrobin.FR.Nov14.01.htm
--
Other toxicological studies. Investigations into replicative
DNA synthesis: No evidence of replicative DNA synthesis in rat
or mouse heptocytes following 3-months administration in diet.
Investigations into mitochondrial function: In
vitro studies in isolated rat liver mitochondria indicated
trifloxystrobin caused a significant concentration
dependant inhibition of mitochondrial respiration....
Ref:
Review report for the active substance trifloxystrobin. Trifloxystrobin.
SANCO/4339/2000-Final. 7 April 2003. Finalised in the [European
Commission] Standing Committee on the Food Chain and Animal Health
at its meeting on 15 April 2003 in view of the inclusion of trifloxystrobin
in Annex I of Directive 91/414/EEC.
http://www.fluorideaction.org/pesticides/trifloxystrobin.eu.april.03.pdf
Trifloxysulfuron-sodium
- Herbicide - CAS No. 199119-58-9
-- 90-Day oral toxicity
in nonrodents. NOAEL = 3.9/3.7 (m/f)
mg/kg/day LOAEL = 146.9/159.9 (m/f) mg/kg/day based on decreased
mean body weight and body weight gain, decreased hematocrit, hemoglobin,
RBC`s, SGOT, SGPT, ALP, absolute and relative liver and testes
weight; microscopic abnormalities
of the liver and testes.
-- Carcinogenicity mice NOAEL = 14.6
mg/kg/day LOAEL = 349 mg/kg/day based on increased
liver weight and increased hepatic cell tumors (adenomas and/or
carcinomas combined. (Possible) evidence of carcinogenicity
Ref: Federal Register: June 12, 2002 (Volume
67, Number 113). Triflusulfuron Methyl; Pesticide Tolerance. Final
Rule.
http://www.fluorideaction.org/pesticides/triflusulfuron.m.fr.june.02.htm
-- Chronic toxicity
dogs NOAEL = 26.9 mg/kg/day LOAEL = 116.6 mg/kg/day based on increased
liver weight, alkaline phosphatase, and
hepatocellular hypertrophy.
Ref:
Federal Register: June 12, 2002 (Volume 67, Number 113). Triflusulfuron
Methyl; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/triflusulfuron.m.fr.june.02.htm
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;
FRL-6795-4]
http://www.fluoridealert.org/pesticides/Triflusulfuron.M.FR.Aug8.01.htm
Triflumizole
- Fungicide - CAS No. 68694-11-1
-- Reproduction and
fertility effects (rat): ... Parental/Systemic: LOAEL = 21 mg/kg/
day based on decreased body weight and overall body weight gain,
increased relative liver weights,
and increased mortality in females.
-- Chronic toxicity nonrodents (dog): LOAEL = Males: 34.10 mg/kg/day;
Females: 35.17 mg/ kg/daybased on increased alkaline phosphatase
activity and a mild, macrocytic anemia
in males, increased absolute and relative liver
weights in both sexes, and on macroscopic findings in the
liver of both sexes.
-- Carcinogenicity (mouse): LOAEL = Males: 67.4 mg/kg/day; Females:
86.1 mg/ kg/day based on microscopic lesions of the liver.
No evidence of carcinogenicity.
-- 90-Day oral toxicity rodents (rats): LOAEL = Males: 176.5 mg/kg/day;
Females: 217.9 mg/ kg/daybased on increased kidney and liver
weights and the accumulation of fat droplets in the
liver.
Ref: Federal Register: June 12, 2002. Triflumizole;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Triflumizole.FR.June12.2002.htm
-- Chronic feeding/oncogenicity studies were conducted in both
the rat and mouse. The chronic feeding study in the rat suggests
that the liver is the main target organ
with the ovary and
kidney as secondary
target organs. Although there was an accompanying increase in
organ weights, no carcinogenic effects were seen. In the chronic
feeding study in mice, the results of blood chemistry, organ weights
and gross and histological examinations also indicate the liver
as the target organ...
-- A 2-year feeding/oncogenicity study with Sprague-Dawley rats
was conducted. Rats were fed 0, 5, 20 or 80 mg/kg/day doses of
triflumizole equivalent to 0, 100, 400 and 1600 ppm triflumizole
for 104 weeks with an interim sacrifice at 52 weeks. Numerous
organ weights, clinical chemistry and hematology parameters and
microscopic changes indicate the main target organ is the
liver, with fatty vacuolization and periacinar hepatic
hypertrophy seen at all dose levels tested...
-- A 2-year feeding/oncogenicity study with male and female mice
using dietary concentrations of 0, 100, 400 and 1600 ppm equivalent
to 0, 15, 60 and 240 mg/kg/day was conducted. There were interim
sacrifices at 26, 54, 78 and 104 weeks. Major effects were seen
in the liver at all doses tested.
Clinical chemistry changes reflecting liver
toxicity included changes in alkaline phosphatase, BUN, SGOT,
SGPT and cholesterol. Absolute and
relative liver weights were increased
at all time periods in the high dose males and females and in
some animals of the mid dose groups. At sacrifice, liver
changes in all dose groups included hepatic
nodules and cytoplasmic alterations. The systemic NOEL
was less than 100 ppm. Although there was a slight increase the
incidence of lymphoma in both treated males and females, it was
judged not be compound-related.
-- A 30-day feeding study with rats was conducted using dietary
concentrations of 20, 200 and 2000 ppm equivalent to 0, 2, 20
and 200 mg/kg/day. The NOEL was 200 ppm and the LEL was 2000 ppm
based on liver changes, necrosis
and fatty metamorphosis.
Ref: EPA Pesticide Fact Sheet September
1991. Triflumizole (Terraguard, Procure).
http://pmep.cce.cornell.edu/profiles/fung-nemat/tcmtb-ziram/triflumizole/fung-prof-triflumizole.html
Abstract: The hepatotoxic
effects of 22 pesticides were studied. Hepatocytes, mitochondria,
and microsomes were prepared from Sprague-Dawley-rats and incubated
with the test substances in-vitro ... Hepatic
mitochondrial respiration was affected by ...
triflumizole (68694-11-1).
Ref: Effects of pesticides on isolated
rat hepatocytes, mitochondria, and microsomes II; by YAMANO T,
MORITA S. ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY;
28 (1). 1995. 1-7.
Trifluralin
- Herbicide - CAS No. 1582-09-8
• Long term toxicity (Annex IIA, point 5.5). Target/critical
effect ‡ Body weight reduction, anemia, liver
& kidney effects (mouse, rat).
(page 46).
• Absorption,
distribution, excretion and metabolism in mammals (Annex IIA,
point 5.1). Widely distributed;
highest concentration in adrenals, fat, kidneys,
liver, skin and blood (page 45)
Ref: 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.
http://www.fluoridealert.org/pesticides/trifluralin.eu.long.2005.pdf
Triflusulfuron-methyl - Herbicide
- CAS No. 126535-15-7
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;
FRL-6795-4]
http://www.fluoridealert.org/pesticides/Triflusulfuron.M.FR.Aug8.01.htm
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