Anatomy of the pituitary
The pituitary gland is sometimes called the "master"
gland of the endocrine system, because it controls the functions
of the other endocrine glands. The pituitary gland is no
larger than a pea, and is located at the base of the brain.
The gland is attached to the hypothalumus (a part of the
brain that affects the pituitary gland) by nerve fibers.
The pituitary gland itself consists of three sections:
* the anterior lobe
* the intermediate lobe
* the posterior lobe
Functions of the pituitary
lobe of the pituitary gland produces certain hormones.
* growth hormone
* prolactin - to stimulate milk production after giving
* ACTH (adrenocorticotropic hormone) - to stimulate the
* TSH (thyroid-stimulating hormone) - to stimulate the thyroid
* FSH (follicle-stimulating hormone) - to stimulate the
ovaries and testes
* LH (luteinizing hormone) - to stimulate the ovaries or
* melanocyte-stimulating hormone - to control skin pigmentation
* ADH (antidiuretic hormone) - to increase absorption of
water into the blood
by the kidneys
* oxytocin - to contract the uterus during childbirth and
stimulate milk production
The Endocrine System:
Illustration by K. Born in Our
Stolen Future (1996)
by Theo Colborn, Dianne Dumanoski and JP Myers
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.
Insecticide, Fungicide, Propellant - CAS No. 75-45-6
Increased kidney, adrenal
and pituitary weights... The female
rats in the 50,000-ppm group exhibited a statistically significant
increase in liver (absolute and relative), kidney (absolute),
adrenal (absolute), and pituitary
(absolute, at interim sacrifice--pituitaries
were not weighed at terminal sacrifice) weights. No nonneoplastic
histopathological changes attributable to exposure to HCFC-22
were observed. The liver weight effect was not considered adverse
because it did not exceed a 10% weight change and there was no
histopathology observed. Based on effects on kidney,
adrenal, and pituitary weight,
a NOAEL of 10,000 ppm [NOAEL(HEC) = 5260 mg/cu.m] and a LOAEL
of 50,000 ppm [LOAEL(HEC) = 26,300 mg/cu.m] can be estimated.
Ref: US EPA IRIS for Chlorodifluoromethane.
- Wood Preservative, Antifoulant, Fungicide, Acaracide -
CAS No. 1085-98-9
-- One-year Study A
repeat-exposure study using Beagles (4/dose/sex) is available;
it was GLP and OECD Annex V compliant. Animals were administered
either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid
(90 % purity) in capsule form for one year. The top dose was reduced
at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity...
The pituitary glands of several animals
from the top-dose group were found to have mild to severe hyperplasia
(2 males and 2 females) of large pale staining cells (basophils)
in the pars distailis, among pituitary basophils are the thyrotrophs.
Testicular degeneration was noted in 2 animals receiving 37.5
mg kg -1 d -1 , the lesion was widespread and of moderate/severe
grade. Thymic atrophy was also reported in males receiving 37.5
mg kg -1 d -1 (3/4 animals).
-- Rat Two-Year Combined Chronic Toxicity And Carcinogenicity
Study A 2-year combined chronic toxicity and carcinogenicity study
is available. This study was carried out to EPA guidelines and
was both GLP and Annex V compliant. Wistar rats (BOR:WISW strain,
50 group/sex, plus 10/sex group interim kill) received dietary
administration of either 0, 180, 900 or 4500 ppm dichlofluanid
(89-93 % purity). This was equivalent to 9.4, 54.4 or 301.3 mg
kg -1 d -1 and 13.5, 73.1 or 420.7 mg kg -1 d -1 for males and
females respectively. Those animals scheduled as interim kills
were sacrificed after 53 weeks and study termination was scheduled
for 106 weeks. Interim blood samples were taken at weeks 26, 53
and 79 for clinical chemistry and haematology. Urinalysis was
also carried out at these time points. Deaths were reported in
both the satellite and main groups. In the main study the terminal
mortalities were 12 %, 18 %, 30 % and 16 % at 0, 180, 900 and
4500 ppm in males and 26 %, 26 %, 22 % and 20 % at 0, 180, 900
and 4500 ppm in females.... No treatment-related neoplastic alterations
were reported in the satellite group. Tumours found were a malignant
lymphoma (male 4500 ppm), a malignant fibrosarcoma of the skin
(male 4500 ppm) and a benign pituitary adenoma
(female 180 ppm). In the main group, treatment-related
tumours of the thyroid were noted.
2003 - Evaluation
on: Booster biocides in antifouling products. Full review of Dichlofluanid.
No. 206. Evaluation of Fully Approved or Provisionally Approved
Products. Prepared by : The 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 available
- Insecticide - CAS No. CAS No. 55-91-4
Sixteen of 100 rats
administered DIFP at a dose of 0.5 mg/kg every 72 hours for 730
days developed chromophobe adenomas of the pituitary
gland, a tumor with a rare spontaneous incidence.
Ref: TOXNET Hazardous Substances Data Base
for DIISOPROPYL FLUOROPHOSPHATE.
Fungicide - CAS No. 135319-73-2 (formerly
A series of mechanistic studies were performed to elucidate and
define the aromatase enzyme inhibition properties of epoxiconazole.
The following conclusions can be drawn from
the in vivo data: The effects on the ovaries are assessed to be
the result of the following: Decreasing aromatase enzyme activity
which is responsible for converting both testosterone and adrostendione
(male sex-steroids) into female sex steroids (e.g., estradiol).
This action would result in decreased estradiol (i.e., estrogen)
and increased androgen. As a consequence of reduced estradiol
levels, measured LH and FSH concentrations are slightly altered.
The increased incidences of neoplasms in the ovaries are
considered to be the result of a continuous cell proliferation
by these stimulating [[Page 57342]] hormones of the regulating
hormones of the pituitary-gonadal axis
(LH and FSH). The changes adrenals are assessed to be the result
of the following: Decreasing adrenal-cortical
enzyme activity. This action would result in decreased adrenal
hormones such as corticosterone levels. As a consequence
of reduced corticosterone levels, pronounce ACTH concentrations
are found. The increased incidences of neoplasms in the adrenals
are considered to be the result of a continuos cell proliferation
by these stimulating hormones of the pituitary-adrenal
Ref: Federal Register: September 22, 2000
[Page 57338-57344]. Notice of Filing Pesticide Petitions to Establish
Tolerances for Certain Pesticide Chemicals in or on Food. http://www.fluoridealert.org/pesticides/Epoxiconazole.FR.Sept.2000.htm
106325-08-0 Banned. Low degradability, toxic to water-living organisms
and endocrine effects. 1997."
Definition: "Banned. A substance which for health or environmental
reasons by an authority decision is either no longer approved
for any area of application, or for which an approval or registration
has been denied from the first instance."
Ref: Euopean Commission. Appendix 5. Substances
which may not be included as active ingredients in approved pesticide
products, Chapter 15, Section 2, subsection one.
- CAS No. 120068-37-3
-- Reproduction toxicity
studies. The data base for reproductive toxicity is considered
complete. No additional studies are required at this time. An
acceptable two-generation reproduction study in the rat using
fipronil concluded that the LOEL for parental (systemic) toxicity
was 30 ppm (2.54 mg/kg/day for males and 2.74 mg/kg/day for females)
based on increased weight of the thyroid
glands and liver in males and females; decreased weight
of the pituitary gland in females;
and an increased incidence of follicular
epithelial hypertrophy in the females. The NOEL for parental (systemic)
toxicity was 3 ppm (0.25 mg/ kg/day for males and 0.27
mg/kg/day for females).
-- Carcinogenic classification and risk quantification. EPA has
classified this chemical as a Group C--Possible Human Carcinogen,
based on increases in thyroid
follicular-cell tumors in
both sexes of the rat, which were statistically significant by
both pair-wise and trend analyses. EPA has used the RfD methodology
to estimate human risk because the thyroid tumors are due
to a disruption in the thyroid-pituitary
status. There was no apparent concern for mutagenicity.
Ref: Federal Register: July 17, 1998. Fipronil;
Pesticide Tolerance. Final Rule.
and developmental toxicity. In
a two-generation rat study, the NOEL for
parental (systemic) toxicity was 3 ppm (0.26 mg/kg/day for both
sexes combined), based on increased
weight of the thyroid glands and liver in males and females,
decreased weight of the pituitary gland in females, and
an increased incidence of follicular epithelial hypertrophy in
females at 30 ppm.
Ref: August 24, 2005.
Federal Register. Fipronil; Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
- Herbicide - CAS No. 69806-50-4
Fluazifop butyl was evaluated for reproductive and developmental
effects in 2 successive generations of Charles River Wistar strain
rats (30/sex/group) exposed continuously to 0, 10, 80 and 250
ppm in the diet. Each respective parent generation had received
treatment for a minimum of 100 days (F0) and 120 days (F1) prior
to mating. F0 and F1 dams weaned their progeny for 25 days postpartum
to time of offspring selection for mating and continued study
(F1) or sacrifice (F1, F2). Thirty days after sacrifice of their
offspring, the surviving F1 females and select F1 males were sacrificed
and with representative F1 and F2 offspring were examined histologically...
Necropsy of F0 parents revealed no gross pathology and, although
testes and epididymis of F0 males of a 250 ppm exposure were reduced,
histological review identified no treatment-related changes. Conversely,
F1 parents were found with gross indications of toxicity.. . Testis
and epididymis weights in the males (80, 250 ppm), and
pituitary gland (80, 250 ppm), uterus
(80, 250 ppm), brain (250 ppm) and lung weights (250 ppm) in females
were significantly reduced. Female
F1 ovarian weights were increased relative to controls in association
with a 250 ppm dietary exposure. Upon histological investigation,
increased incidence geriatric nephropathy [kidney](both sexes,
80 and 250 ppm), distension of mesenteric and/or cervical lymph
nodes (250 ppm) and increased severity of nephrocalcinosis (females,
80 and 250 ppm), and an increased slight testicular tubular atrophy
in males (250 ppm) were noted... [ICI
AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance
of Rats Treated Continuously Through 2 Generations (Final Report);
03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
- Herbicide - CAS No. 79241-46-6
The chronic dietary (all populations), intermediate-term dermal
and inhalation, and intermediateterm incidental oral endpoints
were selected from the 2-generation reproduction study in rats
based on decreased spleen, testes
and epididymal weights in males, and decreased
pituitary weights in females (page 5) ... Reproduction
and fertility effects (rats). Reproductive NOAEL = M/F 0.74/0.88mg/kg/day
LOAEL = M/F 5.8/7.1 mg/kg/day based on decreased abs. & rel
testes & epididymal weight and in females decreased pituitary
& uterine weights (age 23) ...
F1 adult females showed an absolute (28%) and relative (18%) statistically
significant increase in ovarian weight at 250 ppm. In F1 adult
females, absolute pituitary weights (13%20%)
and uterine weights (18%-25%) were statistically
significantly reduced at 80-250 ppm. Relative pituitary
weights (18%-27%) and uterine weights (19%-29%) were reduced in
F1 adult females at 80-250 ppm.
• Comments about Study/Endpoint/Uncertainty Factor: The
study/dose/endpoint is appropriate for the route (oral) and duration
(chronic) of concern. Although the endpoint of concern in based
on male reproductive effects, decreases
in pituitary and uterine weights were seen in females at a comparable
NOAEL (0.88 mg/kg/day) and LOAEL (7.1 mg/kg/day) (page
December 10, 2004. US
EPA> Fluazifop-P-butyl: Revised HED Chapter of the Tolerance
Reassessment Eligibility Decision (TRED) Document. EPA Docket
Acaricide, Insecticide - CAS No. 70124-77-5
-- Groups of 6 male
and 6 female Beagle dogs received technical flucythrinate (87.3%
pure) in the diet at 0, 30, 100, or 300 ppm daily for 24 months...
At sacrifice, the relative liver, kidney,
and pituitary weights were increased
in both high-dose males and females, while increases in relative
spleen, testis and lung weights were
noted for high-dose males only... ((Spicer et al., 1984).
Ref: 1985 World Health Organization Review
- Herbicide - CAS No. 2164-17-2
A histological re-examination and statistical analysis of pituitary
adenomas in Fischer 344 rats from a combined chronic toxicity/oncogenicity
study (0, 10, 300, or 1000 ppm [83-51) indicated no significant
increasing trends in male rats, but a significant
difference was observed in a pairwise comparison of the 10 and
1000 ppm dose groups with the controls for pituitary adenomas
was significant at p < 0.05, and a significant difference observed
in the pair-wise comparison of the 300 ppm dose group with the
controls for pituitary adenomas at p < 0.01. The pituitary
adenoma tumor rates in male rats were 3/47,9/51, 1 1/51, and 9/58,
respectively (L. Taylor Memorandum 9/13/95. TXR 012742). There
were no compound related tumors observed in female rats. Two other
studies submitted by the National Cancer Institute (NCI) for both
mice and rats were either unremarkable or the results equivocal.
However, genotoxicity studies with fluometuron were negative.
February 1, 2005. US EPA: Fluometuron: Revised HED Risk Assessment
for Phase III of the Reregistration Eligibility Decision. Docket
Identification Number: OPP-2004-0372-0008.
- CAS No. 136426-54-5
-- Oral long-term toxicity
and carcinogenicity. 2-year dietary study in rats. groups of 50
male and 50 female outbred albino Sprague-Dawley CRL :COBS CD(SD)BR
rats were administered fluquinconazole (93.2% purity) in the diet
at concentrations of 0 (control), 1, 20 or 100 ppm. Additionally
20 animals/sex/dose designated for the interim-kill received the
test compound at concentrations of 0, 1, 5, 10 or 100 ppm for
12 months... Mortalities over the 24-month period were 24/50,
28/50, 28/50 and 31/50 in males and in females 33/50, 36/50 and
39/50 at dose levels of 0, 1, 20 and 100 ppm... Post-mortem examinations
showed the most probable cause of deaths in males to be pituitary
tumors followed by chronic progressive
urinary tract infections. In females mammmary
tumors followed by pituitary tumors
were considered the most probable cause of morbidity... In the
thyroid gland a significantly higher incidence in follicular
cell tumors were noted in the 100 ppm dose level in both
sexes. Historical tumor incidences provided showed that the slight
statistically non-significant increase in thyroid follicular cell
tumors at the lowest and intermediate dose levels were
at the upper limit of the historical control range and therefore
in the absence of a dose response they were considered to be not
of toxicological significance...
Ref: Evaluation on: Fluquinconazole. May
1999. No. 184. Evaluation of Fully Approved or Provisionally Approved
Products. Department for Environment, Food and Rural Affairs,
Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme
Green, York YO1 7 PX, UK. Available online:
- Herbicide - CAS No. 141112-29-0
Isoxaflutole demonstrates developmental toxicity and has been
classified as a Group B2 carcinogen (probable human carcinogen).
-- In a combined chronic toxicity/carcinogenicity study in rats,
evidence of systemic toxicity was observed at 500 mg/kg/day and
included: abnormal gait, limited use of limbs, lower body weight
gains and food consumption, decreased food efficiency during the
first 14 weeks of the study, elevated cholesterol levels throughout
the 104-week study, increased absolute and relative liver weights,
and thyroid hyperplasia. Increased incidence of periacinar hepatocytic
hypertrophy, portal tract (senile) bile duct changes, focal cystic
degeneration of the liver was observed in males at 20 mg/kg/day
and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy
changes in eyes, corneal lesions, degeneration of sciatic nerve
and thigh muscles was observed in males at 20 mg/kg/day and higher
doses and in females at 500 mg/kg/day. The chronic LOAEL is 20
mg/kg/day based on liver, thyroid, ocular, and nervous system
toxicity in males and liver toxicity in females. The chronic NOEL
is 2.0 mg/kg/day.
-- Under the conditions of this study, isoxaflutole induced benign
and malignant tumors of the liver in both sexes at 500 mg/kg/day
hepatocellular adenomas and hepatocellular carcinomas. Combined
incidences of liver adenoma/carcinoma in males and females showed
animals bearing carcinomas in the majority. Thyroid follicular
adenomas occurred with increased frequency in 500 mg/kg/day males.
The tumor incidences exceeded the historical incidence of these
tumors for this strain in the laboratory. The study demonstrated
that isoxaflutole is carcinogenic to rats at a dose of 500 mg/kg/day.
The chemical was administered at a dose sufficient to test its
carcinogenic potential. At 500 mg/kg/day, there were alterations
in most of the parameters measured including clinical signs of
toxicity, body weight gain, food consumption, food conversion
efficiency, and clinical as well as post-mortem pathology. Thyroid
stimulating hormone (TSH) was not measured in this study. However,
in a separate special study investigating the mechanism of action
of isoxaflutole on the thyroid, tested at the same doses as this
study, TSH was indirectly measured since there was a significant
reduction in T4 level and thyroid gland weights were significantly
results were sufficient to support the hypothesis that isoxaflutole
may have induced thyroid tumors in male
rats through a disruption in the thyroid-pituitary hormonal feedback
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole
Reason for Issuance: Conditional Registration Date Issued: September
- Herbicide - CAS No. 42874-03-3
Absolute and/or relative organ weights in the high-dose groups
that showed statistically significant changes
relative to control weights (thyroid gland in both
sexes and kidney in females at 12 months and brain, pituitary,
and spleen in females sacrificed at 24 months) had no microscopic
correlates and are not considered toxicologically significant.
Ref: US EPA. Toxicology Chapter for RED.
August 8, 2001.
- Fungicide - CAS No. 124495-18-7
-- 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
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 - Fluoride exposure can
cause moderate functional changes in the hypophysis-thyroid gland
system without any clinical manifestations.
note: Hypophysis = Pituitary gland]
Hazardous Substances Data Bank for SODIUM HYDROGEN DIFLUORIDE CASRN:
Tembotrione - Herbicide - CAS No. 335104-84-2
• Certain changes in multiple organs seen in the subchronic, chronic, dermal, and reproduction studies (e.g., microscopic changes in the thyroid gland, adrenal gland, and pancreas; increased number of corpora lutea in the ovary, and delayed preputial separation) may be due to various mechanisms including possible liver-pituitary-thyroid homeostatic disruption or inhibition of steroid synthesis (Page 6)... When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, tembotrione may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption (page 29).
• In the 2-generation reproduction study in rats, offspring effects. Treatment-related decreases (p≤0.05) in pup body weights were observed: in the F1 pups at 200 and 1500 ppm beginning on PND 7 and continuing throughout the reminder of the post-natal period; and in the F2 pups at 200 ppm beginning on PND 21 and at 1500 ppm beginning on PND 14. Body-weight gains in these groups were dose-dependently decreased. Compared to controls, the time until preputial separation was dose-dependently delayed in all treated groups in the F1 and F2 offspring. This effect was considered treatment related. Also, the time to vaginal opening was longer in the 1500 ppm F1 offspring (page 68).
• In the 2-generation reproduction study in rats, offspring effects. The LOAEL for offspring toxicity is 20 ppm (equivalent to 1.4/1.6 mg/kg/day in males/females) based on effects on the eyes, including corneal opacity, acute inflammation, and neovascularization; increased incidences of minimal extramedullary hematopoeisis in the spleen, delayed preputial separation, and decreased absolute brain weight. The NOAEL was not observed (page 68).
• In a carcinogenicity study with mice (MRID 46695706), AE 0172747 (95% w/w a.i.; Batch No. PFI 0195) was administered in the diet to C57BL/6 J@ Ico mice (50/sex/dose) at doses of 0, 30, 300, 1000, or 3000 ppm (equivalent to 0/0, 4/5, 43/54, 146/179, and 440/552 mg/kg/day in males/females) for up to 78 weeks. Additionally, 10 mice/sex/dose were treatedsimilarly for up to 52 weeks. At 1000 ppm and above at 18 months, the incidences of the following lesions were increased in males:
(i) minimal to marked epithelial hyperplasia (multifocal/diffuse) in the gallbladder;
(ii) minimal to marked focal tubular degeneration (bilateral) in the testes; and
(iii) minimal to slight interstitial cell hyperplasia (focal/multifocal) in testes. Increased incidences of dilatation of uterine horns were noted grossly at ≥1000 ppm.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.
• Thyroid gland toxicity was observed in the 21/28-day dermal toxicity study in the rat and chronic oral toxicity study in the dog. Dermal exposure (21/28-day study) resulted in colloid alteration and hypertrophic follicular epithelium in the thyroid gland in the rat. Also observed were degenerative changes in the pancreas, increased proteinacious material in the Ratche pouch in the pituitary gland and basophilic tubules in the kidneys. Pigmentation of the thyroid gland along with hematological changes and microscopic changes in the sciatic nerve were observed in the dog.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.
- Fungicide - CAS
• Chronic & Carcinogenicity Studies.
Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to males
only) of tetraconazole in the diet for 2 years... Pituitary
weights were reduced, with enlarged or vacuolated cells in the
pars anterior in males at 640 and 1280 ppm. (page 5)
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
- Herbicide - CAS No. 117718-60-2
-- There was no evidence
of carcinogenic effects in an 18-month chronic/oncogenicity study
in mice at dose levels up to and including 800 ppm (216 mg/kg/day).
In rats, an increased incidence of thyroid
follicular tumors in males at the two highest doses, 1000 (44.2
mg/kg/day, males) and 3000 ppm, (136.4 mg/kg/day) was observed,
and there was a low incidence of renal tubular adenoma at the
high dose only in females. The thyroid
tumors were determined in three special thyroid function studies
to be secondary to a disturbance of thyroid/pituitary homeostasis
and were attributed to a hormonally-mediated
mechanism for thyroid tumor induction.
The effects were dose-responsive and with the exception of thyroid
weight, all effects were completely reversible when thiazopyr
was removed from the diet. Based on limited evidence for carcinogenicity,
thiazopyr is classified as Category C, possible human carcinogen,
by the USEPA Health Effects Division Carcinogenicity Peer Review
Committee. A NOEL of 4.4 mg/kg/day
and a Margin of Exposure approach were selected for use
in carcinogenicity risk assessment.
-- Special mechanistic studies for mode of toxic action on
thyroid function. The results of three studies on the effects
of thiazopyr on thyroid function and mechanisms involved
in the disposition of T4 in rats were reviewed. These studies
are described below:
---- a. Thiazopyr was administered through
the diet at 0 and 150 mg/kg/day rats to determine the subchronic
effect on hormone level and other biochemical endpoints. Animals
were assayed at 7, 14, 28, 56 or 90 days. Significant decreases
in body weight gain were observed at 90 days. Early in the study
the treated rats showed increases in TSH (ranging from 133 to
200% of controls) and decreases in T4 (ranging from 43% to 76%
of controls). In addition there were increases in liver and thyroid
weights and increases in thyroid follicular cell hypertrophy/hyperplasia.
Reverse T3 was increased at 28 days, and T3 was either not affected
or increased. There were indications of increases in hepatic UDPGT
activity and significant increases in T4 UDPGT activity. Hepatic
5'-monodeiodinase activity was either not affected or decreased.
The effects observed in this study were supportive of the theory
that thiazopyr may induce thyroid
tumors through a disruption in the thyroid-pituitary hormonal
---- b. 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.
---- c. A third thyroid function study on the biochemical mechanisms
involved with disposition of T4 in rats fed dosages of 0 and 150
mg/kg/day for 56 days was conducted. Rats feed thiazopyr had increase
T4 UDPGT activity and total deiodinase activity in their livers.
There was also a two-fold increase in mixed function oxidase
-- Results of the three studies suggest
that increased glucuronidation, deiodination of T4 and T3, and
increased rate of clearance of T4 from the blood and excretion
of the hormone and its metabolites in the bile could significantly
reduce the level of circulating T4 in the male rat. Results of
these studies support the hypothesis tht thiazopyr may induce
thyroid tumors through a disruption of the
thyroid-pituitary hormonal feedback mechanism circulating T4 in
the male rat.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr
Reason for Issuance: Registration of a New Chemical Date Issued:
February 20, l997.
- Fungicide -
CAS No. 141517-21-7
In the rat chronic/carcinogenicity study, the NOAEL of 11.0 mg/kg
bw/day was set based on the reduction in body-weight gain in both
sexes, decreased food consumption and slightly
increased incidence of developmental cyst in pituitary gland and
angiomatous hyperplasia of the mesenteric
node in males. An effect on the liver (increased relative
weight) was seen only in females at the highest dose level of
73 mg/kg bw/day.
Ref: January 30, 2004 - Regulatory
Note REG2004-03. Canada Pest Management Regulatory Agency.
Also available at: