Return to Chlorfenapyr Index Page

ACTIVITY: Acaricide, Insecticide (pyrrole)
Structure:

Adverse Effects:
Anemia
Body Weight Decrease
Bone
Brain
Cancer: Suggestive - LIVER, TESTES, UTERINE
Cholesterol
CNS
Dermal
Endocrine: Testicular
Endocrine: Uterine
Liver
Spinal Cord
Environmental

Anemia (click on for all fluorinated pesticides)

-- MRID No. 42770219 (1993)-- 90-Day oral toxicity rats. NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on spongiform myelopathy in the brain and spinal cord of male rats, decreased body weight gain and increased relative liver weight in males and females, increased absolute liver weight in females, and decreased hemoglobin in females.
-- MRID No. 43492837 (1994). Combined chronic/ carcinogenicity in rat. NOAEL = 15 mg/kg/day, males. LOAEL = 30.8 mg/kg/day, males, based on anemia. NOAEL = 3.6 mg/kg/day, females LOAEL = 18.6 mg/kg/day, females, based on decreased body weight/ body weight gain.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

Body Weight Decrease (click on for all fluorinated pesticides)

-- MRID No. 42770219 (1993)-- 90-Day oral toxicity rats. NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on spongiform myelopathy in the brain and spinal cord of male rats, decreased body weight gain and increased relative liver weight in males and females, increased absolute liver weight in females, and decreased hemoglobin in females.
-- MRID No. 43492830 (1994). 90-Day oral toxicity mouse. NOAEL = 27.6/40, M/F. LOAEL = 62.6/78, M/F, based on reduced body weights/body weight gains, and spongiform encephalopathy in both sexes.
-- MRID No. 42770220 (1993). 90-Day oral toxicity dog. NOAEL = 3.9/4.5 mg/kg/ day, M/F. LOAEL = 6.7/6.8 mg/kg/ day, M/Fbased on emaciation, decreased body weight gains, and decreased food efficiency.
-- MRID No. 42884202 (1993). Prenatal developmental rat. Maternal NOAEL = 25 mg/kg/day, based on decreased body weight gain and relative food consumption during treatment Developmental NOAEL >=225 mg/kg/day. Developmental LOAEL = not identified.
-- MRID No. 42770222 (1993). Prenatal developmental rabbit. Maternal NOAEL = 5 mg/kg/day. Maternal LOAEL = 15 mg/ kg/day, based on decreased body weight gain during treatment Developmental NOAEL = 15 mg/kg/day Developmental LOAEL = 30 mg/kg/day, based on increased post implantation loss.
-- MRID No. 43492836 (1994). 2-Generation reproduction and fertility effects rat. Parental systemic NOAEL = 4.4-4.5 mg/kg/day, M. Parental systemic LOAEL = 22.2-22.5 mg/kg/day, M, based on decreased absolute body weight/body weight gains of P1 males during premating. Offspring systemic NOAEL = 4.4-5.1 mg/kg/day. Offspring systemic LOAEL = 22.2-25.6 mg/kg/day, based on decreased pup weights at weaning. Reproductive NOAEL >=44- 50.7 mg/kg/day. Reproductive LOAEL: not identified.
-- MRID No. 43492834 (1994). Chronic toxicity dog. NOAEL = 4.0/4.5 mg/kg/day, M/F. LOAEL = 8.7/10.1 mg/kg/ day, M/F, based on decreased body weight/body weight gains.
-- MRID No. 43492838 (1994). Carcinogenicity mouse. NOAEL = 2.8/3.7 mg/kg/day, M/F. LOAEL = 16.6/21.9 mg/kg/day, M/F, based on decreased body weight gains, brain vacuolation, and scabbing of the skin (males) No evidence of carcinogenicity.
-- MRID No. 43492837 (1994). Combined chronic/ carcinogenicity in rat. NOAEL = 15 mg/kg/day, males. LOAEL = 30.8 mg/kg/day, males, based on anemia. NOAEL = 3.6 mg/kg/day, females LOAEL = 18.6 mg/kg/day, females, based on decreased body weight/ body weight gain.
-- MRID No. 43492833 (1994). Chronic neurotoxicity rat. NOAEL = 2.6/3.4 mg/kg/day, M/F. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the central nervous system (CNS) in male rats and decreased average body weights/body weight gains, food efficiency, absolute food consumption (females) and water consumption (males)
-- Chronic neurotoxicity study - rat. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the CNS in male rats and decreased average body weights, body weigh gains, food efficiency, absolute food consumption (F), and water consumption (M). Supporting this endpoint are similar CNS lesions and skin lesions observed in the mouse carcinogenicity study (NOAEL = 2.8).
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

-- CHRONIC TOXICITY, DOG ** 062; 147071; "One Year Dietary Toxicity Study with AC 303,630 in Purebred Beagle Dogs"; (Kelly, C.M.; Pharmaco LSR Inc., East Millstone, NJ; Study No. 92-3107; 8/31/94); AC 303,630 Technical (purity: 94.5%) was administered in the diet to 5 dogs/sex/group at doses of 0, 60 and 120 ppm and to 6 dogs/sex at 240 ppm for 12 months (M-0, 2.1, 4.0, 8.7 mg/kg/day, F-0, 2.3, 4.5, 10.1 mg/kg/day). Reduced body weight gain was evident in the high dose animals. The relative mean liver weights were slightly increased in the high dose group. No treatment-related effects were noted for hematology or clinical chemistry. No treatment-related lesions were evident. No adverse effects were indicated. NOEL: 120 ppm (M/F) (based on increase in relative mean liver weight and reduced body weight gain of animals in the 240 ppm treatment group); NOAEL: 240 ppm; Study acceptable. (Moore, 7/15/96)
-- REPRODUCTION, RAT ** 063; 147072; "A Pilot Dietary Reproduction Study in Rats with AC 303,630", (R.E. Schroeder; Pharmaco LSR Inc., East Millstone, NJ; Study No. 91-3755; 7/20/94); AC 303,630 Technical (purity: 94.5%) was administered to 10 animals/sex/group in the diet at doses of 0, 60, 300 and 600 ppm for 10 weeks during a premating period, a 10 day mating period and the ensuing gestation and lactation periods. Reduced body weight gain was noted in the females of the 300 and 600 ppm groups during the premating period. Pup survival was reduced in the 600 ppm treatment group during the 0 to 4 day post-natal period. Pup weight gain was reduced in the high dose group over the lactation period. No adverse effect indicated. Parental NOEL: 60 ppm (based upon reduced body weight gain in the 300 ppm treatment group), Reproductive/Developmental NOEL: 300 ppm (based upon the reduced pup survival and body weight gain in the 600 ppm treatment group), NOAEL: 600 ppm; Study supplemental. (Moore, 7/29/96)
-- REPRODUCTION, RAT ** 064; 147073; "A Two-Generation (One-Litter) Reproduction Study with AC 303,630 in Rats"; (R.E. Schroeder, Pharmaco LSR Inc., East Millstone, NJ; Study No. 90-3638; 8/8/94); AC 303,630 technical (purity 94.5%) was administered in the feed of 30 animals/sex/group for two generations at doses of 0, 60, 300, and 600 ppm (P1 (M) 0, 4.2, 20.9, 41.1 mg/kg/day, (F) 0, 6.0, 29.3, 57.2 mg/kg/day, F1 (M) 0, 3.7, 19.0, 38.3 mg/kg/day, (F) 0, 6.0, 29.5, 58.7 mg/kg/day). Reduced body weight gain was noted for both the adult males and females in the 300 and 600 ppm treatment groups of the F1 generation. This reduced weight gain was apparent in these animals during the lactation period and continued during the premating period. Reproductive parameters were not affected by treatment. No adverse effects indicated. Parental NOEL: 60 ppm (based upon reduced body weight gain in the 300 and 600 ppm F1 generation males and females); Reproductive NOEL: 600 ppm; Developmental NOEL: 60 ppm (based upon reduced body weight gain of pups during lactation period). Study acceptable. (Moore, 8/1/96)
Ref: August 24, 2001 - Summary of Toxicological Data. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. Also available at:
http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf

Bone (click on for all fluorinated pesticides)

TERATOLOGY, RAT ** 012; 125176; "An Oral Developmental Toxicity (Embryo-Fetal Toxicity/Teratogenicity) Definitive Study with AC 303,630 in Rats", T. Martin; 833; Rat; Argus Research Laboratories, Inc., Horsham, PA; Report No. 101-015; 7/22/93; AC 303,630 Technical (purity: 94.5%); 25 females/group; Doses: 0, 25, 75 and 225 mg/kg/day, by gavage, in aqueous 0.5% (w/w) carboxymethyl cellulose, from day 6 through day 15 of gestation; Maternal: no mortality; Clinical Observations: reduced food consumption during dosing period (75, 225 mg/kg/day); Necropsy: no treatment-related lesions; Development: increased incidence of unossified sternabrae (225 mg/kg/day), no treatment-related effects upon number of live fetuses, fetal weight, and number of resorptions; No adverse effect indicated; NOEL: Maternal-25 mg/kg/day (based upon reduced food consumption in 75 and 225 mg/kg/day treatment groups), Developmental: 75 mg/kg/day (based upon incidence of unossified sternabrae in the 225 mg/kg/day treatment group); Study acceptable. (Moore, 2/6/95)
Ref: August 24, 2001 - Summary of Toxicological Data. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. Also available at:
http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf

Brain (click on for all fluorinated pesticides)

ii. Subchronic Oral Toxicity in Mice... Spongiform encephalopathy was noted in the brain and myelin of the spinal cord of both males and females receiving the 320 ppm treatment level. The LEL is 14.8 mg/kg/day (80 ppm) for male mice and 40.0 mg/kg/day (160 ppm) for female mice, based on hepatic cell hypertrophy in
20% of the test animals at this treatment level. The NOEL is 7.1 mg/kg/day (40 ppm)... The RfD Committee also recommended that a special developmental neurotoxicity study be conducted based upon the effects of a spongyform myelopathy and/or vacuolation seen in the brain and spinal cord of treated rats and mice. They concluded that the registrant should also conduct a mechanistic study to determine the cause/relationship of CNS/myelinopathic alterations to neurotoxicity (including developmental)...
Chronic-Term (greater than several months) Occupational/Residential Dermal NOEL: 3 mg/kg/day (decreased body weight gains brain lesions (vacuolation) and/or scabbing of the skin in a 1 year neurotoxicity study in rats and a chronic/carcinogenicity study in mice) Acceptable MOE = 1000 (includes FQPA Factor)
Ref: US EPA, Feb 12, 1998: Chlorfenapyr - 129093: Health Effects Division Risk Characterization for Use of the Chemical Chlorfenapyr.
http://www.epa.gov/opprd001/chlorfenapyr/memohed2.pdf

Note: Page 19-20: "Other chronic effects. For other chronic effects, a Reference Dose (RfD) has been established at 0.003 mg/kg/day based on decreased body weight gains and brain lesions (vacuolation) observed in the 1-year rat neurotoxicity study. An uncertainty factor (UF) of 1000 was applied to account for interspecies extrapolation, intraspecies variability and the additional FQPA Factor of 10. The FQPA factor has been retained because chlorfenapyr has produced central nervous system lesions in several studies in both rats and mice. It will be reevaluated after the developmental neurotoxicity study has been submitted."
Ref: US EPA. March 13, 2000. "Denial of Registration of Chlorfenapyr for Use on Cotton."
http://www.epa.gov/opprd001/chlorfenapyr/chlorfenapyr.pdf

Note: In a search of EPA's OPP database <http://www.epa.gov/pesticides/search.htm> for "spongiform encephalopathy" - "spongyform myelopathy" and "spongyform" - , the only substance cited was Chlorfenapyr. Mad Cow Disease is also called Bovine spongiform encephalopathy (BSE) which is a chronic, degenerative disorder affecting the central nervous system of cattle. In the US, up until 2002, there were 19 tolerances for residues of Chlorfenapyr in or on: Cotton, Milk, Cattle, Hog, Sheep, Horse, and Goat - see:
http://www.fluorideaction.org/pesticides/chlorfenapyr.us.residuefood.htm

ONCOGENICITY, MOUSE . 066; 147076; "A Chronic Dietary Toxicity and Oncogenicity Study with AC 303,630 in Mice" (L. Bernier, Bio-Research Lab., Ltd., Quebec, Canada, Project # 84580, 8/22/94). AC 303,630 (Batch AC-7504-59A, 94.5% purity) administered orally in the diet to 65 CD-1 mice/sex/dose for 80 weeks at 0, 20, 120, or 240 ppm (Males: 0, 2.8, 16.6, or 34.5 mg/kg/day; Females: 0, 3.7, 21.9, or 44.5 mg/kg/day). Reduced survival rate was noted in high dose females (60% vs. 80%, p < 0.05). However, overall survival rate of this group was more comparable to that of the historical controls. Treatment with AC 303,630 resulted in reduced mean body weight gain in high dose males and females and in mid dose females (Males: 70% of control, p < 0.01, Females: 86% of control, p < 0.05 for mid and high dose groups). Food consumption was also reduced in mid and high dose animals. Histopathology revealed vacuolation of the white matter of the brain in animals treated at mid and high dose levels. Also, vacuolation was detected in spinal cord sections as well as optic nerve tissues in mice at 240 ppm. There was no evidence of carcinogenicity. NOAEL (M/F) = 240 ppm [No adverse effect]. NOEL (M/F) = 20 ppm (2.8 and 3.7 mg/kg/day for males and females, respectively; based on histopathological changes in the brain, optic nerve and spinal cord). acceptable (Leung, 7/24/96)
Ref: August 24, 2001 - Summary of Toxicological Data. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. Also available at: http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf

NEUROTOXICITY ** 061; 147070; "A One-Year Dietary Neurotoxicity Study with AC 303,630 in Rats"; (J.A. Foss; Argus Research Laboratories, Inc., Horsham, PA; Study No. 101-019; 5/10/94); AC 303,630 technical (purity: 94.5%) was administered in the diet to 25 animals/sex/group at doses of 0, 60, 300, and 600 ppm for up to 52 weeks ((M)-0, 2.6, 13.6, 28.2 mg/kg/day, (F)-0, 3.4, 18.0, 37.4 mg/kg/day). Surviving animals were observed for an additional 16 weeks of a recovery phase. No treatment-related effects were noted in the functional observational battery or the motor activity evaluation. In the neurohistopathology, myelin sheath swelling of the spinal nerve roots was evident in the males of the 600 ppm treatment group after 13 and 52 weeks of treatment. Extensive vacuolar myelinopathy was noted in the brain and spinal cord of the 300 and 600 ppm males after 52 weeks of treatment. These effects were no longer present after the 16 week recovery period. No treatment-related lesions were noted in the females. No adverse effects were evident. NOEL: (M) 60 ppm (based upon the incidence of extensive vacuolar myelinopathy in the central nervous system); (F) 600 ppm; NOAEL: 600 ppm (based on recovery). Study acceptable. (Moore, 7/29/96)
Ref: August 24, 2001 - Summary of Toxicological Data. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. Also available at: http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf

SUBCHRONIC STUDIES ** 010, 031; 125163; "AC 303,630: A 13 Week Dietary Toxicity Study in the Albino Rat", J.E. Fischer; 821; Rat; American Cyanamid Co., Agricultural Research Division, Toxicology Department, Princeton, NJ; Study No. T-0316; 4/8/93; AC 303,630 Technical (purity: 93.6%); 20 animals/sex/group; Doses: 0, 150, 300, 600, 900, 1200 ppm (M: 0, 10.9, 22.0, 44.9, 69.5, 92.2 mg/kg/day, F: 0 11.7, 24.1, 48.4, 72.5, 97.5 mg/kg/day), in the diet, 13 weeks; No treatment-related mortality; Clinical Observations: red. body wgt. gain (M,F-900, 1200 ppm), red. food consumption (M-600 ppm and up); Ophthalmology, Urinalysis: no treatment-related effects; Hematology: red. hematocrit (M,F-1200, F-900 ppm), red. hemoglobin (M,F-1200, F-600, 900 ppm), red blood cells (M,F-1200, F-900 ppm), Clinical Chemistry: incr. BUN (M,F-1200 ppm, week 6, M-1200 ppm, week 13), incr. alk. phosphatase activity (M,F-900, 1200 ppm, week 13); Necropsy: incr. mean abs. liver wgt. (F-600 ppm and up), red. abs. kidney wgt (M,F-900, 1200 ppm), incr. abs. spleen wgt. (M,F-900, 1200 ppm), incr. rel. liver wgt. (M,F-600, 900, 1200, M-300 ppm), increased relative spleen weight (M,F-900, 1200 ppm); Histopathology: spongiform myelopathy in brain, spinal cord (M-(2/20), 1200, 900 ppm, (1/20), 600 ppm), lesion present in sciatic nerve (M-(1/20), 1200 ppm), lymphoid cell infiltrate in kidneys (M,F-900, 1200 ppm); Target organ: central nervous system; Adverse Effect: spongiform myelopathy in the nervous system; NOEL: (M) 300 ppm (occurance of spongiform myelopathy in the nervous system of the 600 ppm group) (F) 300 ppm (based on increased mean abs. liver wgt. in 600 ppm group); (Study previously unacceptable, possibly upgradeable with submission of GLP compliance and QA audit statements (Moore, 2/1/95)) requested information submitted; Study acceptable. (Moore, 8/9/95)
Ref: August 24, 2001 - Summary of Toxicological Data. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. Also available at: http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf

-- MRID No. 42770219 (1993)-- 90-Day oral toxicity rats. NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on spongiform myelopathy in the brain and spinal cord of male rats, decreased body weight gain and increased relative liver weight in males and females, increased absolute liver weight in females, and decreased hemoglobin in females.
-- MRID No. 43492830 (1994). 90-Day oral toxicity mouse . NOAEL = 27.6/40, M/F. LOAEL = 62.6/78, M/F, based on reduced body weights/body weightgains, and spongiform encephalopathy in both sexes.
-- MRID No. 43492838 (1994). Carcinogenicity mouse. NOAEL = 2.8/3.7 mg/kg/day, M/F. LOAEL = 16.6/21.9 mg/kg/day, M/F, based on decreased body weight gains, brain vacuolation, and scabbing of the skin (males) No evidence of carcinogenicity.
-- MRID No. 43492833 (1994). Chronic neurotoxicity rat. NOAEL = 2.6/3.4 mg/kg/day, M/F. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the central nervous system (CNS) in male rats and decreased average body weights/body weight gains, food efficiency, absolute food consumption (females) and water consumption (males)
-- Chronic neurotoxicity study - rat. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the CNS in male rats and decreased average body weights, body weigh gains, food efficiency, absolute food consumption (F), and water consumption (M). Supporting this endpoint are similar CNS lesions and skin lesions observed in the mouse carcinogenicity study (NOAEL = 2.8).
-- Conditions: A developmental neurotoxicity study to determine the cause/relationship of potential central nervous system/myelinopathic alterations to neurotoxicity in the developing young.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

Also see the following. • December 22, 2004, US EPA's response to FAN's Comments on Chlorfenapyr effects on brain - see http://www.fluorideaction.org/pesticides/chlorfenapyr.2005.epa.response.pdf - (Online at US EPA Docket OPP-2004-0362-0002) • August 11, 2003, comments submitted to US EPA by FAN's Pesticide Project on the pesticide petition from BASF Corporation to establish a tolerance for residues of chlorfenapyr on all food items in food handling establishments where food products are held, processed, and/or prepared at 0.01 parts per million (ppm). http://www.fluorideaction.org/pesticides/chlorfenapyr.comments.aug03.htm - (Online at US EPA Docket OPP-2003-0205) • September 17, 2003, reply to comments from FAN's Pesticide Project, from Daniel J. O'Byrne, Product Registrations Manager, BASF Corporation. http://www.fluorideaction.org/pesticides/chlorfenapyr.basf.sept.2003.pdf - (Online at US EPA Docket OPP-2003-0205)

Cancer - Suggestive (click on for all fluorinated pesticides)

-- Classification: ``Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential'' based on significant trends in liver tumors (adenomas and combined adenomas/ carcinomas), malignant histiocytic sarcomas, and testicular cell tumors in male rats and uterine polyps in female rats seen at the highest dose.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential. The overall evidence in animals was Not persuasive, but could not be dismissed. Increase in tumors in rats occurred with significant positive trends only, and mainly at the highest dose.
Ref: April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs. From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

page 3: ... BASF Corporation submitted a comprehensive weight-ofevidence analysis to argue that the USEPA classification of chlorfenapyr as “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential” should be modified to “not likely to be a human carcinogen.” When we compared the registrant’s weight-of-evidence analysis with the carcinogenicity study data reviewed by the USEPA’s Cancer Peer Review Committee (Memorandum, January 9, 1997: Carcinogenicity Peer Review of Chlorfenapyr), we found that overall the registrant’s argument is not sufficiently persuasive that chlorfenapyr should be classified as “not likely to be a human carcinogen.” The main thrust of the registrant’s argument is that overall there is no increase in liver adenomas/carcinomas, malignant histiocytic sarcomas, testicular interstitial cell tumors and uterine endometrial stromal polyps by pair-wise comparisons between groups of rats fed different doses of chlorfenapyr. The registrant further argues that the positive trends in tumor incidence resulting from oral exposure to increasing doses of chlorfenapyr are not significant when compared to the tumor incidence in historical controls. To support their argument, the registrant cites only maximum percent control tumor incidence values instead of the mean values and ranges which would better illustrate background tumor incidence. Furthermore, the registrant dismisses the experimental control values obtained from the rat carcinogenicity study on chlorfenapyr, by stating that these values are “...uniquely and abnormally low.” While we acknowledge that the registrant makes some valid points in their analysis, we believe that the USEPA’s classification of the carcinogenic potential of chlorfenapyr as “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential” is appropriate and should not be reclassified to “not likely to be a human carcinogen.” In addition, the registrant’s focus on specific carcinogenicity issues to the exclusion of the other issues raised in our initial review (i.e., the comparative risks posed by this product and the need for use on fruiting vegetables) does not address the overall concerns for registering this product.
Ref: October 3, 2005, letter to BASF from New York State Bureau of Pesticides Management.
http://www.fluorideaction.org/pesticides/chlorfenapyr.pylon.nys.reg.2005.pdf

Cholesterol (click on for all fluorinated pesticides)

The 100-fold margin of safety is adequate to assure a reasonable certainty of no harm to infants and children from the proposed use. As stated earlier, the NOAEL is based on the effects observed in the rat and mouse chronic oncogenicity studies, (reduced bwt gains, increased globulin and cholesterol values and increased liver weights in the rat and reduced bwt gains and vacuolation of white matter of the mouse brain), the 1-year neurotoxicity study in the rat, (reduced bwt gains and vacuolar myelinopathy of [[Page 46680]] the brain and spinal cord that is completely reversible following termination of treatment and is not associated with any damage to neuronal cell bodies or axons; vacuolation of the white matter is a consequence of edema (water) formation between the myelin layers which result from the unrestricted movement of ions across the cell membranes) and the 2-generation rat reproduction study, (reduced bwt gains for parental animals and reduced pup body weights for the F1 and F2 litters; however no behavioral changes were observed in either F1 or F2 offsprings in the 2-generation reproduction study)...
Ref: Federal Register: August 26, 1999 [Page 46677-46680]. Notice of Filing; Pesticide Petition.
http://www.fluoridealert.org/pesticides/Chlorfenapyr.FR.Aug.26.1999.htm

CNS (click on for all fluorinated pesticides)

-- MRID No. 43492833 (1994). Chronic neurotoxicity rat. NOAEL = 2.6/3.4 mg/kg/day, M/F. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the central nervous system (CNS) in male rats and decreased average body weights/body weight gains, food efficiency, absolute food consumption (females) and water consumption (males)
-- Chronic neurotoxicity study - rat. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the CNS in male rats and decreased average body weights, body weigh gains, food efficiency, absolute food consumption (F), and water consumption (M). Supporting this endpoint are similar CNS lesions and skin lesions observed in the mouse carcinogenicity study (NOAEL = 2.8).
-- Conditions: A developmental neurotoxicity study to determine the cause/relationship of potential central nervous system/myelinopathic alterations to neurotoxicity in the developing young.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

Dermal (click on for all fluorinated pesticides)

-- MRID No. 43492838 (1994). Carcinogenicity mouse. NOAEL = 2.8/3.7 mg/kg/day, M/F. LOAEL = 16.6/21.9 mg/kg/day, M/F, based on decreased body weight gains, brain vacuolation, and scabbing of the skin (males) No evidence of carcinogenicity.
-- Chronic neurotoxicity study - rat. LOAEL = 13.6/18 mg/kg/ day, M/F, based on the presence of myelinopathic alterations in the CNS in male rats and decreased average body weights, body weigh gains, food efficiency, absolute food consumption (F), and water consumption (M). Supporting this endpoint are similar CNS lesions and skin lesions observed in the mouse carcinogenicity study (NOAEL = 2.8).
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

Endocrine: Testicular (click on for all fluorinated pesticides)

-- Classification: ``Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential'' based on significant trends in liver tumors (adenomas and combined adenomas/ carcinomas), malignant histiocytic sarcomas, and testicular cell tumors in male rats and uterine polyps in female rats seen at the highest dose.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

August 11, 2003, comments submitted to US EPA by FAN's Pesticide Project on the pesticide petition from BASF Corporation to establish a tolerance for residues of chlorfenapyr on all food items in food handling establishments where food products are held, processed, and/or prepared at 0.01 parts per million (ppm). http://www.fluorideaction.org/pesticides/chlorfenapyr.comments.aug03.htm - Also Online at US EPA Docket OPP-2003-0205. 5. Endocrine Disruption. In the petition, BASF states: ... There is no information available which suggests that chlorfenapyr would be associated with endocrine effects. 5.1 However, US EPA noted endocrine effects in the following study: In the rat chronic toxicity/carcinogenicity study (MRID 43492837), there were increased trends in the incidence of hepatocellular adenomas, hepatocellular adenomas and/or carcinomas combined, malignant histiocytic sarcomas and testicular interstitial cell tumors in males rats. In female rats there were significant increasing trends in endometrial stromal polyps. Significant difference in pair-wise comparison of fibroadenomas at the low dose and carcinomas at the mid-dose existed for female rats. There was no evidence of tumorigenic potential in mice.... Ref: US EPA OPPT. February 12, 1998. SUBJECT: Chlorfenapyr - 129093: Health Effects Division Risk Characterization for Use of the Chemical Chlorfenapyr (Alert, EPA File Symbol 5905-GAI) in/on Citrus (6F04623). Case: 287132. Barcode: D221320- http://www.epa.gov/opprd001/chlorfenapyr/memohed2.pdf September 17, 2003, reply to comments from FAN's Pesticide Project, from Daniel J. OÕByrne, Product Registrations Manager, BASF Corporation. http://www.fluorideaction.org/pesticides/chlorfenapyr.basf.sept.2003.pdf - Also online at US EPA Docket OPP-2003-0205. Regarding Point 5: Endocrine Effects This comment addresses findings of endometrial stromal polyps and testicular interstitial cell tumours The occurrence of benign interstitial cell tumors in male rats was 3/65, 1/65, 3/65 and 7/65 (4.6, 1.5, 4.6, 10.8%) in the control and the low-, mid- and high dose, respectively. There was no statistically significant increase in either group when compared to the control group and no clear dose-response relationship. Moreover the incidence of 7/65 was at the upper limit of the historical control range (10.0%). Therefore, the occurrence of this benign proliferative lesion in males of the high-dose group is not considered treatment related.. Overall, there is no indication of an endocrine effect of chlorphenapyr in any of the studies, including the two-generation study in rats and the oncogenicity studies in rats and mice.

Endocrine: Uterine (click on for all fluorinated pesticides)

-- Classification: ``Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential'' based on significant trends in liver tumors (adenomas and combined adenomas/ carcinomas), malignant histiocytic sarcomas, and testicular cell tumors in male rats and uterine polyps in female rats seen at the highest dose.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

August 11, 2003, comments submitted to US EPA by FAN's Pesticide Project on the pesticide petition from BASF Corporation to establish a tolerance for residues of chlorfenapyr on all food items in food handling establishments where food products are held, processed, and/or prepared at 0.01 parts per million (ppm). http://www.fluorideaction.org/pesticides/chlorfenapyr.comments.aug03.htm - Also Online at US EPA Docket OPP-2003-0205. 5. Endocrine Disruption. In the petition, BASF states: ... There is no information available which suggests that chlorfenapyr would be associated with endocrine effects. 5.1 However, US EPA noted endocrine effects in the following study: In the rat chronic toxicity/carcinogenicity study (MRID 43492837), there were increased trends in the incidence of hepatocellular adenomas, hepatocellular adenomas and/or carcinomas combined, malignant histiocytic sarcomas and testicular interstitial cell tumors in males rats. In female rats there were significant increasing trends in endometrial stromal polyps. Significant difference in pair-wise comparison of fibroadenomas at the low dose and carcinomas at the mid-dose existed for female rats. There was no evidence of tumorigenic potential in mice.... Ref: US EPA OPPT. February 12, 1998. SUBJECT: Chlorfenapyr - 129093: Health Effects Division Risk Characterization for Use of the Chemical Chlorfenapyr (Alert, EPA File Symbol 5905-GAI) in/on Citrus (6F04623). Case: 287132. Barcode: D221320- http://www.epa.gov/opprd001/chlorfenapyr/memohed2.pdf September 17, 2003, reply to comments from FAN's Pesticide Project, from Daniel J. OÕByrne, Product Registrations Manager, BASF Corporation. http://www.fluorideaction.org/pesticides/chlorfenapyr.basf.sept.2003.pdf - Also online at US EPA Docket OPP-2003-0205. Regarding Point 5: Endocrine Effects This comment addresses findings of endometrial stromal polyps and testicular interstitial cell tumours The occurrence of endometrial stromal polyps in the uterus was slightly increased in high-dose females, as compared to controls. Although the incidence of endometrial stromal polyps in high-dose females (5/65 or 7.7%) is statistically different from the concurrent control females (0/65) by the Fisher Exact Test (p< 0.05), the incidences are not statistically different using the exact prevalence method. This is the more appropriate method to compare two groups with heterogeneous survival rates (survival was significantly increased in high-dose females). All five females with stromal polyps were sacrificed at termination. Furthermore, the incidence (0/65) of these benign polyps in the control females was unusually low for this commonly occurring proliferative lesion that may represent an aging, hormonal-type response. Moreover, the incidence in high-dose females is only slightly above the overall total mean historical rate (35/727 or 4.8%), and well below the maximal spontaneous incidence (8/60 or 13.3%). Therefore, the occurrence of this benign proliferative lesion in females of the high-dose group is not considered treatment related... Overall, there is no indication of an endocrine effect of chlorphenapyr in any of the studies, including the two-generation study in rats and the oncogenicity studies in rats and mice.

Liver (click on for all fluorinated pesticides)

The 100-fold margin of safety is adequate to assure a reasonable certainty of no harm to infants and children from the proposed use. As stated earlier, the NOAEL is based on the effects observed in the rat and mouse chronic oncogenicity studies, (reduced bwt gains, increased globulin and cholesterol values and increased liver weights in the rat and reduced bwt gains and vacuolation of white matter of the mouse brain)...
Ref: Federal Register: August 26, 1999 [Page 46677-46680]. Notice of Filing; Pesticide Petition.
http://www.fluoridealert.org/pesticides/Chlorfenapyr.FR.Aug.26.1999.htm

-- The no observed adverse effect level from the 28-day dermal toxicity study of 100 mg/kg/day for short- and intermediate-term occupational or residential risk assessments is based on increased cholesterol, relative liver weights and cytoplasmic vacuolation of the liver in male and females rabbits at the lowest observed adverse effect level of 400 mg/kg.
Ref: US EPA. Summary of Chlorfenapyr Risk Benefit Assessment.
http://www.fluorideaction.org/chlor-summ.pdf

-- Subchronic Studies... A 28-Day Rat Feeding Study", J.E. Fischer; Non-guideline; Rat; American Cyanamid Company, Toxicology Department, Princeton, NJ; Report No. T-0221; 8/30/91; AC 303,630 Technical (purity: 98.4%); 5 animals/sex/group; Doses: 0, 600, 900, 1200, 1600, 2000 ppm (males-0, 68.3, 106.3, 134.2, 176.8, 243.0 mg/kg/day, females-0, 71.6, 108.4, 138.5, 184.8, 245.5 mg/kg/day), in the diet, 4 weeks... Necropsy: increased absolute liver weight (M-1600, F-900, 1200, 1600, 2000 ppm)... Target organ: liver; NOEL: (M/F) 1200 ppm (based on increased SGPT activity, incidence of hepatocellular hypertrophy and increased relative liver weight in 1600 ppm treatment group); Study supplemental. (Moore, 1/30/95)
Ref: Summary of Toxicological Data for Chlorfenapyr. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. August 24, 2001.
http://www.fluorideaction.org/pesticides/chlorfenapyr.ca.epa.aug2001.pdf

-- MRID No. 42770219 (1993)-- 90-Day oral toxicity rats. NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on spongiform myelopathy in the brain and spinal cord of male rats, decreased body weight gain and increased relative liver weight in males and females, increased absolute liver weight in females, and decreased hemoglobin in females.
- MRID No. 43492831 (1993). 21/28-Day dermal toxicity rabbit. NOAEL = 100 mg/kg/day. LOAEL = 400 mg/kg/day, for both sexes, based on changes in liver chemistry and morphology.
-- Classification: ``Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential'' based on significant trends in liver tumors (adenomas and combined adenomas/ carcinomas), malignant histiocytic sarcomas, and testicular cell tumors in male rats and uterine polyps in female rats seen at the highest dose.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

Spinal Cord (click on for all fluorinated pesticides)

-- MRID No. 42770219 (1993)-- 90-Day oral toxicity rats. NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on spongiform myelopathy in the brain and spinal cord of male rats, decreased body weight gain and increased relative liver weight in males and females, increased absolute liver weight in females, and decreased hemoglobin in females.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

ii. Subchronic Oral Toxicity in Mice... Spongiform encephalopathy was noted in the brain and myelin of the spinal cord of both males and females receiving the 320 ppm treatment level. The LEL is 14.8 mg/kg/day (80 ppm) for male mice and 40.0 mg/kg/day (160 ppm) for female mice, based on hepatic cell hypertrophy in
20% of the test animals at this treatment level. The NOEL is 7.1 mg/kg/day (40 ppm)... The RfD Committee also recommended that a special developmental neurotoxicity study be conducted based upon the effects of a spongyform myelopathy and/or vacuolation seen in the brain and spinal cord of treated rats and mice. They concluded that the registrant should also conduct a mechanistic study to determine the cause/relationship of CNS/myelinopathic alterations to neurotoxicity (including developmental)...
Chronic-Term (greater than several months) Occupational/Residential Dermal NOEL: 3 mg/kg/day (decreased body weight gains brain lesions (vacuolation) and/or scabbing of the skin in a 1 year neurotoxicity study in rats and a chronic/carcinogenicity study in mice) Acceptable MOE = 1000 (includes FQPA Factor)
Ref: US EPA, Feb 12, 1998: Chlorfenapyr - 129093: Health Effects Division Risk Characterization for Use of the Chemical Chlorfenapyr.
http://www.epa.gov/opprd001/chlorfenapyr/memohed2.pdf

Note: Page 19-20: "Other chronic effects. For other chronic effects, a Reference Dose (RfD) has been established at 0.003 mg/kg/day based on decreased body weight gains and brain lesions (vacuolation) observed in the 1-year rat neurotoxicity study. An uncertainty factor (UF) of 1000 was applied to account for interspecies extrapolation, intraspecies variability and the additional FQPA Factor of 10. The FQPA factor has been retained because chlorfenapyr has produced central nervous system lesions in several studies in both rats and mice. It will be reevaluated after the developmental neurotoxicity study has been submitted."
Ref: US EPA. March 13, 2000. "Denial of Registration of Chlorfenapyr for Use on Cotton."
http://www.epa.gov/opprd001/chlorfenapyr/chlorfenapyr.pdf

Note: In a search of EPA's OPP database <http://www.epa.gov/pesticides/search.htm> for "spongiform encephalopathy" - "spongyform myelopathy" and "spongyform" - , the only substance cited was Chlorfenapyr. Mad Cow Disease is also called Bovine spongiform encephalopathy (BSE) which is a chronic, degenerative disorder affecting the central nervous system of cattle. In the US, up until 2002, there were 19 tolerances for residues of Chlorfenapyr in or on: Cotton, Milk, Cattle, Hog, Sheep, Horse, and Goat - see:
http://www.fluorideaction.org/pesticides/chlorfenapyr.us.residuefood.htm

ONCOGENICITY, MOUSE . 066; 147076; "A Chronic Dietary Toxicity and Oncogenicity Study with AC 303,630 in Mice" (L. Bernier, Bio-Research Lab., Ltd., Quebec, Canada, Project # 84580, 8/22/94). AC 303,630 (Batch AC-7504-59A, 94.5% purity) administered orally in the diet to 65 CD-1 mice/sex/dose for 80 weeks at 0, 20, 120, or 240 ppm (Males: 0, 2.8, 16.6, or 34.5 mg/kg/day; Females: 0, 3.7, 21.9, or 44.5 mg/kg/day). Reduced survival rate was noted in high dose females (60% vs. 80%, p < 0.05). However, overall survival rate of this group was more comparable to that of the historical controls. Treatment with AC 303,630 resulted in reduced mean body weight gain in high dose males and females and in mid dose females (Males: 70% of control, p < 0.01, Females: 86% of control, p < 0.05 for mid and high dose groups). Food consumption was also reduced in mid and high dose animals. Histopathology revealed vacuolation of the white matter of the brain in animals treated at mid and high dose levels. Also, vacuolation was detected in spinal cord sections as well as optic nerve tissues in mice at 240 ppm. There was no evidence of carcinogenicity. NOAEL (M/F) = 240 ppm [No adverse effect]. NOEL (M/F) = 20 ppm (2.8 and 3.7 mg/kg/day for males and females, respectively; based on histopathological changes in the brain, optic nerve and spinal cord). acceptable (Leung, 7/24/96)
-- NEUROTOXICITY ** 061; 147070; "A One-Year Dietary Neurotoxicity Study with AC 303,630 in Rats"; (J.A. Foss; Argus Research Laboratories, Inc., Horsham, PA; Study No. 101-019; 5/10/94); AC 303,630 technical (purity: 94.5%) was administered in the diet to 25 animals/sex/group at doses of 0, 60, 300, and 600 ppm for up to 52 weeks ((M)-0, 2.6, 13.6, 28.2 mg/kg/day, (F)-0, 3.4, 18.0, 37.4 mg/kg/day). Surviving animals were observed for an additional 16 weeks of a recovery phase. No treatment-related effects were noted in the functional observational battery or the motor activity evaluation. In the neurohistopathology, myelin sheath swelling of the spinal nerve roots was evident in the males of the 600 ppm treatment group after 13 and 52 weeks of treatment. Extensive vacuolar myelinopathy was noted in the brain and spinal cord of the 300 and 600 ppm males after 52 weeks of treatment. These effects were no longer present after the 16 week recovery period. No treatment-related lesions were noted in the females. No adverse effects were evident. NOEL: (M) 60 ppm (based upon the incidence of extensive vacuolar myelinopathy in the central nervous system); (F) 600 ppm; NOAEL: 600 ppm (based on recovery). Study acceptable. (Moore, 7/29/96)
-- SUBCHRONIC STUDIES ** 010, 031; 125163; "AC 303,630: A 13 Week Dietary Toxicity Study in the Albino Rat", J.E. Fischer; 821; Rat; American Cyanamid Co., Agricultural Research Division, Toxicology Department, Princeton, NJ; Study No. T-0316; 4/8/93; AC 303,630 Technical (purity: 93.6%); 20 animals/sex/group; Doses: 0, 150, 300, 600, 900, 1200 ppm (M: 0, 10.9, 22.0, 44.9, 69.5, 92.2 mg/kg/day, F: 0 11.7, 24.1, 48.4, 72.5, 97.5 mg/kg/day), in the diet, 13 weeks; No treatment-related mortality; Clinical Observations: red. body wgt. gain (M,F-900, 1200 ppm), red. food consumption (M-600 ppm and up); Ophthalmology, Urinalysis: no treatment-related effects; Hematology: red. hematocrit (M,F-1200, F-900 ppm), red. hemoglobin (M,F-1200, F-600, 900 ppm), red blood cells (M,F-1200, F-900 ppm), Clinical Chemistry: incr. BUN (M,F-1200 ppm, week 6, M-1200 ppm, week 13), incr. alk. phosphatase activity (M,F-900, 1200 ppm, week 13); Necropsy: incr. mean abs. liver wgt. (F-600 ppm and up), red. abs. kidney wgt (M,F-900, 1200 ppm), incr. abs. spleen wgt. (M,F-900, 1200 ppm), incr. rel. liver wgt. (M,F-600, 900, 1200, M-300 ppm), increased relative spleen weight (M,F-900, 1200 ppm); Histopathology: spongiform myelopathy in brain, spinal cord (M-(2/20), 1200, 900 ppm, (1/20), 600 ppm), lesion present in sciatic nerve (M-(1/20), 1200 ppm), lymphoid cell infiltrate in kidneys (M,F-900, 1200 ppm); Target organ: central nervous system; Adverse Effect: spongiform myelopathy in the nervous system; NOEL: (M) 300 ppm (occurance of spongiform myelopathy in the nervous system of the 600 ppm group) (F) 300 ppm (based on increased mean abs. liver wgt. in 600 ppm group); (Study previously unacceptable, possibly upgradeable with submission of GLP compliance and QA audit statements (Moore, 2/1/95)) requested information submitted; Study acceptable. (Moore, 8/9/95)
Ref: August 24, 2001 - Summary of Toxicological Data. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. Also available at: http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf