Kidney - Adverse Effects
Fluorinated and Fluoride Pesticides
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A-E F • G-P Q-Z
See short description and definitions on kidney

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.

Gliftor - Rodenticide - Rodenticide - CAS No. 8065-71-2

Abstract. Rats were subjected to the single inhalation effect of vapors of the zoocide gliftor (I; 50, 100, 350, 520, and 1100 mg/m-3). Morphological changes were noted beginning with a concentration of 350 mg/m-3. In a chronic experiment (4 mo.) the rats were subjected to I poisoning in a concentration of 10, 13, 64, and 110 mg/m-3. Distinct morphological changes in the organs were noted under the effect of concentrations 64 and 110 mg/m-3. Under the chronic effect of I there were considerable circulatory disorders and destructive changes of the interanl organs, especially in the liver, lungs, spleen, and kidneys.
Ref: Pathomorphological changes in internal organs of white rats under the inhalation effect of gliftor; by KNYSH VS, TKACH NZ, TSAREVSKII LP, MILOVANOVA VI. TR INST KRAEV PATOL AKAD NAUK KAZ SSR; 22 1971 23-28. [Abstract from Toxline at Toxnet.]

Haloxyfop - Herbicide - CAS No. 69806-34-4

The subchronic toxicity of haloxyfop (2-(4-((3-chloro-5-(trifluoromethyl)-2- pyridinyl)oxy)phenoxy)propanoic acid) herbicide, a peroxisome proliferator, was evaluated in rats, mice, dogs and monkeys. Male rats given 0.2 or 2.0 mg/kg/day and female rats given 2.0 mg/kg/day in feed for 16 weeks had peroxisome associated hepatocellular hypertrophy. Male and female rats given 2.0 mg/kg/day for 37 weeks also had increased renal tubular pigment. Mice given 2.0 mg/kg/day in feed for 13 weeks had peroxisome associated hepatocellular hypertrophy. Dogs fed 20 mg/kg/day and monkeys gavaged with 30 mg/kg/day for 13 weeks had hepatocellular hypertrophy, decreased size of thyroid follicles, and decreased red blood cell counts and serum cholesterol. Hepatocellular effects in dogs and monkeys were not associated with peroxisome proliferation. No-observed effect levels were between 0.02 and 0.2 mg/kg/day for rats, 0.2 mg/kg/day for mice, and 2 mg/kg/day for dogs and monkeys. There were no effects on reproduction in rats at dose levels up to 1.0 mg/kg/day or evidence of teratogenicity in rats or rabbits at dose levels up to 7.5 or 20 mg/kg/day, respectively.
Ref: Subchronic and reproductive toxicity and teratology of haloxyfop herbicide. Authors: Quast JF Yano BL Dietz FK Marler RM Hayes WC. Source: Toxicologist 1990 Feb;10(1):175. As cited at Toxnet.

Haloxyfop-methyl - Herbicide - CAS No. 69806-40-2

-- 3) 13-Week Feeding - monkey: Dietary levels tested: 0, 2, 10, and 30 mg/kg/day; Cynomolgus monkeys (4/sex/dose level) were administered haloxyfop- methyl by nasogastric intubation for 13 weeks. A statistically significant decrease in triglyceride values was reported for males and females dosed at 2 mg/kg/day. The statistically significant decrease in triglyceride values in males and females dosed at 10 mg/kg/day was accompanied by a nonsignificant decrease (15%) in cholesterol values for females at this level. Female livers appeared pale with an accentuated lobular pattern. Slight hepatocellular hypertrophy was observed for male and females at this level. Relative kidney weights were significantly increase for males and females by 12 and 37%, respectively. The LEL for systemic toxicity is 2 mg/kg/day, the lowest dose tested, based on a statistically significant decrease in triglyceride values in males and females. A NOEL for systemic toxicity was not established; core grade minimum (Dow Chemical Co., 1987b)
-- 7) 36-Week Feeding - mouse: Dietary levels tested: 0, 0.02, and 2.0 mg/kg/day; B6C3F1 mice (10/sex/group) were administered haloxyfop-methyl in the diet for 9 months. A significant increase in serum alkaline phosphatase was reported for males at the 2.0 mg/kg/day level with a slight increase in serum alkaline phosphatase for females. The liver was slightly enlarged and darkened for both males and females at 2.0 mg/kg/day. A significant increase in the liver absolute weight and organ-to-body weight ratio of both males and females fed 2.0 mg/kg/day was observed. Males also exhibited a significant decrease in kidney and heart weights compared with the control organ weight. Livers of males and females at the 2.0 mg/kg/day dose exhibited an enlargement of centrilobular hepatocytes cells with an increase cytoplasmic homogenity and increased eosinophilia. Kidneys of males fed 2.0 mg/kg/day showed a decrease of cytoplasmic vacuolation of the proximal convoluted tubular cells. Based on the above effects, the LEL for systemic toxicity is 2.0 mg/kg/day. The NOEL for systemic toxicity is 0.02 mg/kg/day; core supplementary (Dow Chemical U.S.A., 1982d)
-- Critical Effect: Reduced relative kidney weights in F0, F1, and F2b adults; Reduced fertility in the F1/F2b generation. 3-Generation Rat Reproduction Study. Dow Chemical U.S.A.,1985a. NOEL: 0.005 mg/kg/day; LEL: 0.05 mg/kg/day.... Signs of toxicity in parental rats at 1 mg/kg/day level were reduced body weight gain and reduced food consumption without increased mortality or obvious toxicity to the offspring. In addition, a significant increase in relative liver weight and enlarged livers were observed, however this finding was more frequent in males than females. A significant decrease in relative kidney weight was observed at 0.05 and 1 mg/kg/day, but it again occurred more frequently in the F0, F1, and F2b adult male rats. Renal pigmentation was also reported at 1 mg/kg/day for male and female adult rats after the gross and histopathological examinations. Based on decreases in relative kidney weights, the LEL for systemic toxicity is 0.05 mg/kg/day. The NOEL for systemic toxicity is 0.005 mg/kg/day.
-- 4) 2-Year Feeding (carcinogenicity) - rat: Dietary levels tested: Male: 0, 0.01, 0.03, 0.065, and 0.1 mg/kg/day; Female: 0, 0.01, 0.03, 0.065, and 1.0 mg/kg/day; CDF Fischer 344 rats (50/sex/dose) were administered haloxyfop- methyl in the diet for 2 years. No effects were observed in the male at any dose tested. The LEL for systemic toxicity is 1 mg/kg/day based on a significant decrease in female absolute (8%) and relative (9%) kidney weights accompanied by a significant increase in the incidence (24/50) in renal pigmentation reported for females of this level. Kidney function was not impaired as the urinalysis parameters between test and control values were comparable. The NOEL for systemic toxicity is 0.065 mg/kg/day; core grade guideline for chronic toxicity (Dow Chemical U.S.A., 1984b)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).

Hexafluoropropene, polymer with tetrafluoroethylene - EPA List 3 Inert - CAS No. 25067-11-2

Animal carcinogenicity data
Tetrafluoroethylene was tested for carcinogenicity in one study in mice and one study in rats by inhalation... In rats of both sexes, it increased the incidence of hepatocellular carcinomas and kidney tubule cell adenomas.
Other relevant data
Tetrafluoroethylene is metabolized by hepatic glutathione S-transferase and the resulting cysteine conjugate is further metabolized by renal b-lyase. This pathway results in the formation of a reactive thiol that causes kidney toxicity in rats.
There is sufficient evidence in experimental animals for the carcinogenicity of tetrafluoroethylene.
Overall evaluation
Tetrafluoroethylene is possibly carcinogenic to humans (Group 2B).
Ref: International Agency for Cancer Research (IARC):

Hexaflumuron - Insecticide, Plant Growth Regulator - CAS No. 86479-06-3

Recruit (hexaflumuron) Health Effects: eye irritant, liver and kidney damage
Ref: Physical Properties And Health Effects of Pesticides Used On National Park Service Collections. Conserve O Gram. U.S. National Park Service. September 2001. Number 2/17.

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

Subchronic Toxicity - In a 90 day feeding study in rats, MRID 00032641, groups of 20 male and 20 female Sprague-Dawley rats were dosed with hydramethylnon in their feed at 0, 50, 100, 200, or 400 ppm (equivalent to 0, 2.5, 5.0, 10.0 or 20.0 mg/kg/day). Due to significant decreases in body weight gain and food consumption during the first two weeks of the study at the highest dose (400 ppm, 20 mg/kg/day), this dose level was reduced to 25 ppm (1.25 mg/kg/day) on study day 15. Thus, the dose levels tested were 0, 25, 50, 100, or 200 ppm (0, 1.25, 2.5, 5.0, or 10.0 mg/kg/day)... On study day 68, a 50 ppm male was sacrificed moribund, and a 200 ppm (10.0 mg/kg/day) female died. The 200 ppm female had a blood urea nitrogen (BUN) value 4-fold higher than that of the controls on day 45. Histopathologic evaluation of this female revealed nephrocalcinosis and hydronephrosis...
-- In a carcinogenicity study, MRID 00101563, groups of 50 male and 50 female Charles River CD-1 mice received diets containing hydramethylnon at dose levels of 0, 25, 50, 100, or 200 ppm (0, 3.57, 6.93, 14.2, or 28.6 mg/kg/day in males, and 0, 4.45, 6.87, 17.3, or 33.1 mg/kg/day in females, based on food consumption) for 18 months. The 200 ppm males and females were sacrificed after 55 weeks because of high mortality. Survival after 18 months at the 50 and 100 ppm doses was 72% and 46% in males, and 66% and 46% in females (compared to control survival of 86% in males and 76% in females)... Dose-related amyloidosis was seen in the kidneys of the 50 and 100 ppm females.
In a chronic toxicity/carcinogenicity study, MRID 00101565, groups of 50 male and 50 female Charles River CD rats were fed diets containing hydramethylnon at dose levels of 0, 25, 50, 100, or 200 ppm (0, 1.2, 2.4, 4.9, or 10.0 mg/kg/day in males, and 0, 1.5, 3.0, 6.2, or 12.1 mg/kg/day in females, respectively based on food consumption) for two years... Body weights in the males were as much as 17% less than the controls at 200 ppm, and 5% at 100 ppm. Body weights in the females were as much as 42% less than the controls at 200 ppm, and 22% at 100 ppm. Body weights were comparable in the other groups. Food consumption was reduced an average of 7% in the 200 ppm males, and 16% in the 200 ppm females. The other groups were comparable... Glomerulonephrosis was greater in the treated males and females than in the controls, but there was no dose-response relationship.

Ref: US EPA. Reregistration Eligibility Decision (RED) Hydramethylnon. EPA 738-R-98-023. December 1998.

18-Month Feeding (oncogenic) - mouse: Systemic NOEL=25 ppm (2.75 mg/kg/day); Systemic LEL=50 ppm (3.75 mg/kg/day) (increased testicular lesions, decreased body weight gain, increased renal amyloidosis); core grade minimum (American Cyanamid, 1982d).
Ref: US EPA IRIS for Amdro (CASRN

Chronic toxicity... In an 18-month cancer assay, hydramethylnon at about 3.8 mg/kg/day was associated with amyloidosis, a syndrome in which abnormal protein deposition in the kidney fitration unit (glomerulus) results in damage [13].
Ref: E X T O X N E T Extension Toxicology Network Pesticide Information Profiles for Hydramethylnon.

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

-- **52425-047 162215 "Chronic Toxicity Study of DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127) One Year Feeding Study in Dogs" (Mertens, J. 831-WIL Research Laboratories, Inc. Ashland, Ohio. Study HLO 885-96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062- 106, 47.5% DPX-KN128) was administered orally (via the feed) to 5 Beagle dogs/sex/dose at levels of 0, 40, 80, 640 and 1280 ppm for 52 weeks. There was a treatment-related decrease in body weight, body weight gain and food consumption in 1280 ppm dogs during the first three months of the study. Reduced mean hemoglobin, RBC count and hematocrit was noted in the 80, 640 and 1280 ppm groups during all periods tested; increased Heinz bodies in these groups indicated hemolysis. Increased mean reticulocyte counts and MCV and decreased corpuscular hemoglobin concentration, erythrocyte morphologic changes and increased mean platelet counts indicated responses to hemolytic anemia. Significantly decreased RBC counts were also reported in 40 ppm males at week 25 and 51. Females at 40 ppm also showed reductions in RBC, but the differences were not statistically significant. Mean liver weights were increased in males (640 and 1280 ppm groups) and females (1280 ppm only). Microscopic changes in groups 40 ppm and above included increased pigment (hemosiderin) in liver Kupffer cells, kidney tubule epithelium, spleen and bone marrow and increased extramedullary hematopoiesis in the spleen and bone marrow hyperplasia. NOEL (M/F)=40 ppm (males: 1.1 mg/kg/day; females: 1.3 mg/kg/day based on biologically significant hemolytic anemia at 80 ppm and above). Acceptable. Kellner, 1/12/99.
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

Chronic toxicity--dogs. NOAEL = 0.79 mg/kg/day. LOAEL = 3.96 mg/kg/day based on increased incidence of proteinaceous casts in the kidneys, and statistically significant increases in the absolute weights of the thyroid and adrenal glands in males.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.

Results of several subchronic and chronic studies indicated the liver and kidney as target organs for lactofen. Increased absolute and relative liver weight and hepatocytomegaly (the LOEL was 1.5 mg/kg/day; the NOEL was not determined) were observed in male mice fed lactofen for 78 weeks. At 37.5 mg/kg/day, there was also an increased incidence of cataracts and renal pigmentation. Based on the LOEL, an oral RfD of 0.002 mg/kg/day was derived. Renal dysfunction and decreased hemoglobin and hematocrit levels and red blood cell counts (the LOEL was 25/75 mg/ kg/day; the NOEL was 5 mg/kg/day) were observed in a 1-year feeding study in dogs. Increased renal and hepatic pigmentation (the LOEL was 50 mg/kg/day; the NOEL was 25 mg/kg/day) were noted in a 2-year feeding study in rats. In a 90-day mouse study, increased alkaline phosphatase, serum glutamate oxaloacetate transaminase (SGOT), and serum gleutanic pyruvic transaminase (SGPT) activities, increased liver weight, hepatic necrosis, biliary hyperplasia, decreased hematocrit and hemoglobin levels and red blood cell counts, extramedullary hematopoiesis, and kidney nephrosis and fibrosis (the LOEL was 26 mg/kg/day; the NOEL was not determined) were seen. Decreased hemoglobin and hematocrit levels, decreased red blood cell counts, and brown pigment in the kidney and liver (the LOEL was 50 mg/kg/day) were noted in a 90-day feeding study in rats. EPA believes that there is sufficient evidence for listing lactofen on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available carcinogenicity data and hepatic, renal, and hematological 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.

Chronic Toxicity- A complete chronic data base supported by appropriate subchronic studies for lactofen is available to the Agency. Lactofen Technical causes adverse health effects when administered to animals for extended periods of time. These effects include proliferative changes in the liver, spleen, and kidney; hematological changes; and blood biochemistry changes. Based on the Lowest Effect Level (LEL) of 1.5 mg/ kg/day in the 18-month mouse feeding study and an uncertainty factor of 1,000, a reference dose (RfD) of 0.002 mg/kg/day has been established for lactofen. An uncertainty factor of 1,000 was used since a clear NOEL was not established.
-- Reproduction-- Rats. Groups of male and female rats were fed 0, 50, 500 or 2,000 ppm of Lactofen Technical continuously in their diets for 2-generations. Adult systemic toxicity (mortality, reduced body weight, increased liver and spleen weight, decreased kidney weight and histological changes in the liver and testes) was observed at levels of 500 ppm and greater.
-- Chronic/carcinogenicity feeding study-- Rat-- 24-month. In a 2- year chronic feeding/oncogenicity study of Lactofen Technical in rats at dosages of 0, 500, 1,000 and 2,000 ppm in the diet, an increase in liver neoplastic nodules and foci of cellular alteration was observed in both sexes at 2,000 ppm. The NOEL for systemic toxicity is 500 ppm based on kidney and liver pigmentation.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.

Mefluidide, diethanolamine salt - Herbicide - CAS No. 53780-36-2

The studies reviewed below were conducted with either the free acid or the diethanolamine salt of mefluidide. The diethanolamine salt is the registered active ingredient in California. Possible toxicological differences between the free acid and diethanolamine salt were not considered in the following reviews. The free acid and diethanolamine salt have been grouped by the US EPA (Morris, 10/5/93)...
-- ** 386-026 037397, "Twelve Month Diet Feeding Study of MBR-12325 in Dogs", (Riker Laboratories, experiment no. 0280CD0021, 11/1/82). Technical MBR-12325 (Mefluidide), purity 93% and 91% at pre-study and post-study, respectively, fed at 0, 60, 600 or 6000 ppm in the diet to Beagle dogs, 6/sex/group for one year. Positive for adverse effects on kidney at high dose. NOEL kidney = 600 ppm; body weight = 60 ppm. Nephrosis or degeneration of proximal convoluted renal tubular epithelium in 4/12 at high dose. Record 059988 contains the diet analyses for content, stability and homogeneity. ACCEPTABLE. (Gee, 3/17/86 and 7/14/88). EPA one-liner: Minimum. NOEL = 60 ppm (weight loss); LEL = 600 ppm (cortical nephrosis). EPA one-liner: Minimum. NOEL = 60 ppm (weight loss); LEL = 600 ppm (cortical nephrosis).
Ref: Mefluidide, diethanolamine salt: Summary of Toxicology Data. 1986. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

Nissol (also known as MNFA) - Acaricide, Insecticide - CAS NO. 5903-13-9

Abstract. The accumulation of citrate was studied in spider-mites, house-flies and mice after treatment with the acaricide Nissol (5903139). Male Swiss-Webster-mice were injected with various concentrations of Nissol. House-flies were treated topically with Nissol at various concentrations or received thoracic injections. A slide/dip technique was used to dose two-spotted-spider mites with Nissol. Mortality was recorded at 24 hours after treatment and the median lethal dose (LD50) was calculated for each species. The citric-acid (77929) content was determined in homogenates of whole mice in brains, hearts, livers, and kidneys photospectrometrically. Citric-acid content was also determined in homogenates of flies and mites. The LD50 for intraperitoneal administration in mice was 200 milligrams per kilogram (mg/kg). The topical LD50 in house-flies was 525mg/kg and the injected LD50 was 14mg/kg. The LD50 for contact administration to spider mites was 250 parts per million. Citric-acid increased substantially in each species even by 3 hours after dosing. The maximum accumulation in mice occurred at 6 hours. Flies and mites continued to show increased accumulation through 12 hours. In the mouse citric-acid was accumulated in decreasing order in the heart, kidney, brain, and liver. The authors conclude that mites, flies and mice accumulate citrate when treated with Nissol. The toxicity of this acaricide may be related to inhibition of aconitase which catalyzes transformation of citric-acid.
Ref. Citrate Accumulation In Twospotted Spider Mites, House Flies, And Mice Following Treatment With The Acaricide 2-Fluoro-N-methyl-N-(1-naphthyl) Acetamide; by Johannsen FR. Knowles CO. Journal of Economic Entomology, Vol. 65, No. 6, pages 1754-1756, 14 references, 1972.

Abstract. The effects of a single dose and repeated doses of N-methyl-N- ( 1- naphthyl ) monofluoroacetamide (MNFA) on the fluctuation of citrate in animals and the replationship between the activity of MNFA hydrolysis and the acute toxicity of MNFA in various species were investigated. MNFA was administered intraperitoneally at 25 mg/kg to male Wistar strain rats, 2.0 mg/kg to guinea pigs and 300 mg/kg to monkeys. At specified periods after dosing, the animals were sacrificed and the citrate content of heart, kidneys, liver and brain was determined. For the multiple dose study, MNFA was administered orally to male rats at doses of 0.625, 1.25, 2.5, 5.0 and 10.0 mg/kg/ day for 180 days and the citrate content was determined in the brain, heart, liver, kidney, testis and blood. In the rat, after a single dose of MNFA, the citrate level increased to 27, 10, 10 and negligible times the normal value in heart, kidneys, brain and liver, respectively. In the chronic toxicity experiment, the only increase (3 times the control value) was in the testes of rats receiving 10 mg/ kg/day of MNFA. In all other groups, the level in liver and kidney decreased significantly in comparison with the levels in animals receiving a single dose. It is suggested that this difference was due to metabolism and to the detoxification mechanism of the liver and kidney which may have been accelerated by the chronic administration of MNFA. The citrate level in the monkeys after a single dose was much lower than in the rat. In guinea pigs it increased to the maximum at 9 hr when it reached 30 times the control value in the kidney, 10 times in the heart, 6 times in the brain while no appreciable increase was found in the liver. The hydrolysis of MNFA by liver homogenates was closely related to the acute toxicity and the product of the hydrolysis was determined as N-methyl-1-naphthylamine. The enzyme activity in the guinea pig was about 35 times that of the rat or mouse. The LD50 of MNFA was 3.1 times that of N- ( 1-naphthyl ) monofluoroacetamide ( NFA ) and the amount hydrolyzed after 30 min incubation was about one- fifth.
Ref: Studies of the biochemical lesions caused by a new fluorine pesticide, N-methyl-N- ( 1-naphthyl )
monofluoroacetamide; by Noguchi T, Hashimoto Y, Miyata H. Toxicol. Appl. Pharmacol.; 13(2), 189-98, 1968.

Norflurazon - Herbicide - CAS No. 27314-13-2

-- A two-year carcinogenicity study was conducted in male and female CD-1 HaM/ICR Swiss mice in which 125 mice/sex/dose were administered technical norflurazon in the diet at dose levels of 0, 85, 340, or 1360 ppm (0, 12.8, 58.7, or 218.8 mg/kg/day) for 100-104 weeks... The systemic LEL was determined to be 58.7 mg/kg/day (340 ppm) for male mice, based on the increased incidence of enlarged spleen, increased absolute and relative liver weight, and increased incidence of nephritis...
-- A chronic toxicity and carcinogenicity study was conducted in Sprague-Dawley rats. In this study, technical norflurazon was administered in the diet at dose levels of 0, 125, 375, or 1025 ppm (0, 6.25, 18.75, or 51.25 mg/kg/day) for 104 weeks... The systemic LEL was determined to be 1025 ppm (51.25 mg/kg/day) in both sexes, based on the increased kidney weight and accompanying microscopic pathologic changes, as well as the increase in liver weight in male and female rats and the increase in thyroid weight in males...
-- A 2-generation reproductive toxicity study was conducted in male and female Wistar rats. In this study, norflurazon technical was administered in the diet at dose levels of 0, 150, 750, or 1500 ppm over 2 generations (0, 10.2, 50.8, or 102.5 mg/kg/day for F males; 0, 12.1, 0 62.0, or 129.7 mg/kg/day for F females; 0, 13.2, 67.8, or 138.6 0 mg/kg/day for F males; 17.1, 81.7, and 173.0 mg/kg/day for F1 1 females). The NOEL for systemic toxicity was determined to be 150 ppm (10.2 mg/kg/day for males and 12.1 mg/kg/day for females), and the systemic toxicity LEL was determined to be 750 ppm (50.8 mg/kg/day for males and 62.0 mg/kg/day for females), based on significant increases in liver and kidney weights observed in both generations of parental rats and the increased incidence of hepatocellular hypertrophy in both generations of parental rats...
-- A nine-month oral toxicity study (MRID 00091056) was conducted using the F generation of rats from a two-year carcinogenicity study (MRID 00082019). In this study, rats were given technical norflurazon in the diet at dose levels of 0, 125, 250, or 500 ppm (0, 6.25, 12.5, and 25 mg/kg/day) for 39 weeks... Kidney weight was not significantly affected, but the incidence of hyaline pigment deposition (many tubules) in male rats and hyaline pigment deposition (few tubules) in female rats was increased, as was the incidence of medullary congestion in high dose female rats. The incidence of tubular degeneration was increased in both sexes at the 500 ppm dose level. ... The systemic LEL was determined to be 500 ppm (25 mg/kg/day) in both sexes, based on the dose-related increase in liver weight in male and female rats at 39 weeks, the increase in gonad weight of females, and the microscopic changes observed in kidneys of both sexes. Although dramatic effects on thyroid weight were observed at 250 ppm in both sexes, there were no data indicating any alteration in histology of this organ. Thus, the weight change, while indicative of an effect of norflurazon, is not supported as a toxic effect based on available data (guideline: non-guideline study; classified as core supplementary; MRID 00091056).

Noviflumuron - Insecticide - CAS No. 121451-02-3

-- “XDE-007: Two-year Dietary Chronic Toxicity/Oncogenicity and Chronic Neurotoxicity Study in Fischer 344 Rats,” (Yano, B.L., Dryzga, M.D., Thomas, J.; Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI; Laboratory Project Study ID: 011168; 4.22.05). Noviflumuron ((N-[3,5-dichloro-2-fluoro-4(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-N’-(2,6-difluorobenzoyl)urea; XDE-007, 97.9% pure) was fed in diet to Fischer 344 rats (75/sex/dose) for 90 days, 1 or 2 years at 0, 0.1, 1.0, 75 or 300 mg/kg/day. Subchronic toxicity was assessed after 90 days of treatment on 10/sex/dose at 0 and 1.0 mg/kg/day doses only. At 1 year,10/sex/dose (chronic toxicity group), and 5/sex/dose (chronic neurotoxicity group) were necropsied. The remaining 50/sex/dose were necropsied after 2 years (oncogenicity group). Chronic NOEL = 1.0 mg/kg/day (At > 75 mg/kg/day there were decreased body weights and body weight gains along with increases or decreases in absolute and/or relative organ weights (liver, kidney, brain, heart, adrenal, testes, spleen, epididymides were affected) at 12 and/or 24 months. Skin/tail papules and pustules were observed in males (300 mg/kg/day) and females (> 75 mg/kg/day) in the second year. Females showed an increase in phthisis bulbi at 300 mg/kg/day. Prothrombin time in males and cholesterol levels in females were increased at > 75 mg/kg/day at 24 months. ALP activities were increased in both sexes at > 75 mg/kg/day at 24 months. Urine specific gravity was decreased (both sexes at > 75 mg/kg/day) and urine volume was increased (M 300 mg/kg/day and F > 75 mg/kg/day) at 24 months. Lung inflammation, hepatocytic hypertrophy (both sexes > 75 mg/kg/day), mineralization of renal pelvic epithelium (M > 75 mg/kg/day), epididymal aspermia* (M > 75 mg/kg/day), atrophy of seminiferous tubules (300 mg/kg/day), tail hyperkeratosis +/- inflammation (both sexes 300 mg/kg/day), tail tip necrosis (M 300 mg/kg/day) and hyperplasia of renal pelvic epithelium (M 300 mg/kg/day) were observed at 24 months. Leukemia was decreased in both sexes at > 75 mg/kg/day at 24 months.) Possible adverse effect: Hepatocellular adenomas (benign, M 300 mg/kg/day), uterine stromal polyps (F > 75 mg/kg/day), and liver foci (M > 75 mg/kg/day) were increased at 24 months. Acceptable. Silva, 8/19/05
-- “XDE-007: Two-Generation Dietary Reproduction Toxicity Study in CD Rats,” (Carney, E.W., Zablotny, C.L., Liberacki, A.B., Yano, B.L.;Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI; 3/22/04). XDE -007 (97.9% pure) was fed in diet to Crl:CD (SD) IGS BR rats (30/sex/dose/generation) at 0, 0.5, 5 or 25 mg/kg/day continuously from pre-mating of parental generation 1 (P1) through weaning of offspring through 2 generations (2 matings for P2 generation) to F2b weaning. Parental Systemic NOEL = 5.0 mg/kg/day (There were increased absolute and relative liver weights in both sexes of P1 and P2 adults at 25 mg/kg and in P1 female liver weights at 5.0 mg/kg. P1 male relative kidney weights, P2 female absolute kidney weights, P2 male relative spleen and thyroid weights and P2 female absolute and relative adrenal weights were increased at 25 mg/kg.) ...
Ref: August 2005 - Summary of toxicological data. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

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

-- Renal toxicity was most severe in the 2-generation reproduction study in rats,in which pelvic mineralization occurred.Other studies had indications of renal toxicity:increases in organ weight and occasional histopathological observations.
-- In a third subchronic dietary toxicity study (MRID 00117603),oxyfluorfen (72%) was administered to 10 CRJ-CDF rats/group at dietary concentrations of 0,200,1000,or 5000 ppm for 13 weeks.Doses corresponded to 0,14,71,or 361 mg/kg/day in males and 0,18,75,or 396 mg/kg/day in females... At necropsy,dark-brown livers and/or kidneys in mid-and high-dose males and females were noted... Microscopic kidney lesions in high-dose males and mid-and high-dose females included calcium deposition,vacuolar degeneration of distal tubules,hypertrophy/hyperplasia of transitional epithelium,and yellow pigment in renal tubular epithelium.The microscopic liver and kidney lesions were generally classified slight in mid-dose animals and slight to moderate in high-dose animals... The NOAEL is 200 ppm (males:14 mg/kg/day; females:18 mg/kg/day).The LOAEL is 1000 ppm (males:71 mg/kg/day);females:75 mg/kg/day)based upon brown livers and kidneys in males and females, increased relative liver weights in males, decreased absolute and relative thymus weights in males, and microscopic liver and kidney lesions in males and females (classified slight).
-- Reproductive Toxicity. Adequacy of data base for Reproductive Toxicity: There is an acceptable reproductive study with 71%technical material. The data base for reproductive toxicity is complete and no additional studies are required at this time. Parental toxicity included mortality, body weight decrements, and microscopic liver and kidney lesions. The kidney lesion was microscopic mineralization, which was not observed in other rat feeding studies.
-- Reproduction and Fertility Effects -Rat Goal Herbicide (71.4%a.i.)was administered to groups of 25 male and 25 female Crl:CD ®BR rats in the diet at concentrations of 0,100,400,or 1600 ppm of active ingredient for two generations (MRID 42014901).One litter was produced in each generation. Premating doses for the adult F0 males were 0,7.8,30.9,and 120.0 mg/kg/day and for the F0 females were 0,8.5,32.8,and 131.2 mg/kg/day,respectively. Premating doses for the adult F1 males were 0, 8.9,36.4,and 146.3 mg/kg/day and for the F1 females were 0,8.9,35.7,and 151.3 mg/kg/day, respectively.F1 pups chosen to produce the F2 litters were weaned onto the same diets as their parents .Animals were given test or control diet for 10 (F0)or 14 (F1)weeks then mated within the same dose group... Gritty material was observed in the renal pelvis of 2/25 high-dose F0 males and in 1/25 and 5/25 mid- and high-dose F1 males, respectively. This was not observed in any control or low-dose males. Dose-related increases in the incidence rates of liver and kidney lesions were observed in males and females of both generations... The incidence rates of mineralization of the renal pelvis were 0/25,1/25,3/25,7/25 (p #0.01)in F0 males;4/25,2/25,3/25,7/25 in F0 females; 1/25,1/25,5/25,11/25 (p #0.01)in F1 males; and 3/25,2/25,8/25,13/25 (p #0.01)in F1 females, respectively. In the kidney of high-dose F1 animals, there were increased incidences of dilatation of the collecting ducts (0/25,0/25,2/25,11/25 [p #0.01 ] males and 1//25,0/25,0/25, 9/25 [p #0.01 ] females)) and hyperplasia of the pelvic/papillary epithelium (4/25,5/25,6/25, 11/25 [p #0.05 ] males and 1//25,3/25,2/25,8/25 [p #0.05 ] females)). The NOAEL for parental toxicity is 400 ppm (males:30.9 mg/kg/day;females:32.8 mg/kg/day).The LOAEL for parental toxicity is 1600 ppm (males:120.0 mg/kg/day; females:131.2 mg/kg/day) based on mortality, body weight decrements, and microscopic kidney and liver lesions.
-- 870.4100a (870.4300)Chronic Toxicity – Rat In a chronic toxicity/carcinogenicity study (MRID 00083445,00135072,92136061),RH- 2915 technical (82.2%and 85.7%a.i.)was administered in the diet to groups of 50 male and 50 female Long Evans rats at concentrations of 1.0,20.0,or 400.0 ppm for weeks 1 –2;1.4,28.3,or 565.6 ppm for week 3 –4;2.0,40.0,or 800.0 ppm for weeks 5 –56 (800 ppm was actually 686 ppm for weeks 6-48);and 2.0,40.0,or 1600 ppm for weeks 57 –104. Based on %active ingredient,doses in males were approximately equivalent to 0,0.10,1.94,and 56.96 mg/kg/day, and in females were 0,0.12,2.43,and 72.57 mg/kg/day,in the respective dose groups. The mortality rate at study termination was 54,48,52,and 40%for male and 22,40,26, and 20%for females administered the control ,low,mid,and high doses,respectively;no treatment-related effect was observed... 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. Gross lesions were not observed in animals sacrificed at 12 or 24 months... The changes that were statistically increased in the 24-month group were polypoid hyperplasia of the papillary epithelium in the kidney of high dose females (20/40 vs 13/45 controls,p<0.05) and cortical cysts in the kidney of mid-and high-dose males (6/25 (p<0.01) and 4/40 (p<0.05)vs 0/45 for controls). The lack of a dose-response relationship for the changes in males and the high background for the finding in females suggest that the microscopic findings were not treatment related.
Ref: August 8,2001. OXYFLUORFEN. Toxicology Chapter for RED. Submission No.S549936. P.C.Code:111601. Tox.Chem.No.188AAA. US EPA.

Penoxsulam - Herbicide - CAS No. 219714-96-2

-- Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or urinary tract (kidneys and bladder) as target organs in rats, mice, and dogs following a 4-week and 13-week administration... Effects noted in the kidneys included crystal deposition, most likely from precipitation of penoxsulam from the urine, with resultant irritation, inflammation, and hyperplasia of renal pelvic transitional epithelium. Other than the crystal deposition in the kidneys, all effects following subchronic exposure to rats appeared to be reversible...
-- Chronic toxicity. Chronic exposure in the dog indicated that the renal effects were not exacerbated with long-term exposure. Following long-term exposure in rats, the kidneys and urinary bladder were the primary target organs. Histologic changes seen at the end of 2 years of exposure consisted of inflammation and hyperplasia of the renal pelvic transitional epithelium, crystal deposition in the kidneys and urinary bladder, and hyperplasia of the mucosa of the urinary bladder...
-- Reproductive and developmental toxicity. Penoxsulam did not have any effect on reproductive parameters at dose levels that induced treatment-related effects in parental rats. At the highest dosage tested (HDT) (300 mg/kg/day), body weights and weight gains in both males and females were depressed, liver and/or kidney weights were increased, and histologic changes were noted in the liver (males) and kidneys (females). At 100 mg/kg/day, increased liver weights were recorded in males, with no histologic correlate, and histologic changes noted in the kidneys of females...
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

-- Endocrine Disruption. For penoxsulam, effects which indicate potential endocrine disruption include kidney lesions (crystals) in female rats and delay in preputial separation in male rats. When the appropriate screening and/or testing protocols being considered under the Agency‘s EDSP have been developed, penoxsulam may be subjected to additional screening and/or testing to better characterize effects related to endocrine disruption.
Reference: September 2004. US EPA Fact Sheet on Penoxsulam. Page 4.

PFOA - Insecticide, US EPA List 3 Inert

Abstract: Response of rat kidney to the challenges by perfluorooctanoic acid (PFOA) was studied using microsomal 1-acyglycerophosphocholine (1-acyl-GPC) acyltransferase as a parameter. Marked induction of the enzyme was brought about in kidney of male rats, whereas the induction in kidney of female rats was far less pronounced. The sex-related difference in the response of kidney to PFOA was much more marked than those seen with p-chlorophenoxyisobutyric acid (clofibric acid) or 2,2'-(decamethy-lenedithio)diethanol (tiadenol). Hormonal manipulations revealed that the sex-related difference in the response of kidney to PFOA was strongly dependent on the state of gonadal hormones of rats. Even after a prolonged administration of PFOA for up to 26 weeks, this sex-related difference was still evident. Induction of peroxisomal beta-oxidation was brought about concurrently with microsomal 1-acyl-GPC acyltransferase and a high correlation was confirmed between the inductions of these two parameters.
Ref: 1991. Biochem Pharmacol Oct 24;42(10):1921-6. Induction by perfluorooctanoic acid of microsomal 1-acylglycerophosphocholine acyltransferase in rat kidney. Sex-related difference; by Kawashima Y, Matsunaga T, Uy-Yu N, Kozuka H.

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....
F1 Males ...
... Necroscopic examination revealed statistically significant treatment-related effects at 3,10,and 30 mg/kg/day ranging from tan areas in the lateral and median lobes of the liver to moderate to slight dilation of the pelvis of one or both kidneys... The absolute weights of the left and/or right kidneys were significantly increased in the 1 and 3 mg/kg/day dose groups and significantly decreased in the 30 mg/kg/day dose group...
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.

Potassium bifluoride - Wood preservative - CAS No. 7789-29-9

Ingestion: May cause osseous fluorosis (increased radiographic density of the bones). May cause kidney damage, asthma and symptoms resembling rheumatism. Target Organ Effects: Chronic ingestion may cause kidney damage.
Ref: Material Safety Data Sheet for Potassium Hydrogendifluoride [synonym]. LA-CO INDUSTRIES, Inc./Markal Co. Product Name: SILVER BRAZING FLUX PASTE Revision #: 1.5 Date Prepared: March 1, 1995. Date Revised: August 6, 2002.

Primisulfuron-methyl - Fungicide, Herbicide- CAS No. 86209-51-0

-- Chronic toxicity: Doses of 125 mg/kg/day administered in the diet to dogs over a 1-year period produced decreased body weight gain, anemia, increased liver weight, and thyroid hyperplasia (abnormal growth) [15]. Rats fed dietary doses of about 180 mg/kg/day over 90 days showed effects similar to those noted in dogs, as well as spleen weight increases [24]. In another study, doses of 480 mg/kg/day in rats over 18 months produced increased incidence of tooth disorders, chronic nephritis (kidney damage), and testicular atrophy [4]. In two 18-month studies in mice, testicular atrophy, chronic nephritis, and increased tooth and bone disorders were seen at doses of 180 mg/kg/day and 360 mg/kg/day, respectively [4].
-- Organ toxicity: Target organs identified in animal studies include the liver,
kidneys, spleen, and testes, as well as the skeleton.
Ref: E X T O X N E T Extension Toxicology Network Pesticide Information Profiles. Revised June 1996.

Pyraflufen-ethyl - Herbicide - CAS No. 129630-19-9

-- Short term toxicity Target / critical effect: Liver, kidney, red blood cells. Lowest relevant oral NOAEL / NOEL: 200 ppm (20 mg/kg bw/d) 90 day mouse (satellite group in 78 wk study)
Ref: July 2, 2002 - Review report for the active substance pyraflufen-ethyl. Finalised in the Standing Committee on Plant Health at its meeting on 29 June 2001 in view of the inclusion of Pyraflufen-ethyl in Annex I of Directive 91/414/EEC. SANCO/3039/99-FINAL. European Commission Health & Consumer Protection Directorate-General.

Pyridalyl - Insecticide - CAS No. 179101-81-6

Subchronic toxicity.
-- A 13-week feeding study in mice was conducted. Effects included decreased body weight gain, hematological and blood biochemical effects,increased liver weight, decreased kidney and ovary weights and histopathological changes in liver, kidney, ovary and adrenal. The NOAEL is 70 ppm in males (8.169 mg/kg/day) and 700 ppm in females (86.78 mg/kg/day).
-- A 13-week oral (capsule) toxicity study was conducted in
dogs. Effects included decreased body weight gain, clinical signs indicative of respiratory distress, hematological and blood biochemistry effects, increased liver, lung and kidney weights and histopathological alterations of the lung, kidney, adrenal and liver. The NOAEL was 10 mg/kg/day.
Chronic toxicity.
-- Pyridalyl was administered in the diet to mice for 78-weeks. Effects included decreased body weight gain and food consumption/efficiency, and increased liver and kidney weights. The NOAEL of the study was 50 ppm (5.04 mg/kg/day in males and 4.78 mg/kg/day in females)
Ref: Federal Register: December 5, 2003. Pyridalyl; Notice of Filing a Pesticide Petition.

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