Microsoft word - permethrin safety review 2.19.08.doc

Safety Review: PermethrinPrepared byLynette CasparRoy Upton Permethrin is one of a class of insecticides known as pyrethroids. Like other pyrethroids,permethrin kills insects by strongly exciting their nervous systems. In mammals it has beenshown to cause a wide variety of neurotoxic symptoms including tremors, incoordination, elevatedbody temperature, increased aggressive behavior, and disruption of learning (Cox 1998).
Permethrin is classified as a “potential human carcinogen” by the EPA, and tests with humancells have shown it to be mutagenic. It is listed as a suspected endocrine disruptor, and bothestrogen-like and antiandrogen-like effects have been observed in test animals. Studies haveshown that pyrethroid exposure may be neurotoxic during development and that humannewborns may be more sensitive to permethrin than adults. Children exposed to permethrin havedeveloped immune-mediated respiratory and dermal irritation. It has also been shown to reducecholinesterase activity in the kidneys and livers of test animals.
Permethrin is highly toxic to a wide variety of animals including honey bees (and other beneficialinsects), fish, aquatic insects, crayfish, and shrimp. It is especially toxic to cats. Studies haveshown that most cats (96%) exposed to permethrin develop toxic effects, including excitability,twitching, tremors, convulsions, muscular weakness, respiratory distress, vomiting, diarrhea,hypersalivation, and death.
The toxic effects of permethrin are often greatly increased when combined with other chemicals.
Several studies have linked a variety of health problems (commonly referred to as Gulf WarSyndrome) reported by 30,000 veterans who served in the Persian Gulf War, with exposure to acombination of permethrin, the anti-nerve gas drug pyridostigmine bromide, and the insectrepellent DEET.
chem class – pyrethroid (synthetic insecticides structurally similar to pyrethrins, whichare naturally occurring insecticidal compounds. Many pyrethroids are suspectedendocrine disruptors.) (PAN Database) N (dangerous for the environment) (EC Annex II; Gestis Database) R20/22 (harmful by inhalation and if swallowed) R43 (may cause sensitization by skin contact) R50/53 (very toxic to aquatic organisms, may cause long-term adverse effects inthe aquatic environment) (EC Annex III; Gestis Database) Comments regarding this document should be forwarded to Roy Upton( S13 (keep away from food, drink and animal feeding stuffs) S36/37/39 (wear suitable protective clothing, gloves and eye/face protection) S60 (this material and its container must be disposed of as hazardous waste) S61 (avoid release to the environment) (EC Annex IV; Gestis Database) WHO (World Health Organization) Classification Inhalation LC50 Rat : 485 mg/m³ (MP Biomedicals MSDS) Inhalation LC50 Mouse : 685 mg/m³ (MP Biomedicals MSDS) Oral LD50 Rat : 383 mg/kg (MP Biomedicals MSDS) Oral LD50 Mouse : 424 mg/kg (MP Biomedicals MSDS) Dermal LD50 Rabbit : >2 gm/kg (MP Biomedicals MSDS) harmful if swallowed (Sigma-Aldrich MSDS) burning sensation, diarrhea, vomiting (NIOSH - ICSC 0312) may be irritating to mucous membranes and upper respiratory tract; harmful ifinhaled (Sigma-Aldrich MSDS).
can cause skin or respiratory reactions in people with hay fever or in peoplesensitive to ragweed or pollen; reactions may include irritation or inflammation ofthe skin (contact dermatitis), sneezing, nasal stuffiness, or asthmatic breathing(NPIC 1997).
may cause eye irritation (Sigma-Aldrich MSDS) risk of serious damage to eyes (MP Biomedicals MSDS) may be harmful if absorbed through the skin (Sigma-Aldrich MSDS) may cause allergic skin reaction (Sigma-Aldrich MSDS) redness, burning sensation (NIOSH - ICSC 0312) acute exposure in adults has been shown to result in skin irritation (EPA 2006b;EPA-TEACH 2007; HHS 2003) exposure to permethrin may occasionally produce temporary numbing, tingling,and burning sensations of the skin (NPIC 1997) can cause skin or respiratory reactions in people with hay fever or in peoplesensitive to ragweed or pollen; reactions may include irritation or inflammation ofthe skin (contact dermatitis), sneezing, nasal stuffiness, or asthmatic breathing(NPIC 1997) experiments with laboratory animals indicate that the immune system “appears tobe a sensitive target for permethrin activity.” Ingestion of permethrin reduces theability of immune system cells called T-lymphocytes to recognize and respond toforeign proteins (Cox 1998).
doses equivalent to 1/100 of the LD50, have been shown to inhibit T-lymphocytesover 40 percent (Cox 1998).
permethrin ingestion has also been shown to reduced the activity of a secondtype of immune system cell, natural killer cells, by about 40 percent.(Blaylock etal. as cited by Cox 1998).
studies in adult humans and experimental animals have demonstrated thatpermethrin, like other pyrethroids, alters nerve function by altering the Comments regarding this document should be forwarded to Roy Upton( biochemistry of nerve membrane sodium channels (EPA 2006a, 2006b, EPA-TEACH 2007).
acute exposure in adults has been shown to result in dizziness, twitching, andnervous disorders (EPA 2006b; EPA-TEACH 2007; HHS 2003).
has complex effects on the nervous system in mammals; causes repetitive nerveimpulses, and also inhibits a variety of nervous system enzymes: ATPase: whose inhibition results in increased release of theneurotransmitter acetylcholine (Al-Rahji 1990 as cited by Cox 1998).
monoamine oxidase-A: the enzyme which maintains normal levels ofthree other neurotransmitters (Rao & Rao 1993 as cited by Cox 1998).
acetylcholinesterase: the enzyme that breaks down acetylcholine (Rao &Rao 1995 as cited by Cox 1998).
inhibits the GABAA receptor (a nervous system receptor) producing excitabilityand convulsions (Ramadan et al. 1988a as cited by Cox 1998).
inhibits respiration in a manner similar to other neurotoxic drugs (Gassner et al.
1997 as cited by Cox 1998).
at relatively high doses, neurotoxic symptoms of permethrin include tremors,incoordination, hyperactivity, paralysis, and an increase in body temperature,these symptoms can persist up to three days (IPCS 1989 as cited by Cox 1998).
shown to reduce cholinesterase activity in the kidneys and livers of test animals(Khan et al. 2003).
the liver is a sensitive target for permethrin effects. In an EPA summary of 17medium-term and long-term laboratory studies that exposed test animals topermethrin, effects on the liver were noted at the “lowest effect level” in all ofthem (EPA 1997 as cited by Cox 1998).
enlarged adrenal glands and increased kidney weights have been demonstratedin laboratory tests (EPA 1997 as cited by Cox 1998).
classified by EPA as “Likely to be Carcinogenic to Humans” by the oral route (thisclassification was based on two reproducible benign tumor types (lung and liver)in the mouse, equivocal evidence of carcinogenicity in Long-Evans rats, andsupporting structural activity relationships (SAR) information) (EPA 2006b) IARC (International Agency for Research on Cancer) Classification: Group 3: unclassifiable because the data are incomplete or ambiguous(PAN Database).
U.S. EPA Office of Pesticide Programs (OPP) Carcinogen List: Suggested: Suggestive evidence of carcinogenicity, but not sufficient toassess human carcinogenic potential. This descriptor is appropriatewhen the evidence from human or animal data is suggestive ofcarcinogenicity, which raises a concern for carcinogenic effects, but isjudged not sufficient for a conclusion as to human carcinogenic potential(PAN Database).
EPA found that permethrin increased the frequency of lung tumors in femalemice, and increased the frequency of liver tumors in male and female mice (EPA1997 as cited by Cox 1998).
WHO (World Health Organization) reports that permethrin increased thefrequency of lung tumors in females in two out of the three mouse studies itreviewed (WHO 1990 as cited by Cox 1998).
two proposed molecular mechanisms could explain permethrin’s carcinogenicity: 1. permethrin reduces the activity of an enzyme involved in the breakdown of the amino acid tryptophan. This can lead to the buildup ofcarcinogenic tryptophan breakdown products (El-Touky et al. 1989 ascited by Cox 1998).
Comments regarding this document should be forwarded to Roy Upton( 2. permethrin inhibits what is called “gap junctional intercellular communication” (GJIC), chemical communication between cells. GJICplays an important role in the growth of cells, and some cancerpromoting chemicals inhibit GJIC (Tateno et al. 1993 as cited by Cox1998).
shown to be mutagenic (damaging to genetic material) in tests with human cellcultures, hamster cells, and fruit fly larvae (Cox 1998).
in cultures of human lymphocytes (white blood cells), permethrin exposurecaused an increase in chromosome aberrations, chromosome fragments(Barrueco et al. 1992 as cited by Cox 1998), and DNA lesions (Surralles et al.
1995 as cited by Cox 1998).
in hamster ovary cell cultures, permethrin exposure caused chromosomeaberrations (Barrueco et al. 1994 as cited by Cox 1998).
no available weight-of-the-evidence summary assessment (PAN Database).
evidence is accumulating that pyrethroid exposure may be neurotoxic duringdevelopment (Shafer et al. as cited by EPA -TEACH 2007).
there is concern for developmental neurotoxicity based on evidence ofneurotoxicity at high doses in a subchronic neurotoxicity study (EPA 2006b).
affects both male and female reproductive systems (Cox 1998).
shown to cause reduced testes weights in a long term feeding study of mice(EPA 1997 as cited by Cox 1998).
in females, permethrin exposure has caused embryo loss in pregnant rabbits(EPA 1997 as cited by Cox 1998) and in pregnant rats (Spencer & Berhane 1982as cited by Cox 1998).
binds to receptors for androgen, a male sex hormone, in skin cells from humanmales, causing researchers to “advise protection from any form of contact oringestion of the pyrethroids” (Eil & Nisula 1990 as cited by Cox 1998).
binds to a different receptor, called the peripheral benzodiazepine receptor, thatstimulates production of the male sex hormone testosterone (Ramadan et al.
1988b as cited by Cox 1998).
test results suggest that permethrin may cause mitochondrial membraneimpairment in Leydig cells and disrupt testosterone biosynthesis by diminishingthe delivery of cholesterol into the mitochondria and decreasing the conversion ofcholesterol to pregnenolone in the cells, thus reducing subsequent testosteroneproduction (Zhang et al. 2007).
test results showed estrogen-like effects in female rats, but antiandrogen-likeeffects in males (Kim et al. 2005).
results of animal studies suggest that human newborns may be more sensitive topermethrin than adults (NPIC 1997).
recent studies of children have reported immunotoxic effects following exposureto pyrethroids, with increased incidence of anti-nuclear antibodies associatedwith autoimmune disease (Rosenberg et al. 1999 as cited EPA -TEACH 2007).
permethrin exposure may impact the immune system in children (EPA -TEACH2007); case reports indicated that children exposed to permethrin developedimmune-mediated respiratory and dermal irritation (Fuortes 1999 as cited by EPA-TEACH 2007).
exposure of toddlers to permethrin exceeded the U.S. EPA Level of Concern(LOC) when combined chronic exposure via dietary sources (food and drinkingwater) and short-term exposure via contact with permethrin-treated lawns andindoor surfaces (particularly with carpets in treated rooms) was taken intoaccount (EPA 2006b as cited by EPA -TEACH 2007); this led to new EPA risk Comments regarding this document should be forwarded to Roy Upton( mitigation measures (EPA 2006a, 2006b as cited by EPA -TEACH 2007);mitigation measures include discontinued use of sponge applications;discontinued use of broadcast, crack and crevice sprays on all residential indoorsurfaces (except for aerosol sprays); and concentration limits on aerosol andtotal release fogger formulations (EPA 2006a as cited by EPA -TEACH 2007).
synergy between two or more chemicals occurs when their combined exposure causesmore adverse effects than the sum of their individual effects (as defined by Cox 1998).
Several studies have linked health problems reported by 30,000 veterans who served inthe Persian Gulf War, to exposure to a combination of permethrin, the anti-nerve gasdrug pyridostigmine bromide, and the insect repellent DEET (Abdel-Rahman et al. 2001;Abdel-Rahman et al. 2002; Abdel-Rahman et al. 2004; Abou-Donia et al. 1996; Abou-Donia et al. 2001; Baynes et al. 2002; Cox 1998; etc.) neurotoxic symptoms, including decreased activity, diarrhea, shortness of breath,tremors, inability to walk, and damage to nerves, were observed in hens exposed to allthree chemicals, but not in hens exposed to permethrin alone. Permethrin with justpyridostigmine bromide or just DEET also caused tremors and inability to walk, butsymptoms were not as severe (Abou-Donia et al. 1996 as cited by Cox 1998).
toxic to honey bees and other beneficial insects, fish, aquatic insects, crayfish, andshrimp; for many species, concentrations of less than one part per billion are lethal;causes deformities and other developmental problems in tadpoles, and reduces thenumber of oxygen-carrying cells in the blood of birds (Cox 1998).
inappropriate use of PSOs (permethrin spot-on products) on cats can causesevere toxicity, and frequently result in convulsions and fatalities (Meyer 1999,Bates 2000, Gray 2000, Martin and Campbell 2000 as cited by Sutton et al.
most cats (over 96%) exposed to permethrin develop toxic effects (Sutton et al.
2007); clinical signs of feline permethrin toxicosis usually present within 3 hoursof exposure but may be delayed up to 72 hours (Merola and Dunayer 2006 ascited by Sutton et al. 2007).
symptoms of toxicity include excitability, twitching, tremor, hyperaesthesia,convulsions, muscular weakness, fasciculations, hyperthermia, respiratorydistress, vomiting, diarrhea, hypersalivation, anorexia, tachypnoea, death (Suttonet al 2007: Whittem 1995 as cited by Sutton 2007).
bees - highly toxic to honeybees, as well as other beneficial insects (EPA 2006a).
fish – highly toxic to both freshwater and estuarine aquatic organisms (EPA 2006a).
classified as “hazardous waste” under the European Waste Catalogue Ordinance (AVV)(Gestis Database).
classified as “dangerous for the environment” under European labeling (GestisDatabase).
classified as “very toxic to aquatic organisms, may cause long-term adverse effects in theaquatic environment” under European labeling (Gestis Database).
ground water contaminant - prevent escape into water, drainage, sewer, or ground(Gestis Database); hazard for drinking water sources when only small quantities get intogroundwater (Gestis Database); classified as WGK 3 “severe hazard to waters” under theEuropean Administrative Regulation of Substances Hazardous to Water (VwVwS) (GestisDatabase).
Comments regarding this document should be forwarded to Roy Upton( Abdel-Rahman A, Shetty AK, and Abou-Donia MB. 2001. Subchronic dermal application ofN,N-diethyl m-toluamide (DEET) and permethrin to adult rats, alone or in combination,causes diffuse neuronal cell death and cytoskeletal abnormalities in the cerebral cortexand the hippocampus, and Purkinje neuron loss in the cerebellum. Experimental Neurology.
172(1):153-171. PubMed (accessed 2/13/08). Abdel-Rahman A, Shetty AK, and Abou-Donia MB. 2002. Disruption of the blood-brain barrierand neuronal cell death in cingulate cortex, dentate gyrus, thalamus, and hypothalamus ina rat model of Gulf-War syndrome. Neurobiology of Disease. 10(3):306-326. PubMed(accessed 2/13/08). Abdel-Rahman A, Abou-Donia S, El-Masry E, Shetty A, and Abou-Donia M. 2004. Stress andcombined exposure to low doses of pyridostigmine bromide, DEET, and permethrinproduce neurochemical and neuropathological alterations in cerebral cortex,hippocampus, and cerebellum. Journal of Toxicology & Environmental Health. Part A.
67(2):163-192. PubMed (accessed 2/13/08). Abou-Donia MB. et al. 1996. Neurotoxicity resulting from coexposure to pyridostigminebromide, DEET, and permethrin: Implications of Gulf War chemical exposures. J. Toxicol.
Environ. Health 48:35-56. PubMed (accessed 2/13/08). Abou-Donia MB. et al. 2000. Locomotor and sensorimotor performance deficit in ratsfollowing exposure to pyridostigmine bromide, DEET, and permethrin, alone and incombination. Toxicological Sciences 60, 305-314. (accessed 2/13/08). Al-Rahji DH. 1990. Properties of Ca2+ + Mg2+- ATPase from rat brain and its inhibition bypyrethroids. Pest. Biochem. Physiol. 37:116-120. (accessed 2/12/08) Barrueco C. et al. 1992. Cytogenetic effects of permethrin in cultured lymphocytes. Mutag.
7:433-437. PubMed (accessed 2/11/08). Barrueco C. et al. 1994. Induction of structural chromosomal aberrations in humanlymphocyte cultures and CHO cells by permethrin. Terat. Carcin. Mutag. 14:31-38. PubMed(accessed 2/11/08). Baynes RE, Monteiro-Riviere NA, and Riviere JE. 2002. Pyridostigmine bromide modulatesthe dermal disposition of [C-14] permethrin. Toxicology & Applied Pharmacology. 181(3):164-173. PubMed (accessed 2/13/08). Blaylock R.L. et al. 1995. Suppression of cellular immune responses in BALB/c micefollowing oral exposure to permethrin. Bull. Environ.Contam. Toxicol. 54:768-774. ProQuest- Comments regarding this document should be forwarded to Roy Upton( CSA (accessed 2/11/08). Cox C. 1998. Permethrin insecticide factsheet. Journal of Pesticide Reform SUMMER 1998VOL.18, NO. 2. NCAP (Northwest Coalition for Alternatives to Pesticides) website (accessed2/6/08). Eil C, Nisula BC. 1990. The binding properties of pyrethroids to human skin fibroblastandrogen receptors and to sex hormone binding globulin. J. Steroid Biochem. 35:409-414.
PubMed (accessed 2/11/08). El-Touky et al. 1989. In vivo studies of the effect of some insecticides on the hepaticactivities of L-tryptophan 2,3 dioxygenase and pyridoxal phosphokinase of male mice. J.
Environ. Sci. Health B24(3):265-276. ProQuest-CSA (accessed 2/12/08). EPA. 2006a. Permethrin Facts (Reregistration Eligibility Decision (RED) Fact Sheet). EPAwebsite (accessed 2/8/08). EPA. 2006b. Reregistration Eligibility Decision (RED) for Permethrin. EPA website (accessed2/8/08). EPA. Office of Pesticide Programs. Health Effects Division. 1997. Tox oneliners: Permethrin.
Washington D.C., June 24.
EPA -TEACH (Toxicity and Exposure Assessment for Children’s Health) Database. Permethrin& Resmethrin (Pyrethroids) TEACH Chemical Summary. 2007. EPA (accessed 2/14/08). European Commission. Directive 67/548/EEC. European Commission website (accessed1/15/08). Annex II – hazard symbols Annex III – risk phrases Annex IV - safety phrases Fuortes L. 1999. Urticaria due to airborne permethrin exposure. Vet.Hum.Toxicol. 41(2):92-93. PubMed (accessed 2/14/08). Gassner, B. et al. 1997. The pyrethroids permethrin and cyhalothrin are potent inhibitors ofthe mitochondrial complex I. J. Pharmacol. Exper. Therap. 281:855-860. Journal ofPharmacology and Experimental Therapeutics (accessed 2/13/08). Gestis Substance Database. BGIA website (accessed 2/6/08). International Programme on Chemical Safety. 1989. Permethrin health and safety guide.
Health and Safety Guide No. 33. Geneva, Switzerland: World Health Organization, UnitedNations Environment Programme, and International Labor Organization. (accessed 2/13/08) Comments regarding this document should be forwarded to Roy Upton( Khan MZ, Tabassum R, Naqvi SNH, Shah EZ, Tabassum F, Ahmad I, Fatima F, Khan MF.
2003. Effect of Cypermethrin and Permethrin on Cholinesterase Activity and ProteinContents in Rana tigrina (Amphibia). Turk J Zool. 27: 243-246. (accessed 2/15/08). Kim SS, Lee RD, Lim KJ, Kwack SJ, Rhee GS, Seok JH, Lee GS, An BS, Jeung EB, and ParkKL. 2005. Potential estrogenic and antiandrogenic effects of permethrin in rats. Journal ofReproduction & Development. 51(2):201-210. (accessed 2/14/08). MP Biomedicals. Permethrin MSDS. ChemQuik MSDS Management System (linked from UCSC (accessed 2/6/08). (type in CAS # 52645-53-1, click on chemicalname) NIOSH (National Institute for Occupational Safety and Health). Permethrin – ICSC 0312. CDCwebsite (accessed 2/6/08). NPIC (National Pesticide Information Center) (a cooperative agreement between Oregon StateUniversity and the U.S. Environmental Protection Agency). 1997. Permethrin Factsheet. NPICwebsite (accessed 2/7/08). PAN Database. Permethrin. Pub Med - Ramadan AA. et al. 1988a. Action of pyrethroids on GABAA receptor function. Pest.
Biochem. Physiol. 32:97-105. ProQuest-CSA (accessed 2/13/08). Ramadan AA. et al. 1988b. Actions of pyrethroids on the peripheral benzodiazepinereceptor. Pest. Biochem. Physiol. 32:106-113. ProQuest-CSA (accessed 2/11/08). Rao GV. and KSJ Rao. 1993. Inhibition of monoamine oxidase-A of rat brain by pyrethroids-an in vitro kinetic study. Mol. Cell. Biochem.124:107-114. SpringerLink (accessed 2/12/08) Rao GV & Rao KSJ. 1995. Modulation of acetylcholinesterase of rat brain by pyrethroids invivo and an in vitro kinetic study. J. Neurochem. 65:2259-2266. PubMed (accessed 2/12/08) Rosenberg AM. et al. 1999. Prevalence of antinuclear antibodies in a rural population.
J.Toxicol.Environ.Health A 57(4):225-236. PubMed (accessed 2/14/08) Shafer TJ et al. 2005. Developmental neurotoxicity of pyrethroid insecticides: critical reviewand future research needs. Environ Health Perspect. 113(2):123-136. EHP online (accessed2/14/08). Comments regarding this document should be forwarded to Roy Upton( Sigma-Aldrich MSDS - Spencer F, Berhane Z. 1982. Uterine and fetal characteristics in rats following apostimplantational exposure to permethrin. Bull. Environ. Contam. Toxicol. 29:84-88.
Surrallés J. et al. 1995. The suitability of the micronucleus assay in human lymphocytes asa new biomarker of excision repair. Mut. Res.342:43-59. PubMed (accessed 2/11/08). Sutton NM, Bates N, Campbell A. 2007. Clinical effects and outcome of feline permethrinspot-on poisonings reported to the Veterinary Poisons Information Service (VPIS),London. J Feline Med Surg. Aug;9(4):335-9. Epub 2007 Jul 12. (accessed 2/13/08) Tateno C. et al. 1993. Effects of pyrethroid insecticides on gap junctional intercellularcommunications in Balb/c3T3 cells by dye transfer assay. Cell Biol. Toxicol. 9:215-222.
SpringerLink (accessed 2/12/08). HHS (U.S. Department of Health and Human Services) – ATSDR (Agency for Toxic Substancesand Disease Registry). 2003. Toxicological profile for pyrethrins and pyrethroids. (accessed2/14/08). WHO (World Health Organization). 1990. Permethrin. Environmental Health Criteria 94. Geneva,Switzerland: World Health Organization, United Nations Environment Programme andInternational Labor Organization. pp.76-78.
Zhang SY, Ito Y, Yamanoshita O, Yanagiba Y, Kobayashi M, Taya K, Li CM, Okamura A, MiyataM, Ueyama J, Lee CH, Kamijima M, and Nakajima T. 2007. Permethrin may disrupttestosterone biosynthesis via mitochondrial membrane damage of leydig cells in adultmale mouse. Endocrinology. 148(8):3941-3949. (accessed 2/14/08). Comments regarding this document should be forwarded to Roy Upton(


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