Thymus - Adverse Effects
Fluorinated and Fluoride Pesticides

Some background information: The thymus gland lies in the upper part of the mediastinum behind the sternum and extends upwards into the root of the neck. It weighs about 10 to 15 g.(about half an ounce) at birth and begins to grow until the individual reaches puberty when it begins to atrophy. It’s maximum weight is around 30 - 40g (around 1 to 1.5 ounces) by the age of 40 it has returned to it’s weight at birth. The thymus consists of two lobes connected by areolar tissue. The lobes are enclosed in a fibrous capsule which dips into their substance dividing them into lobules that consist of an irregular branching framework of epithelial cells and lymphocytes.
Function: Lymphocytes originate from haemocytoblasts (stem cells) in red bone marrow. Those that enter the thymus mature and develop into activated T-lymphocytes i.e. able to respond to antigens encountered elsewhere in the body. They then divide into two groups :
those that enter the blood, some of which remain in circulation and some lodge in other lymphoid tissue
those that remain in the thymus gland and are the source of future generations of T-lymphocytes.
The maturation of the thymus and other lymphoid tissue is stimulated by thymosin, a hormone secreted by the epithelial cells that form the framework of the thymus gland. Involution of the gland begins in adolescence and, with increasing age the effectiveness of T- lymphocyte response to antigens declines. Ref:

The Endocrine System:

Illustration by K. Born in Our Stolen Future (1996)
by Theo Colborn, Dianne Dumanoski and JP Myers

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.

Acrinathrin - Acaracide, Insecticide - CAS No. 103833-18-7

SUBCHRONIC TOXICITY STUDIES 1. Rats Study by Dietary Repeat Dose for 90 Days Followed by a 28-Day Recovery Period Group of 20 male and 20 female CD (SD) rats were fed diet containing 0, 30, 100 or 300 ppm of acrinathrin for 90 days... Other microscopic findings observed were lymphoid deletion in the spleen and thymus in 5 females of the 300 ppm group and medullar [marrow] atrophy in 2 females of the 300 ppm group... The No Observed Effect Level (NOEL) for this study was considered to be 30 ppm (male: 2.4 mg/kg/day; female: 3.1 mg/kg/day) (Centre International de Toxicologie, 1988).
Ref: Summary of Toxicological Studies on Acrinathrin Market Development, AgrEvo Japan Limited (Received January 26, 1998 ; Accepted March 20, 1998).

Carfentrazone-ethyl - Herbicide - CAS No. 128639-02-1

Short-Term Studies... In dogs (1/sex/group) given capsules containing carfentrazone-ethyl at doses up to 1000 mg/kg bw/day for 28 days, food consumption and body weight gain were decreased, plasma urea was slightly increased and plasma glucose was slightly decreased. Total urinary porphyrins were elevated in the male at 1000 mg/kg bw/day and in females at ¥ 500 mg/kg bw/day. Decreased thymus weight and cortical atrophy were observed in animals at 1000 mg/kg bw/day and decreased uterus weights were observed in females at this dose.
Ref: April 2000 - Australia. Evaluation of the new active CARFENTRAZONE-ETHYL in the product AFFINITY 400 DF HERBICIDE. National Registration Authority for Agricultural and Veterinary Chemicals. NRA Ref. 51555.
Also available at

Clodinafop-propargyl - Herbicide - CAS No. 105512-06-9

Subchronic toxicity. A 90-day feeding study in rats at 1,000 ppm resulted in reduced body weight gain, increased liver weights, hematological changes, and increased serum activities of the alkaline phosphatase. Target organs were liver (increased weight), thymus (atrophy) and spleen (reduced weight). The changes were reversible during 4 weeks of recovery. The NOAEL was 15 ppm (0.92 mg/kg in males and 0.94 mg/kg in females). The EPA HIARC suggested the NOAEL in female rats was 8.24 mg/kg bw/day.
Ref: Federal Register: April 26, 2000 [Page 24471-24477].

Cyfluthrin - Insecticide - CAS No. 68359-37-5

28-day rat inhalation study (short-term): Decreases in body and thymus weights, hypothermia and clinical pathology in rats in a 28-day study (short-term) and behavioral effects in rats in a 90-day study (intermediate/ chronic)
Ref: Federal Register: May 17, 2001, Cyfluthrin; Pesticide Tolerances for Emergency Exemptions. Final Rule.

Cyhalofop-butyl - Herbicide - CAS No. 122008-85-9

Palatability and Four-Week Dietary Probe Study in Beagle DogsÓ; (M.J. Mizell, K.T. Hart and J.W. Crissman; The Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical Company, Midland, MI; Study ID. DR-0298-8876-004; 9/11/90); In a preliminary palatability study, one beagle dog/group received 250, 500 or 1000 mg/kg/day of XRD-537 nBu (Technical) (AGR 276541, purity: 98.2%) for up to 2 weeks... In the second study, 2 beagle dogs/sex/group received targeted doses of 0, 35, 100 or 350 mg/kg/day for 4 weeks. Based on the food consumption, the low dose animals received doses of 36, 36, 34 or 53 mg/kg/day, the intermediate dose animals consumed doses of 85, 86, 133 or 138 mg/kg/day and the high dose animals received doses of 193, 203, 37 or 292 mg/kg/day, respectively... Gross examination of the tissues revealed slight to very severe atrophy of the thymus in a dose-related manner... In the microscopic examination, multifocal vasculitis and thrombosis was noted in the kidneys of the 2 high dose males and one intermediate and one high dose female, respectively. Diffuse atrophy of the thymus ranged from slight to very severe in a dose-related manner for the males in all of the groups and from moderate to severe for the intermediate and high dose females. In the testes, spermatogenesis was moderately to severely reduced in the high dose males with a concomitant increase in multinucleated spermatids. Apparent target organs: thymus and testes; Possible adverse effect: atrophy of the thymus and reduced spermatogenesis in the testes; NOEL can not be determined; Study supplemental. (Moore, 11/20/00)
Ref: February 16, 2001. California Environmental Protection Agency Department of Peticide Regulation. Medical Toxicology Branch. Summary of Toxicological Data. Cyhalofop-Butyl. Chemical Code # 5748, Tolerance # 52840 SB 950 # New A.I.

Diflufenican - Herbicide - CAS No. 83164-33-4

--Subacute toxicity studies... In a 13-week oral study in the dog, the minimum effect level was 250 mg/kg bw based on enemis and increased cholesterol levels at the 250 mg/kg bw/day dose level. The observed effects at higher dose levels included impaired body weight gain, emesis, increased plasma cholesterol and increase in the relative thymus weights.
-- Acceptable daily intake (ADI). The acceptable daily intake of 0.2 mg/kg bw/day is derived from the critial minimum effect level of 500 ppm (24 mg/kg bw/day), derived from the 24-month chronic dietary study in the rat or the multigeneration study in the rat and allows for a 100-fold safety factor. The observed effects included minimal reductions in body weight gain and a slight reduction in thymus weights at the 500 ppm dose level.
Ref: September 1995. Evaluation on Diflufenican. 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 7PX, UK. Available at:

Diflufenzopyr - Herbicide - CAS No. 109293-97-2

Toxicological Profile... A 90-day feeding study in the dog at approximate doses of 0, 0.25, 1, 5, 50, 150, or 400 mg/kg/day. Liver, kidney, stomach, and thymus were identified as target organs. The NOEL was 50 mg/kg/day. The maximum tolerated dose was exceeded at > 150 mg/kg/day.
Ref: Federal Register: November 21, 1997 [Page 62304-62308].

Dithiopyr - Herbicide - CAS No. 97886-45-8

The following results were presented by a Monsanto scientist.
-- Four-week Feeding Study in Mice. Dithiopyr was administered via the diet to groups of 6 male and 6 female CD-1 mice for 4 weeks at concentrations of 0, 300, 1000, 3000, 10,000 and 30,000 ppm... [No concentrations listed for the following effects:]-- Liver enlargement and discoloration, adrenal enlargement, and atrophy of the thymus, spleen, seminal vesicles, ovaries and uterus were noted on gross post-mortem examination... (The Institute of Environmental Toxicology, 1987)
Ref: Summary of Toxicology Studies With Dithiopyr. Dennis P. WARD. Toxicology Department, The Agricultural Grop, A Unit of Monsanto Company (Received February 20, 1993). Also available at

Flonicamid - Insecticide - CAS No. 158062-67-0

90-Day oral toxicity (nonrodents- dogs). NOAEL is 8 mg/kg/day in males and 20 mg/kg/day for female. LOAEL is 20 mg/kg/day in males and 50 mg/kg/day in females, based on acute clinical signs in males and females (vomiting, first observed on Day 1 and last observed on Day 90), clinical pathology at 7 weeks (increased total protein levels in males, lower red blood cells and higher reticulocytes counts in females), increased adrenal weights in males, decreased thymus gland weights in males, and increased kidney tubular vacuolation in females at study termination.
Ref: August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule. Federal Register.

Fluazifop-butyl - Herbicide - CAS No. 69806-50-4

**411-083 069476 Virgo, D. M., "Fluazifop-butyl: 55 week oral toxicity study in beagle dogs," Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in extremis prior to term, generally after at least 29 weeks on study... Platelet counts were reduced by about half in both sexes. Bone marrow samples taken at weeks 10 and 52 for smear analyses showed "reduced numbers of megakaryocytes," suggesting reduced production as a reason for low platelet counts. Other hematology-related findings included increased incidence/degree of thymic involution, decreased lymphocyte counts, increased degree of hemosiderin-laden Kupffer cells, hypercellular sternal marrow, and severe extramedullary hematopoiesis in 4 male and 1 female decedent. Four of the latter 5 dogs also had substantially increased splenic weights, "pallor" in clinical signs as part of moribund condition, and their final hematology red cell values (RBC count, Hb, HCT) were very low....
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.

• Thymic involution:
-- One major change that occurs as the body ages is a process termed "thymic involution." ... As humans age, the thymus naturally atrophies... Once the immune system fully develops and can protect the host against a myriad of antigens, the thymus may be too costly to maintain, so it is evolutionarily advantageous to decrease the amount of thymic tissue and use the energy that would have supported the thymus for other purposes. However, because T cells play such a prominent role in immunity, longer-lived individuals still need a continuous supply of "fresh" T cells to protect against newly-encountered antigens, and this slow but progressive loss of thymic tissue has profound effects on the entire immune system of the aged.
Ref: The Immunology of Aging
Also see: Thymic involution tied to progression of pediatric HIV infection

Fluazinam - Fungicide - CAS No. 79622-59-6

In subchronic and chronic toxicity studies, fluazinam targeted the following organs: liver, lung, uterus, testes, pancreas, thymus, thyroid, stomach, eyes and brain.
Ref: Canada: Regulatory Note REG2003-12. Fluazinam. Pest Management Regulatory Agency. Health Canada. Ottawa. October 27, 2003.

Flubendiamide - Insecticide - CAS No. 272451-65-7

Results of a reproductive toxicity study in rats (exposure route not stated):
Thyroid, liver, uterine, thymus, and spleen weight changes in 2000 and 20000 ppm F1 and F2 pups.

Ref: TSCA Health & Safety Study Cover Sheet "Public Display Copy"
•• This document was cited at EPA's site: "TSCA 8(e) and FYI Submissions Received from 11-15-04-11-26-04". It is important to note this as the document itself does not identify flubendiamide or its CAS No.
•• This study was conducted in the laboratory of The Institute of Environmental Toxicology - Japan
•• Source of Data/Study Sponsor: Bayer Material Science Corporation, 100 Bayer Road, Pittsburg PA 15205

Fludioxonil - Fungicide - CAS No. 131341-86-1

-- A carcinogenicity study in mice administered technical fludioxonil in the diet at 0, 10, 100, 1,000, and 3,000 ppm (0, 1.1, 11.3, 112, and 360 mg/kg/day for males and 0, 1.4, 13.5, 133, and 417 mg/kg/day for females)... Other macroscopic changes in female mice were an increased incidence of enlarged thymus, spleen, mediastinal lymph node, and liver and an increased incidence of lymphoma in these organs. The LOAEL is 112 mg/ kg/day for male mice, based on the increased incidence of clinical toxicity and 417 mg/kg/day for female mice, based on the increased liver weight and the increased incidence of macroscopic pathology.
Ref: Federal Register. October 7, 1998. Fludioxonil; Pesticide Tolerance. Final Rule.

-- In a 4 week dermal toxicity study, where the animals were treated 5 days per week, there were no signs of skin irritation at up to 1000 mg/kg bw/day. The NOAEl was 200 mg/kg bw/day, based on the presence of enlarged macrophages in the thymic cortices of all females at 1000 mg/kg bw/day. This finding is unexpected since it has not been reproduced in any other study where the animals have been systemically exposed to high doses of fludioxonil for long periods. It may be a phenomenon of high dose exposure via the dermal route.
-- The plant metabolites CGA 192155, CGA 265378, CGA 308103, and the chicken metabolite CGA 309565, were of low acute oral toxicity to the rate with LD50's of >2000 mg/kg bw, except for CGA 309103 where the LD50 was >1000 mg/kg bw. At gross necropsy, spotted thymuses were noted in all females (all of which died within one day of dosing) treated at 2000 mg/kg bw CGA 308103, but not at the lower dose levels, 200, 500 and 1000 mg/kg bw. The significance of the findings in the thymuses of the animals which died was not investigated further. In Salmonella typhimurium reverse mutation assays, the 4 above mentioned plant metabolites showed no evidence of mutagenic potential. The above results give further assurance that consumer risk from exposure to these metabolites is acceptable.

Ref: Evaluation of Fludioxonil. UK Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX. March 1995.
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Flufenpyr-ethyl - Herbicide - CAS No. 188489-07-8

-- EPA has not had the opportunity to review the toxicity studies on flufenpyr-ethyl and has not established toxic endpoints.
-- In an additional study, flufenpyr-ethyl technical was tested in rats at dose levels of 0, 1,000, 10,000, and 20,000 ppm in the diet for 13 weeks. Effects observed included urinary incontinence, increased food and water consumption, and mild urinalysis, hematological and blood biochemistry changes. Thymus weights were slightly increased...
-- Mice. In a 4-week study, CD-1 mice were fed pure flufenpyr- ethyl at dose levels of 0, 300, 1,000, 3,000, and 7,000 ppm. Effects were slight anemia, changes in blood biochemistry, increased liver and thymus weights, and enlarged liver...

Ref: Federal Register: June 25, 2003 (Volume 68, Number 122)] [Notices] [Page 37813-37820]. Flufenpyr-ethyl; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

Flumioxazin - Herbicide - CAS No. 103361-09-7

-- "Three-Month Subacute Toxicity Study of S-53482 by Dietary Administration in Rats"; (Haruhiko Adachi; Sumitomo Chemical Co., Environmental Health Science Laboratory,, Ltd., Osaka, Japan; Study No. 1760; 4/26/91); Sixteen Crj:CD (SD) rats/sex/group were treated in the diet with 0, 30, 300, 1000 or 3000 ppm of S-53482 (lot no. PYG-89021-M, purity: 94.8%). Six of these animals/sex/group were treated for 5 weeks. The remaining 10 animals/sex/group were treated for 13 weeks ((M): 0, 1.94, 19.4, 65.2, 197.3 mg/kg/day, (F) 0, 2.22, 22.4, 72.8, 218.4 mg/kg/day)... Other noted lesions for the 3000 ppm females were... atrophy of the thymus and the presence of thymal foam cells (0:0/10 vs. 3000: 3/10), sinus histiocytosis in the mesenteric lymph node (0:0/10 vs. 3000: 3/10), and cytoplasmic vacuolation in the adrenal cortex (0:0/10 vs. 3000: 3/10)...
Ref: January 32, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

Fluorouracil - Former insect Chemosterilant; now used as a pharmaceutical - CAS No. 51-21-8

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus.
Ref: TOXNET profile from Hazardous Substances Data Base.

Hydramethylnon - Insecticide - CAS No. 67485-29-4

-In a prenatal developmental toxicity study, MRID 00061790, groups of 26 pregnant female Sprague-Dawley rats were given oral administration of hydramethylnon at doses of 0, 3, 10, or 30 mg/kg/day on gestation days 6-15. The vehicle controls were dosed with corn oil. The dams were sacrificed and examined on gestation day 20... At 30 mg/kg/day, a 16% decrease in maternal body weight, increased incidence of clinical signs (nasal mucus, alopecia, soft stool, staining of the ano-genital fur), yellowish discoloration of the fat, and small thymus were observed. For developmental toxicity, the NOAEL was 10 mg/kg/day and the LOAEL was 30 mg/kg/day, based on decreased mean fetal weights, increased incidence of rudimentary structures, and increased incidence of incompletely ossified supraoccipital. This study is classified as acceptable and satisfies guideline requirement 83-3(a) for a developmental toxicity study in rats.
Ref: US EPA. Reregistration Eligibility Decision (RED) Hydramethylnon. EPA 738-R-98-023. December 1998.

Indoxacarb - Insecticide - CAS No. 173584-44-6

**52425-054 162226 "Combined Chronic Toxicity/Oncogenicity Study with DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127) Two-Year Feeding Study in Rats" (Frame, S. 835-E. I. du Pont de Nemours and Company, Haskell Laboratory, Elkton Road, Newark, Delaware, Study HLR 1174-96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062-106, 47.5% DPX-KN128) was given in the diet daily to males at 0, 20, 40, 60, 125 or 250 ppm and females at 0, 10, 20, 40, 60 or 125 ppm for 24 months. Deaths of one female at 60 ppm and seven at 125 ppm during the first year were associated with bone marrow atrophy, splenic lymphoid depletion and thymic necrosis... After two years, secondary changes were seen in the liver, spleen, bone marrow, kidneys and thymus in high dose groups.
Ref: March 11, 1999: Summary of Toxicology Data - Indoxycarb. California EPA Department of Pesticide Regulation, Medical Toxicology Branch.

Lactofen - Herbicide - CAS No. 77501-63-4

-- Subchronic feeding-- Mice-- 3-month. Groups of Male and female mice were fed diets containing Lactofen Technical at concentrations of 0, 40, 200, 1,000, 5,000, and 10,000 for 13-weeks. At week 5, the dosage of the 40 ppm groups was increased to 2,000 ppm. Treatment related mortality occurred at dosages above 1,000 ppm. The LOEL was 200 ppm based on: increased WBC; decreased hematocrit, hemoglobin and RBC; increased alkaline phosphatase, SGOT, SGPT, cholesterol and total serum protein levels; increased weights or enlargement of the spleen, liver, adrenals, heart and kidney; histopathological changes of the liver, kidney, thymus, spleen, ovaries and testes. In general, effects were slight in the 200 ppm groups, and moderate to severe in the 1,000 ppm groups.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.

Oxyfluorfen - Herbicide - CAS No. 42874-03-3

Absolute and relative thymus weights were decreased in mid-dose males (-14%/-10%)and high-dose males (-32%/- 18%)...Vacuolation of the adrenal cortex was present in high-dose females. Thymic atrophy occurred in high-dose males and females.... Fine vacuolation of adrenal glands (slight)and cortical atrophy of the thymus (slight) were increased in high-dose males...
Ref: US EPA. Toxicology Chapter for RED. August 8, 2001.

Quinoxyfen - Fungicide - CAS No. 124495-18-7

-- (Corlett, 8/27/01) 030; 181171; "XR-795: Palatability and Toxicity Probe Study in Beagle Dogs" (Szabo, J.R. and Rachunek, B.L., Health and Environmental Sciences-Texas Lake Jackson Research Center, The Dow Chemical Company, Freeport, Texas, Laboratory Project Study ID: DR-0325-7474-001, 2/28/92). XR-795 (TSN100008, Lot # DECO-36-111, purity = 98.8%) was admixed to the diet at dose levels of 0 (untreated diet only), 100, 500, or 1000 mg/kg/day and fed continuously to 1 beagle dog per sex per dose for 30 days. No clinical signs were observed. A treatment-related decrease in body weight gain or outright body weight loss at all dose levels in males and at 500 and 1000 mg/kg/day in females was observed. A treatment-related decrease in feed consumption in males at all dose levels and in females at 500 and 1000 mg/kg/day was observed. Macroscopic examination revealed a small/atrophic thymus in both the male and the female at 1000 mg/kg/day and small/atrophic testes in the male at 1000 mg/kg/day. Microscopic examination revealed vacuolation of midzonal and centrilobular hepatocytes at 500 and 1000 mg/kg/day in both sexes and thymic lymphoid depletion in the male and female at 1000 mg/kg/day. No adverse effects. NOEL (M) < 100 mg/kg/day, NOEL (F) = 100 mg/kg/day (based on body weight and feed consumption data). Supplemental (only 1 animal per sex per dose was used and the animals were only dosed for 30 days). (Corlett, 8/28/01)
Ref: October 4, 2001 - SUMMARY OF TOXICOLOGY DATA QUINOXYFEN (XDE-795 & XR-795). California EPA, Department of Pesticide Regulation, Medical Toxicology Branch

PFOS - PFOA - Insecticide, US EPA List 3 Inert

Abstract: The effects of peroxisome proliferators on the immune system of male C57B1/6 mice have been investigated. Significant atrophy of the thymus and spleen was observed in animals treated with potent peroxisome proliferators (e.g. perfluorooctanoic acid (PFOA), di(2-ethylhexyl)phthalate (DEHP), Wy-14643 and nafenopin), whereas the effects of a moderate peroxisome proliferator (i.e. acetylsalicylic acid (ASA)) were relatively weak. The time course of thymic and splenic atrophy caused by PFOA was found to resemble the time course of the increase in liver weight and of peroxisome proliferation... Interestingly, in vitro exposure to PFOA for up to 24 h did not produce analogous effects in either thymocytes or splenocytes. Thus, the thymic and splenic atrophy caused by PFOA appears to involve an indirect pathway."
Ref: 2000. Clin Exp Immunol Nov;122(2):219-26. Effects of peroxisome proliferators on the thymus and spleen of mice; by Yang Q, Xie Y, Depierre JW.

3.5 Reproductive Toxicity Studies in Animals
York (2002) conducted an oral two-generation reproductive toxicity study of APFO, which is summarized below. Although this preliminary risk assessment focuses on developmental toxicity, the summary below of the two generation reproductive toxicity study includes all endpoints. Five groups of 30 Sprague-Dawley rats per sex per dose group were administered APFO by gavage at doses of 0,1,3,10, and 30 mg/kg/day six weeks prior to and during mating. Treatment of the F0 male rats continued until mating was confirmed,and treatment of the F0 female rats continued throughout gestation, parturition, and lactation....
Parental Males (F0)... At necropsy, statistically significant reductions in terminal body weights
were seen at 3,10,and 30 mg/kg/day. Absolute weights of the left and right epididymides, left cauda epididymis, seminal vesicles (with and without fluid), prostate, ,left and right adrenals, spleen, and thymus were also significantly reduced at 30 mg/kg/day... All organ weight-to-terminal body weight and ratios were significantly increased in all treated groups...
F1 Males ...
The absolute weight of the thymus was also significantly decreased in the 10 and 30
mg/kg/day dose groups...
The ratios of the spleen weight-to-brain weight were significantly decreased at 1 mg/kg/day and higher, and the ratios of the thymus weight-to-brain weight were significantly decreased at 10 and 30 mg/kg/day...
April 10, 2003: Preliminary Risk Assessment of the Developmental Toxicity associated with Exposure to Perfluorooctanoic Acid and its Salts. US EPA Office of Pollution Prevention and Toxics. 63 pages.

In the rat subchronic study, Goldenthal et al. (1978b) administered CD rats, 5/sex/group, dietary
levels of 0, 30, 100, 300, 1000 or 3000 ppm PFOS (FC-95) for 90 days. The males weighed 196-
232 g and the females weighed 165-206 g at study initiation. The dietary levels were equivalent
to doses of 0, 2, 6, 18, 60 and 200 mg/kg/day... The rats were sacrificed after 90 days of treatment and a gross necrospy was conducted... All of the rats in the 300, 1000 and 3000 ppm groups died. Death occurred between days 13-25 and days 18-28 for the males and females, respectively, in the 300 ppm group...
The rats in all groups showed signs of toxicity including emaciation, convulsions following
handling, hunched back, red material around the eyes, yellow material around the anogenital
region, increased sensitivity to external stimuli, reduced activity and moist red material around
the mouth or nose. Three males and two females in the 100 ppm group died prior to scheduled sacrifice. Two of the males and the two females died during week 5 and the third male died during week 11 of the study... All rats in the 30 ppm group survived until the end of the study... Histologic examination also showed lesions in all treated groups. Centrilobular to midzonal cytoplasmic hypertrophy of hepatocytes and focal necrosis was observed in the liver; the incidence and relative severity were greater in the males. In addition, especially among rats in the 300, 1000 and 3000 ppm groups, treatment related histologic lesions were noted in the primary (thymus, bone marrow) and secondary (spleen, mesenteric lymph nodes) lymphoid organs, stomach, intestines, muscle and skin. In the thymus, this consisted of depletion in the number and size of the lymphoid follicles and in the bone marrow hypocellularity was noted. The spleen was slightly atrophied with a corresponding decrease in the size and number of lymphoid follicles and cells and a similar depletion was noted in the mesenteric lymph nodes.
Ref: August 31, 2000. MEMORANDUM. SUBJECT: Hazard Assessment of PFOS. FROM: Jennifer Seed, Branch Chief, Existing Chemical Assessment Branch, Risk Assessment Division (7403). THRU: Oscar Hernandez , Division Director, Risk Assessment Division (7403). TO: Charlie Auer, Division Director, Chemical Control Division (7405).

Sodium fluoroacetate (Compound 1080) - Insecticide, Rodenticide - CAS No. 62-74-8

-- An acute dermal toxicity study with rabbits used technical sodium fluoroacetate. The LD was 277.1 mg/kg for males and 324.2 mg/kg for 50 females. The animals showed lethargy, diarrhea, and convulsions preceding death, along with extensive hemorrhage of the thymus and congestion of the lungs. This is toxicity category II (MRID 152129).
Ref: US EPA Reregistration Eligibility Decision (RED) for Sodium fluoroacetate. September 1995.

Tetraconazole -Fungicide - CAS No. 112281-77-3

-- A chronic feeding/carcinogenicity study was conducted with tetraconazole in Crl:CD-l (ICR)BR mice at dietary levels of 10, 90, 800, and 1,250 ppm for 80 weeks. Treatment-related non-neoplastic changes were also seen at 1,250 ppm in the lungs, kidneys, testes, epididymides, ovaries and bone, particularly the cranium; a compression of the brain was noted in a number of mice reflecting the extent of cranial bone changes and an increased thymic involution was seen in male mice that died on test. The 1,250 ppm dietary level for tetraconazole, because of the substantial bwt gain changes and increased mortality (more in males), appeared to be above the maximum tolerated dose (MTD). At 800 ppm, there were increases in non neoplastic changes in lungs, kidneys, testes, epididymides, ovaries and bone. In addition, there was substantial reduction in weight gain as compared with zero-dose control animals, but the mortality rate was unaffected. Eight hundred ppm appeared to be a reasonable estimate of the MTD for mouse.
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.

Trifloxystrobin - Fungicide - CAS No. 141517-21-7

Reproductive toxicity. Target / critical effect - Developmental toxicity: Enlarged thymus (rat) and skeletal effects (rabbit) at maternally toxic dose levels. Lowest relevant developmental NOAEL / NOEL: 50 mg/kg bw/day (rabbit)
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.

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.
Ref: Federal Register: November 14, 2001 [Page 57074-57079]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

Trifloxysulfuron-sodium - Herbicide - CAS No. 199119-58-9

-- Short Term Studies. Trifloxysulfuron applied to the skin of rats at doses of 0, 10, 100 or 1000 mg/kg bw/day for 28 days did not result in any deaths, abnormal clinical signs, skin irritation, changes in food consumption, macroscopic changes or microscopic lesions attributable to treatment. Body weight gain was lower in females at 1000 mg/kg/day and haemoglobin and phosphate were slightly lower in males at 1000 mg/kg bw/day. Thymus weights were lower in males at 100 and 1000 mg/kg bw/day and in females at 1000 mg/kg bw/day.
-- Dogs were given trifloxysulfuron at doses of 0, 50, 200 or 500 mg/kg bw/day in gelatin capsules for 28 days. There were no mortalities, changes in food consumption, clinical signs of toxicity or effects on body weight gain. A white material in the faeces of animals at 500 mg/kg bw/day was confirmed by analysis to be the test material. Red blood cell count, haematocrit, haemoglobin, platelet counts and clotting times, plasma bilirubin, protein and albumin were lower and globulin and chloride were higher in both sexes at 500 mg/kg bw/day. Plasma bilirubin was also lower in females at 200 mg/kg bw/day and plasma potassium and calcium were lower in males at 500 mg/kg bw/day. Liver weights were higher in both sexes at 200 and 500 mg/kg bw/day. Thymus weights were marginally lower with one of two males and one of two females at 500 mg/kg bw/day having slight cortical atrophy in the thymus. Testes weight was lower in one of the two males at 500 mg/kg bw/day along with markedly reduced spermatogenesis and some single cell necrosis of tubular cells. This male also had slight follicular hypertrophy in the thyroid. Spleen weights were higher in females at 500 mg/kg bw/day with lymphoid hyperplasia observed in the spleen of males at 200 and 500 mg/kg bw/day and females at all doses. Pneumonia was observed in dogs at 500 mg/kg bw/day.
Ref: August 2002 -
Evaluation of the new active Trifloxysulfuron-sodium in the product ENVOKE HERBICIDE. Public Release Summary. National Registration Authority for Agricultural and Veterinary Chemicals 2002 ISSN1443-1335.

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