Note: This is not an exhaustive list.
As time allows more information will be added.

Chlorodifluoromethane - Insecticide, Fungicide, Propellant - CAS No. 75-45-6

Chlorodifluoromethane (FC-22) was evaluated for embyotoxicity and teratogenicity in groups of 40 pregnant Charles River rats exposed to the test substance by inhalation at concentrations of 0, 0.05, 0.10, and 2.00% on days 6-15 of gestation. No clinical signs of toxicity were observed in maternal animals. The number of implantations, early and late resorptions, and number of live fetuses per litter were unaffected. There was a sporadic appearance of major malformations of the eye in all test groups. The increased incidence of eye defects was not statistically significant. Authors believe that the test substance may have interacted with the genetic make-up of affected fetuses and caused the increased expressivity of a mutant gene. The authors considered the test substance to be a mutagen under the conditions of this study.
Ref: 1992 - INITIAL SUBMISSION: EMBRYOTOXIC AND TERATOGENIC STUDIES IN RATS WITH INHALED CHLORODIFLUOROMETHANE WITH COVER LETTER DATED 06-15-92 AND ATTACHMENTS. HASKELL LABORATORY. Report Nos. NTIS/OTS0540606 and EPA/OTS; Doc #88-920004258.

Teratogenicity was evaluated in 4 groups of 19 pregnant CD female rats receiving Arcton 22 via inhalation at concentration levels of 0, 100, 1,000 and 50,000 ppm for 6 hours per day on gestation days 6 through 15. There were no treatment-related effects in appearance, behavior, mortality, or pregnancy rate. At 50,000 ppm maternal weight gain was slightly lower than the control. There were no effects on body weight at 100 or 1,000 ppm. In all test groups litter size, post-implantation loss, litter wight, and mean fetal weight were similar to the control. At 50,000, there was an increased incidence of anophthalmic• fetuses.
Ref: 1989 -  EFFECT OF ACRTON 22 ON PREGNANT RATS: RELATIONSHIP TO ANOPHTHALMIA AND MICROPHTHALMIA WITH ATTACHMENTS AND COVER LETTER DATED 07-05-89. Report Nos. NTIS/OTS0520413 and EPA/OTS; Doc #87-890000011

• Anophthalmic definition: Absence of an eye(s).  It can be a congenital (born without) or an acquired condition (surgically removed).

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

SUBCHRONIC AND CHRONIC TOXICITY
-- 870.5315 Chromosome Studies; Human Lymphocytes in vitro. Owing to the conflicting results from the cytotoxicity assessment and the presence of rare complex chromosome aberrations both with and without S9 activation, the study is considered inconclusive.
Ref: US EPA Pesticide Fact Sheet. Reason for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf

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

Abstract: ... Our study describes the genotoxic effects of PCP, lindane, transfluthrin, cyfluthrin, and natural pyrethrum on human mucosal cells of the inferior and middle nasal conchae.
METHODS: Epithelial cells were isolated from nasal mucosa, which was removed in the surgical treatment of chronic sinusitis and nasal concha hyperplasia. After the cells had been tested for vitality using the trypan blue exclusion test, the short-term culture method was used. The material was incubated with PCP (0.3, 0.75, and 1.2 mmol), lindane (0.5, 0.75, and 1.0 mmol), transfluthrin (0.05, 0.1, 0.5, 0.75, and 1.0 mmol), cyfluthrin (0.05, 0.1, 0.5, 0.75, and 1.0 mmol), natural pyrethrum (0.001, 0.005, 0.01, 0.05, and 0.1 mmol), and N-methyl-N'-nitro-N-nitrosoguanidine for 60 minutes. Substance-induced DNA damage (single-strand and double-strand breaks) were determined using single-cell microgel electrophoresis. A fluorescence microscope was used together with an image processing system to analyze the results obtained.
RESULTS: After exposure to all tested substances, a high percentage of the cells of the middle nasal concha in particular were found to have severely fragmented DNA as a result of strong genotoxic effects. Although the reaction of the cells of the inferior nasal concha was significantly less strong (p < 0.001), the tested substances were nevertheless found to have a notable genotoxic effect on these cells too.
CONCLUSION: Our study strongly suggests that exposure to PCP, lindane, transfluthrin, cyfluthrin, and natural pyrethrum has a genotoxic effect on the epithelial cells of human nasal mucosa. In addition, we have shown that nasal structures differ in susceptibility to the various pesticides used in the tests. Thus, the study provides new evidence supporting the biological plausibility of PCP- and lindane-induced effects, thereby helping evaluate potential PCP- and lindane-induced mucous membrane carcinomas of these parts of the nose. In addition, our study shows that other substances that today are widely used for controlling pests have a considerable genotoxic effect on human target cells. The results obtained indicate the need for additional studies on the genotoxicity of these substances and their adverse effects on human health.
Ref: Genotoxic effects of pentachlorophenol, lindane, transfluthrin, cyfluthrin, and natural pyrethrum on human mucosal cells of the inferior and middle nasal conchae; by Tisch M, Faulde MK, Maier H. Am J Rhinol. 2005 Mar-Apr;19(2):141-51.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15921213&query_hl=2

Cyhalothrin, lambda - Insecticide - CAS No. 91465-98-6

Abstract (2005): In this study, a synthetic pyrethroid insecticide, lambda-cyhalothrin (LCT), was administered to adult female albino rats (Wistar rats) by gavage dose of 6.12, 3.06, 0.8 mg/kg b.w. repeated for 13 days at 48 h intervals. The cytotoxic and genotoxic effects of LCT were investigated in bone marrow cells, using the structural chromosomal aberration (SCA) and micronucleus (MN) test systems. Mitomycin C (MMC) was also used as positive control (2 mg/kg b.w.). All the doses of LCT increased the number of SCAs and the frequency of micronucleated erythrocytes, with respect to the control group. Only the highest dose of LCT significantly increased the MN frequency compared with control (P<0.01). It was also observed that LCT caused a significant decrease in the number of polychromatic erythrocytes compared with controls (p<0.001). These observations indicate the in vivo suspectibility of mammals to the genetic toxicity and cytotoxicity potential of LCT.
Ref: Evaluation of cytogenetic effects of lambda-cyhalothrin on Wistar rat bone marrow by gavage administration; by Ayla Çelika (a), Birgül Mazmanci, Yusuf Çamlica, Ülkü Çömelekogšlu, and Ali As¸kin
Ecotoxicology and Environmental Safety - Volume 61, Issue 1 , May 2005, Pages 128-133

Abstract (2003). In this study, the genotoxic and cytotoxic potential of lambda-cyhalothrin (LCT), a synthetic pyrethroid insecticide, was investigated in Wistar rat bone-marrow cells, using the structural chromosomal aberration (SCA) and micronucleus (MN) test systems. LCT was administrated to adult female albino rats as repeated i.p. doses of 6.12, 3.06, 0.8 mg/kg BW for 13 days at 48 h intervals. Mitomycin C (MMC) was used as a positive control (2 mg/kg BW). All the doses of LCT increased the number of structural chromosomal aberrations and the frequency of micronucleated erythrocytes, compared with the control group. It was also observed that LCT caused a significant decrease in the number of polychromatic erythrocytes. Our results demonstrate that LCT has a clastogenic/genotoxic potential as measured by the bone marrow SCA and MN tests in Wistar rats.
Ref: Cytogenetic effects of lambda-cyhalothrin on Wistar rat bone marrow; by Celik A, Mazmanci B, Camlica Y, Askin A, Comelekoglu U. Mutat Res. 2003 Aug 5;539(1-2):91-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12948817

Abstract (2003). Micronucleus formation in fish erythrocytes, as an indicator of chromosomal damage, has been increasingly used to detect the genotoxic potential of environmental contaminants. Nucleolar organizer regions (NORs) stained with colloidal silver techniques indicate sites of active RNA transcription. The number and size of NORs in interphase nuclei reflect cellular activities such as proliferation and differentiation of cells. In this study, nuclear (micronucleus frequency) and nucelolar (changes in quantitative characteristics of nucleoli) biomarkers were used to evaluate the functional and structural genotoxic effects of the pyrethroid insecticide lambda-cyhalothrin on Garra rufa (Pisces: Cyprinidae). The frequency of micronuclei was examined in blood smears obtained from fishes exposed to three different concentrations (0.005, 0.01, 0.05 microg/l) for a period of 36 h. Nucleolar parameters (the average number of nucleoli per cell; the volume of a single nucleolus; and the percentage of cells with heteromorphic paired nucleoli) were examined in epithelial cells obtained from the edge of caudal fins at the 90th and 180th minutes of exposure. Results of both tests demonstrated the genotoxic potential of pyrethroid lambda-cyhalothrin on G. rufa. The frequency of micronucleated erythrocytes was significantly increased while the nucleolar parameters were repressed by lambda-cyhalothrin treatment. Our results confirmed that the use of nucleolar biomarkers on fish fin cells, in addition to micronucleus test, could provide valuable information in aquatic genotoxicity studies.
Ref: Evaluation of the genotoxic potential of lambda-cyhalothrin using nuclear and nucleolar biomarkers on fish cells; by Cavas T, Ergene-Gozukara S. Mutat Res. 2003 Jan 10;534(1-2):93-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12504758

Abstract (1999). In order to develop experimental models able to detect genotoxic effects of pollutants in aquatic organisms, the genotoxicity of the pyrethroid lambda-cyhalothrin was studied using the micronucleus test in erythrocytes of Cheirodon interruptus interruptus. The frequency of micronuclei was examined in blood smears obtained from fishes exposed in vivo to three different concentrations (0.05; 0. 01; 0.001 ug/l) of the compound and sacrificed at nine sampling times (24, 48, 72, 96 h and 8, 12, 15, 19 and 23 days). As a positive control fishes were exposed to 5 mg/l of cyclophosphamide. Results obtained demonstrated the genotoxic effects of the pyrethroid in the experimental model employed. The variation in the micronuclei frequencies in the different sampling times could be related to the blood cell kinetics and the erythrocyte replacement. The results could be considered as a validation of the MN test in fishes for the assessment of genotoxic pollutants.
Ref: Genotoxic evaluation of the pyrethroid lambda-cyhalothrin using the micronucleus test in erythrocytes of the fish Cheirodon interruptus interruptus; by Campana MA, Panzeri AM, Moreno VJ, Dulout FN. Mutat Res. 1999 Jan 13;438(2):155-61.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10036336&dopt=Abstract

Dichlorodifluoromethane - Insecticide, Fungicide Propellant, EPA List 2 Inert - CAS No. 75-71-8

Significant mutagenic activity of F 12 at 2.47x10+6 mg/cu m (50%) in air in a Neurospora crassa test system. [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-59 (1980) EPA 440/5-80-051]
---- Note from FAN: Dichlorodifluoromethane is also called Freon 12 or F 12.
Ref: TOXNET profile from Hazardous Substances Data Bank for Dichlorodifluoromethane.
http://www.fluoridealert.org/pesticides/dichlorodifluorometh.toxnet.htm

Dichlofluanid - Wood Preservative, Antifoulant, Fungicide, Acaricide - CAS No. 1085-98-9

Abstract: The cytotoxicity and lipid peroxidation of pesticides containing a halogen group were examined in isolated rat hepatocytes. We examined 9 pesticides of 3 different representative chemical families... The contents of the hydroperoxides in phospholipid, phosphatidylcholine hydroperoxide (PCOOH) and phosphatidylethanolamine hydroperoxide (PEOOH) were determined by the HPLC-chemiluminescence (CL-HPLC) method, which is sensitive and specific for lipid hydroperoxide. Chlorothalonil, dichlofluanid and captan were the most potent cytotoxicants evaluated by lactate dehydrogenase (LDH) leakage. PCP, NIP and CNP exhibited intermediate cytotoxicity. PCNB, fthalide and chlomethoxynil showed low cytotoxicity. The cellular phospholipid hydroperoxide (PCOOH and PEOOH) levels were remarkably increased by chlorothalonil (PCOOH, 23 times and PEOOH, 7 times), dichlofluanid (PCOOH, 523 times and PEOOH, 22 times) and captan (PCOOH, 518 times and PEOOH, 16 times) as compared with the control group. The PCOOH content was slightly increased by PCP (4.8 times) and NIP (6.3 times), whereas the other 4 pesticides did not change the phospholipid hydroperoxide level. Severe cytotoxicity was observed with a remarkable increase of phospholipid hydroperoxide by chlorothalonil, dichlofluanid and captan.
Ref: Biol Pharm Bull 1997 Mar;20(3):271-4. Cytotoxicity of organochlorine pesticides and lipid peroxidation in isolated rat hepatocytes; by Suzuki T, Komatsu M, Isono H.

PubMed abstract: Seven different endpoints for detection of genotoxicity have been used to demonstrate the DNA-altering properties of Dichlofluanid, a fungicide commonly used in viticulture pest control. Each endpoint (DNA synthesis inhibition test, alkaline viscosimetry, umu-test, alkaline filter elution, FADU-test, 32P-postlabeling, and electron microscopy) shows clear evidence of genotoxicity. These data indicate that application of the fungicide dichlofluanid may be mutagenic and/or carcinogenic for exposed humans.
Ref: Environ Mol Mutagen 1991;17(1):20-6. Genotoxicity of the fungicide dichlofluanid in seven assays; by Heil J, Reifferscheid G, Hellmich D, Hergenroder M, Zahn RK.

1,1-Difluoroethane (Freon 152A) - US EPA List 2 Inert - CAS No. 75-37-6

Genetron 23, and Genetron-152A [synonym] exposure increased the mutation rate in progeny of Drosophila melanogaster. Genetron-23 appeared to be more mutagenic. Pronounced phenotypic effects were observed among progeny of exposed males. Part of the observed mutagenic effects of fluorinated hydrocarbon gases may be due to anoxia.
[Foltz VC, Fuerst R; Environ Res 7: 275-85 (1974)]
Ref: Hazardous Substances Data Bank for 1,1-Difluoroethane at Toxnet
http://toxnet.nlm.nih.gov/

Dimefox - Acaricide, Insecticide - CAS No. 115-26-4

PubMed abstract: ... In addition, a series of pesticides structurally related to HMPA, such as dimefox, hexamethylmelamine, hexazinone, alachlor, CAM, pirimicarb, dimetilan, thiram and methabenzthiazuron have been tested with the Oregon-K strain. Some of these pesticides had already been shown to be genotoxic in other systems, whereas others have either not been tested or gave negative results in in vitro systems. Although genotoxicity was expressed only within a narrow dose range, all pesticides were genotoxic in the w/w+ system with the Oregon-K strain. Thus, these compounds may be a genotoxic hazard to man...
Ref: Mutagenesis 1994 Jul;9(4):341-6. The w/w+ SMART is a useful tool for the evaluation of pesticides by Aguirrezabalaga I, Santamaria I, Comendador MA.

Ethalfluralin - Herbicide - CAS No. 55283-68-6

Ethalfluralin was weakly mutagenic in activated strains TA1535 and TA100 of salmonella typhimurium, but not in strains TA1537, TA1538, and TA98 in an Ames assay. In a modified Ames assay with salmonella typhimurium and e- coli, ethalfluralin was weakly mutagenic in strains TA1535 and TA100, with and without activation, and in strain TA98 without activation, at the highest dose. No mutagenicity was found in the mouse lymphoma assay for forward mutation. Ethalfluralin did not induce unscheduled DNA synthesis in rat hepatocytes. In Chinese hamster ovary cells, ethalfluralin was negative without S9 activation, but it was clastogenic with activation.
Ref: Federal Register. November 14, 2001. [PF-1052; FRL-6808-9]
http://www.fluoridealert.org/pesticides/ethalfluralin.fr.nov14.2001.htm

Etoxazole - Miticide, Ovicide - CAS No. 153233-91-1

Abstract: Etoxazole is a member of the diphenyl oxazoline class of insecticide, which was newly developed for use on pome fruits, cotton and strawberries as an acaricide. In the present study, genotoxic effects of acaricide etoxazole (ETX) (miticide/ovicide) were investigated using chromosome aberration (CA) test, sister chromatid exchange (SCE) test, and micronucleus test in human lymphocytes. ETX induced the CAs at all concentrations (5, 10, and 20 g/ml) for 24 h and also induced the CA at the highest concentration (20 g/ml) for 48 h only. The inducing the CAs for 48 h treatment period was dose-dependent. In addition, it induced the SCE at all concentrations and treatment periods in a dose-dependent manner as well. Although ETX decreased the mitotic index (MI) at all concentrations and treatment periods dose-dependently, it did not decrease the replication index (RI) when compared to the negative and solvent controls. In addition, ETX induced the micronucleus at all concentrations except 5 g/ml for 48 h. This inducing was dose-dependent as well. It can be concluded that ETX has a potential genotoxic effects in cultured human peripheral lymphocytes.
Ref: The Genotoxic Effect of the New Acaricide Etoxazole. E. Rencüzogullari; H. Basrila; A. Kayraldiz; M. Arslan; S. Budak Diler; M. Topaktas. Russian Journal of Genetics, November 2004, vol. 40, no. 11, pp. 1300-1304(5).
http://www.ingentaconnect.com/content/maik/ruge/2004/00000040/00000011/00500539

Gene mutation - in vitro forward gene mutation assay in mouse lymphoma cells. When tested up to cytotoxic levels, mutagenic in the presence of S9 activation and equivocal for mutagenicity in the absence of S9 activation.
Ref: Federal Register: September 26, 2003. Etoxazole; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/etoxazole.fr.sept.26.2003.htm

Fipronil - Acaricide, Insecticide, Wood Preservative - CAS No. 120068-37-3

-- Chinese hamster lung cells were treated at different concentations of fipronil (batch number 1747, 98.3%pure) in 1995 in duplicate cultures to examine its potential to induce chromosomal aberrations in the presence or absence of S9 rat liver metabolic activating fracion (derived from Arochlor induced rats). The concentrations tested (see Table 5.14, page 87) were chosen on the basis of preliminary cytotoxicity tests ...There was a dose related increase in aberrations at six hours in the absence of S9 (statistically significant at the top two doses), and a possible increase in the presence of S9 (although the increase at 60 ug fipronil/ml was not statistically significant). The increases in aberrations were due to increases in chromatid breaks and chromatid exchanges. The mechanism is not considered to be due to cytotoxicity (i. as outlined by Kirkland/1) as large proportion of the aberrations seen were chromatid exchanges, whereas only breaks usually characterise the mechanism relating to cytotoxicity ... To conclude fipronil was clastogenic under the conditions of this assay. (pages 86-87).
Summary of genotoxicity studies ... Although the in vitro cytogenetics assay in Chinese hamster lung cells was positive, the mouse micronucleus test indicated that the test material was not actually clastogenic in vivo. It is considered unlikely that a second in vivo assay in a diferent tissue is likely to produce anything other than a negative result. The lack of any tumours that could be attributed to direct genotoxic action in the rat and mouse chronic studies also support the lack of in vivo genotoxicity by fipronil. (page 89)
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf

Flocoumafen - Rodenticide - CAS No. 90035-08-8

Abstract: Embryotoxic and teratogenic effects of flocoumafen (new anticoagulant rodenticide) in chick embryos and white rats were studied. Flocoumafen was injected (2 ug/egg) to the yolk sac of Fayuomi fertile eggs on the 5th and 9th day of incubation. It was orally administered to pregnant female rats (2.5 and 5 ug/kg B. Wt.) on the 8th, 10th and 12th day of gestation. The study revealed that flocoumafen was more embryotoxic than teratogenic in both chick embryos and white rats.
Ref: Khalifa BA et al. (1992). Embryotoxic and teratogenic effects of flocoumafen in chick embryos and white rats. Journal of Applied Animal Research;2(2):81-5

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

Fetotoxicity (delayed ossification and eye opacities) was also demonstrated in New Zealand White rabbits (the LOEL was 30 mg/kg/day; the NOEL was 10 mg/kg/day). EPA believes that there is sufficient evidence for listing fluazifop butyl on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and developmental 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.

-- Reproductive Effects: In a 3-generation reproductive study in rats, effects included reductions in weight gain, fetal weight, ossification, testicular weight, spleen weight, increased prostate weight and gestational length. No Effect Level (NEL) was 1 mg/kg/day. Fetotoxic effects seen in the rabbit, including reduced fetal weight and reduced ossification at higher doses. No Effect Level (NEL) was 30 mg/kg/day in rabbits. The NEL for teratogenic effects is at least 10/mg/day in the rat, with diaphragmatic hernia at higher doses. Not teratogenic at highest dose tested in rabbits (90 mg/kg/day). While fluazifop-p-butyl is fetotoxic when fed to pregnant rats, human exposure data has concluded that female formulation workers are not at increased risk of fetotoxic effects when skin protection measures are applied.
Ref: Material Safety Data Sheet for Fusilade DX (active indredient Fluazifop-P-Butyl). Syngenta. January 21, 2002.
http://www.fluoridealert.org/pesticides/fluazifop-p-butyl.msds.pdf

Fluazifop-P-butyl - Herbicide - CAS No. 79241-46-6

-- Reproductive Effects: In a 3-generation reproductive study in rats, effects included reductions in weight gain, fetal weight, ossification, testicular weight, spleen weight, increased prostate weight and gestational length. No Effect Level (NEL) was 1 mg/kg/day. Fetotoxic effects seen in the rabbit, including reduced fetal weight and reduced ossification at higher doses. No Effect Level (NEL) was 30 mg/kg/day in rabbits. The NEL for teratogenic effects is at least 10/mg/day in the rat, with diaphragmatic hernia at higher doses. Not teratogenic at highest dose tested in rabbits (90 mg/kg/day). While fluazifop-p-butyl is fetotoxic when fed to pregnant rats, human exposure data has concluded that female formulation workers are not at increased risk of fetotoxic effects when skin protection measures are applied.
-- Chronic/Subcrhonic Toxicity Studies: Chronic toxicity studies in rodents have shown liver changes (cellular hypertrophy). The No Effect Level (LEL) in rats is 10 ppm (0.5 mg/kg/day). Long term feeding studies in dogs produced a range of potentially serious effects at high dose rates (red cell, bone marrow and lymphadenopathy changes and liver and spleen damage) with a No Effect Level of 25 mg/kg/day.
Target Organs: Liver, skin, kidney, eye, bone marrow, blood, reproductive system.
Ref: Material Safety Data Sheet for Fusilade DX (active indredient Fluazifop-P-Butyl). Syngenta. January 21, 2002.
http://www.fluoridealert.org/pesticides/fluazifop-p-butyl.msds.pdf

Fluchloralin - Herbicide - CAS No. 33245-39-5

Pub Med Abstract: Fluchloralin is cytotoxic and genotoxic and induces apoptosis in mammalian cells.
The genotoxic and cytotoxic effects of a widely used herbicide, fluchloralin, were assessed using cultured mammalian cells. Treatment of cells for 8-12 hr with fluchloralin resulted in a significant increase in the frequency of metaphase cells with chromosomal damage. At higher concentrations, the herbicide also induced an increase in the frequency of sister chromatid exchange. A 50% loss in viability was observed when cells were exposed to the herbicide for 72 hr. To understand the mechanism of cell death caused by fluchloralin, its effect on DNA synthesis and its ability to induce apoptosis were investigated. Even short (6 hr) treatment of cells with fluchloralin resulted in a 30-50% inhibition of DNA synthesis. Agarose gel electrophoresis of DNA from herbicide-treated cells and cytochemical staining indicate the induction of apoptosis by fluchloralin.
Ref: Environ Mol Mutagen 1998;31(3):257-62. Fluchloralin is cytotoxic and genotoxic and induces apoptosis in mammalian cells. Sinha S, Panneerselvam N, Shanmugam G.

Abstract: The genotoxic effect of fluchloralin (33245-39-5) in cultured human blood lymphocytes was investigated. Venous blood samples were obtained from healthy donors and lymphocyte cultures were established. Cell cultures were treated with 2.5, 5.0, or 10 micrograms/milliliter (microg/ml) fluchloralin for 24 or 48 hours. Following treatment, slides were prepared and cells were scored for chromatid aberrations. In a micronuclei (MN) test, cell were exposed up to 50microg/ml fluchloralin for up to 48 hours. Cell microslides were prepared and scored for MN frequency. Treatment of the lymphocytes for 24 to 48 hours resulted in a significant dose dependent increase in the total number of chromatid type aberrations. The frequency of chromatid aberrations was high compared to isochromatid breaks at all dose levels. The increase in the frequency of isochromatid breaks was notable after 48 hours of treatment. Gap formation was high at all concentrations. Multiple aberrated cells showed a dose dependent increase at both time points. The frequency of occurrence of MN in cultured human blood lymphocytes following fluchloralin treatment was noted. The induction of MN formation was similar and significant at 24 and 48 hours of treatment at 2.5 to 10microg/ml. At the higher concentrations there was a statistically dose related increase in the frequency of micronucleated binucleate cells. The authors conclude that fluchloralin at higher concentrations have the ability to damage the human genome.
Ref: Genotoxicity of the herbicide fluchloralin on human lymphocytes in vitro: chromosomal aberration and micronucleus tests; by Panneerselvam N, Sinha S, Shanmugam G. Mutat Res 1995 Aug;344(1-2):69-72

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

-- Gene mutation and other genotoxic effects were studied using fludioxonil technical: ... iii. Chromosome aberrations assay (in vitro) in Chinese hamster ovary (CHO) cells with and without S9 activation provided convincing evidence that fludioxonil is a clastogen and polyploidy inducer.
Ref: Federal Register. October 7, 1998. Fludioxonil; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/fludioxonil.fr.oct.1998.htm

Flumequine - Microbiocide - CAS No. 42835-25-6

PubMed Abstract: The influence of flumequine on mitogen induced lymphoid cell proliferation in European eels (Anguilla anguilla L., 1758) was studied. For this purpose an in vivo test, using peroral drug administration followed by successive intraperitoneal injections with concanavalin A (ConA) or bacterial lipopolysaccharides (LPS) and 5-bromo-2'-deoxyuridine, was applied. Direct counting of proliferated cells in blood smears revealed that flumequine possesses mitogenic properties. A synergistic and an antagonistic effect of the drug was observed after LPS and ConA stimulation, respectively. Flow cytometric analysis of peripheral blood lymphoid cells showed a significant reduction of the mean proportion surface immunoglobulin positive cells in the flumequine-treated animals. It is concluded that flumequine enhances proliferation of lymphoid cells (probably surface immunoglobulin negative cells) in eel under the present experimental conditions.
Ref: Vet Immunol Immunopathol 1995 Jul;47(1-2):143-52. Influence of flumequine on in vivo mitogen responses of European eel (Anguilla anguilla L., 1758) lymphoid cells. van der Heijden MH et al.

Flumethrin - Acaricide - CAS No. 69770-45-2

Abstract: The genotoxic potential of the pyrethroid flumethrin was evaluated by using the combined protocol of metaphase analysis and micronucleus test in vivo in mouse bone marrow. The dermal route was tested in a single treatment and the intraperitoneal (i.p.) route in a single and a multiple treatment. Flumethrin showed a cytotoxic effect on both myelopoiesis and erythropoiesis, as evidenced by a reduction in the mitotic index and in polychromatic erythrocyte values. An increase in the frequency of gaps after the dermal exposure and of breaks only at the highest dose tested in the i.p. treatment indicates a weak clastogenic potential of the compound. A significant increase in the frequency of micronucleated polychromatic erythrocytes was observed after single and multiple i.p. treatments. In the latter, the induction of micronuclei was highly significant but not accompanied by an increase in breaks. This may indicate that the clastogenic effect might not account by itself for the induction of micronuclei, which could also have arisen from an aneugenic potential of flumethrin.
Ref: Nakano E et al. (1996). Evaluation of the Genotoxic Potential of Flumethrin in Mouse Bone Marrow by Chromosomal Analysis and Micronucleus Test. Teratogenesis, Carcinogenesis, and Mutagenesis, Vol. 16, No. 1, pages 37-48.

The above paper was abstracted in Food and Chemical Toxicology, Volume 34, Issue 10, October 1996, Page 1021 : Flumethrin genotoxicity. Flumethrin, asynthetic pyrethroid insecticide, tested as the technical product Bayticol 60%, induced chromosomal damage in the bone marrow cells when administered to mice by intraperitoneal injection (Nakano et al., Teratogenesis, Carcinogenesis and Mutagenesis 1996, 16, 37).

 

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

Study # 870.4300. Combined chronic carcinogenicity - rat. NOAEL = mg/kg/day: males = 1.8, females = 2.2 LOAEL = mg/kg/day: males = 18.0, females = 21.8 based on increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC) No evidence of carcinogenicity 870.5100 Gene mutation in S. typhimurium and E. coli Neither cytotoxic nor mutagenic up to 2000 g/plate. There were reproducible increases in revertant colonies of S. typhimurium strains TA1538 and TA98 in S9 activated phases of the preliminary cytotoxicity and both mutation assays. [Results considered to be equivocal.]
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

Fluoroacetamine - Insecticide, Rodenticide - CAS No. 640-19-7
(also known as Fluoroacetamide or Compound 1081)

GENOTOXICITY A. Cytogenetic analysis detected chromosome aberrations in the rat in vivo and in mammal lung cells. In Red Muntjac in vitro, fluoroacetamide caused chromosomal breakage, increased rate of sister chromatid exchanges, and a lag in the cell cycle.
Ref: FLUOROACETAMIDE CASRN: 640-19-7. Hazardous Substances Data Bank.
http://www.fluorideaction.org/pesticides/fluoroacetamide.hsdb.htm

Abstract: HAPAB The effects of single sublethal oral doses of fluoroacetamide (15 mg/kg in 0.03% aqueous solution), administered to female white mice 2 days before or 10 days after fertilization, were studied on the embryonal and postnatal development. The fluoroacetamide influenced the ovulation and the viability of the ovi (later the embryonic and the postnatal development) which led to increased prenatal mortality, to prolongation of the pregnancy, and reduced viability of the neonates. Females treated 10 days after fertilization showed the greatest increase (by up to 30 days) in the duration of pregnancy while embryonic mortality was highest in the group treated two days before fertilization (11.7% against a control value of 4.6%). Reduced body weight, cyanosis, respiratory distress, and decreased motility were among the anomalies observed in neonates in the test groups. 1971
Ref: The action of fluoroacetamide on albino mouse fecunidty (preliminary report). Authors: Tokareva TG Turov I Alekseyev AN Source: Zh. Mikrobiol. Epidemiol. Immunobiol.; 48: 24-26; 1971.

Fluorodifen - Herbicide - CAS No. 15457-05-3

Abstract: Twenty-two herbicides were studied in 67 tests for induction of DNA damage, gene mutation and chromosomal changes in vitro and in vivo. Triazine and urea-type herbicides were found to be inactive in all but one test. Of 4 thiocarbamates, molinate and vernolate caused chromosomal changes, namely increased incidence of sister chromatid exchanges and chromosomal aberrations in vitro and increased frequency of micronucleated polychromatic erythrocytes in mouse bone marrow. These compounds, however, did not cause gene mutation and only molinate gave equivocal positive result in bacterial repair test. Out of 11 miscellaneous herbicides, ethofumesate, alachlor, dichlorprop and fluorodifen proved to be positive only in one or two tests. In the light of clastogenicity of some thiocarbamates, serious consideration should be given to start animal carcinogenicity studies with these chemicals.
Ref: Pinter A et al. (1989). Genotoxicity of selected herbicides. Ann Ist Super Sanita; 25(4):577-82.

Fluoroglycofen-ethyl - Herbicide - CAS No. 77501-90-7

The teratogenic potential and maternal toxicity of fluoroglycofen-ethyl was investigated in rats and rabbits. In rats, fluoroglycofen-ethyl was not embryotoxic, fetotoxic or teratogenic at doses of up to 200 mg/kg bw/day. It was maternally toxic at doses of 60 mg/kg bw/day upwards, as seen by overt signs and decreased body weight gain. In rabbits, it was abortifacient (increased abortions) feto- and embyotoxic (increased resorptions, decreased fetal size and viability) and maternally toxic (maternal deaths and decreased maternal weights) at 90 mg/kg bw/day. There was no evidence of teratogenicity in rabbits. The NOEL for embryo/fetotoxicity was 30 mg/kg bw/day in rabbits and >200 mg/kg bw/day in rats. The NOEL for maternal toxicity was 30 mg/kg bw/day in rabbits and 18 mg/kg bw/day in rats.
Ref: Evaluation on: Fluoroglycofen-ethyl. May 1992. Issue No. 50. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, UK.
http://www.pesticides.gov.uk/citizen/evaluations/050_confirm-box.htm

Fluorouracil - Former insect chemosterilant; now used as a chemotherapeutic drug - CAS No. 51-21-8

Ref: Gene-Tox from Toxnet.
GENE-TOX Evaluation B (post-1980):

Fluorouracil Abstract: The chemotherapeutic agent 5-fluorouracil (5-FU) is a known developmental toxicant in the rat both in vivo and in vitro. The mechanism of the drug's embryotoxic effect is unclear, but it has been postulated that 5-FU inhibits thymidylate synthase activity, leading to a deficiency of thymidine and a decrease in DNA synthesis. If this is the case, addition of excess exogenous thymidine should reverse the drug's embryotoxicity. Rat embryos were cultured beginning on day 10 of gestation (for 48 hours) in a whole embryo culture system. For the initial three hours of the culture period, 5-FU was present at a final concentration of 3 ug/mL. Following removal of 5-FU, various concentrations of thymidine were added for the remainder of the culture period. Treatment with 5-FU decreased the morphological score, number of somite pairs, crown-rump and head lengths, as well as DNA and protein contents; the incidence of malformations, particularly those affecting the tail, hindlimb bud, and brain, was increased. With addition of thymidine, there was attenuation of all parameters examined and fewer malformations. Exogenous thymidine was not able to reverse the effects of 5-FU completely, even if it was present for the entire 48 hour culture period, including the three hour 5-FU treatment phase. These results suggest that 5-FU may induce a thymidine deficiency in treated rat embryos, but some other effect(s) also appear to be involved in the embryotoxicity induced by the drug.
Ref: Hansen DK et al. (1988-89). Attenuation of 5-fluorouracil-induced embryotoxicity by exogenous thymidine in vitro. Attenuation of 5-fluorouracil-induced embryotoxicity by exogenous thymidine in vitro. As cited on Toxnet.

Fluorouracil Abstract: 5-Fluorouracil (5-FU) is a widely used antitumor agent that is embryotoxic in rats at maternal therapeutic levels. A biologically based dose-response model (BBDR) was developed that relates a single dose of 5-FU on gestation day 14 in rats to cell cycle effects in developing fetuses, specifically the inhibition of thymidylate synthetase (TS; due to formation of a FdUMP/TS/folate complex) with subsequent reduction in thymidylate (dTMP) levels, thymidine-5'-triphosphate (dTTP; a DNA precursor) and, ultimately, disruption of DNA synthesis. The initial modeling of the pharmacokinetic component of the BBDR model was based upon a two-compartment PBPK model (Collins et al., 1980) for the maternal kinetics with an added compartment for the fetal kinetics of 5-FU. This BBDR model described well the 5-FU concentration data from gestation day 19, but fetal compartment concentrations on day 14 and the time course of the inhibition were modeled empirically rather than mechanistically. To incorporate more physiological information, a pregnant rat PBPK model developed by O'Flaherty et al. (TAP 112:245-256, 1992) for the weak acid dimethyloxazolidine-2,4-dione (DM0) was adapted for use in the 5-FU BBDR model. The O'Flaherty model adjusts for changes in the dam and fetal body weights, blood flows, and organ volumes as the gestation progresses. Metabolism of 5-FU and tissue partitioning was also added to the model. Sensitivity analysis and use of different data sets as the basis for parameter estimates in this more detailed PBPK component provided insights into the importance of 5-FU pharmacokinetics to the resulting changes in thymidylate synthesis compared with other potential pharmacodynamic interactions.
Ref: Setzer RW et al. (2000). Incorporating a validated PBPK pregnant rat model into a BBDR model for the embryotoxicity of 5-fluorouracil. Toxicologist 2000 Mar;54(1):93. As cited on Toxnet.

Fluquinconazole - Fungicide - CAS No. 136426-54-5

-- Developmental toxicity studies. (a) Oral teratology study in rats. In a study (1992), groups of 30 mated outbred albino Sprague-Dawley CRL:COBS CD(SD)BR rats were administered by gavage fluqinconazole (96% purity) in a 1% w/v aqueous methylcellulose solution at concentrations of 0, 0.4, 2 and 20 mg/kg bw/day (based on a range-finding study) from day 6 to 15 of presumed gestation... An increase in abnormal sternebrae was seen in the low dose group (27%) and the high dose group (31%, p<0.05) but not at the mid dose group (15%) when compared to controls (13%) - as the incidence, of this relatively common anomaly, in the low dose group is not statistically significant and not party of a dose response it is considered to be of no biological significance. Fluquinconazole was clearly maternally toxic, producing abortion and mortality at 8 mg/kg bw/day. There was evidence of mild fetotoxicity (abnormal sternebrae) but not teratogenicity at 9 mg/kg bw/day. The NOAEL for maternal and fetotoxicity was 2 mg/kg bw/day based on increased incidence of abortions in dams and increased mortality.
-- In the rabbit the NOEL for maternal and fetal toxicity was 2 mg/kg bw/day. Fluquinconazole was not teratogenic in the rabbit in the presence of maternal toxicity. Fluquinconazole was clearly maternally toxic, producing abortion and mortality at 8 mg/kg bw/day. There was evidence of mild fetotoxicity (abnormal sternebrae) but not teratogenicity at 8 mg/kg bw/day.
Ref: Evaluation on: Fluquinconazole. May 1999. No. 184. Evaluation of Fully Approved or Provisionally Approved Products. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7 PX, UK. Available online: http://www.pesticides.gov.uk/citizen/evaluations/evallist.htm

Fluthiacet-methyl - Herbicide - CAS No. 117337-19-6

-- Cytogenetics. In vitro cytogenetic assays performed with two different mammalian cell lines demonstrated that fluthiacet-methyl is clastogenic both in the presence and absence of S9 activation.
Ref: Federal Register: December 21, 2001. Fluthiacet-methyl; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/fluthiacet.m.fr.dec.21.2001.htm

Haloxyfop-etotyl - Herbicide - CAS No. 87237-48-7

Abstract: The developmental toxicity of haloxyfop-ethoxyethyl-ester (87237487) (HEE) was studied in rats. Pregnant Wistar-rats were gavaged with 5, 10, or 50mg/kg HEE on days six to 16 of gestation. They were observed for clinical signs of toxicity and sacrificed on gestational day 21. The uteri were removed, examined, and the number of implantations, live and dead fetuses, and resorption sites recorded. The live fetuses were weighed and examined for malformations. HEE at 10 and 50mg/kg caused vaginal bleeding in 40 and 50% of the dams, respectively. The 10 and 50mg/kg doses significantly increased the number of resorptions per litter and decreased the number of live fetuses per litter. The 50mg/kg dose caused a significant decrease in fetal weight. HEE caused a significant dose related increase in the number of cachectic fetuses. The proportion of cachectic fetuses• following exposure to 5, 10, and 50mg/kg was 2.0, 6.8, and 20.3%, respectively. Ureterohydronephrosis was the most frequently observed soft tissue malformation, the prevalence of this defect following the 10 and 50mg/kg doses being 42.9 and 54.8%, respectively. The 10 and 50mg/kg doses caused skeletal malformations such as retarded ossification of the sternum and absence of rib 13. The author concludes that haloxyfop-ethoxyethyl-ester is embryotoxic and teratogenic. The no observable effect level is expected to be below 5mg/kg.
Ref: Machera K (1993). Developmental Toxicity of Haloxyfop Ethoxyethyl Ester in the Rat. Bulletin of Environmental Contamination and Toxicology, Vol. 51, No. 4, pages 625-632. As cited at Toxnet.

Definitions:
cachectic - relating to or having the symptoms of cachexia
cachexia - A profound and marked state of constitutional disorder, general ill health and malnutrition. The loss of body weight and muscle mass frequently seen in patients with advanced diseases. Synonyms: cachexy, wasting

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

-- DPX-MP062 No evidence of mutagenic activity at the following concentration range: 1.56-200 [mu]g/mL; cytotoxicity was seen at concentrations of >100 [mu]g/mL DPX-JW062 No evidence of mutagenic activity at the following concentration range: 0.1-50 [mu]g/mL, cytotoxicity observed at >50 [mu]g/mL
Ref: Federal Register: July 18, 2002. Indoxacarb; Pesticide Tolerance. Final Rule. Federal Register. http://www.fluoridealert.org/pesticides/indoxacarb.fr.july.18.2002.htm

Lithium perfluorooctane sulfonate - Insecticide, Adjuvant - CAS No. 29457-72-5

Abstract (rat): Lithium Perfluorooctane sulfonate (LPOS) was administered by gavage at 3, 6, or 12 mg/kg to mated Crl:CD„BR VAF/Plus„ female rats once daily on days 6 through 15 of gestation. Body weights and clinical observations were on days 0, 6, 9, 12, 16, 20 of gestation. Food consumption was also measured. Cesarean sections were done on surviving animals on day 20 of gestation, and the fetuses were removed for examination. The dams were necropsied following sacrifice. Clear maternal toxicity was observed in both the 6 and 12 mg/kg groups. Five out of 25 females in the 12 mg/kg group did not survive to scheduled sacrifice. Both the 6 and 12 mg/kg groups had test material-related changes including lower mean body weights, body weight gains, and food consumption. Treatment at 12 mg/kg resulted in embryolethality as evidenced by lower uterine weights, fewer live fetuses per litter, reduced fetal bodyweights and lower percent of live fetuses than the control treated. There was also significant increased incidences of cleft palate (79%), and edema (36%). Variations at this dose included reduced ossification of bone and unossified bone. The no-observable-effect level (NOEL) for LPOS for teratogenicity in rats is 6 mg/kg, whereas the NOEL for maternal toxicity in rats is 3 mg/kg.
Ref: Toxicologist 1994 Mar;14(1):162; Developmental toxicity study with lithium perfluorooctane sulfonate in rats; by Henwood SM, Costello AC, Osimitz TG

Developmental Toxicity In the developmental study in rabbits, maternal toxicity was observed at 1 mg/kg/day and above, based on reduced body weight gains during the dosing period, followed by a rebound in body weight gains post-dosing. Developmental toxicity was observed at the highest dose tested, 4 mg/kg/day. Effects included fetolethality, skeletal variations (unossified skull bones, sternebrae, talus, pubis and extra full rib) and decreased fetal body weights. A maternal NOAEL was not established and the maternal LOAEL was 1 mg/kg/day, based on reduced body weight gains. The developmental NOAEL was 2 mg/kg/day. In the rat developmental study, maternal toxicity was observed at 6 mg/kg/day based on reductions in mean body weights, mean body weight gains, food consumption and clinical signs (hunched and few feces in one animal). The maternal NOAEL is 3 mg/kg/day. The developmental NOAEL is 6 mg/kg/day and the LOAEL is 12 mg/kg/day based on increased fetolethality, lower fetal body weights, external and soft tissue malformations, and skeletal variations.
Ref: US EPA. New Pesticide Factsheet. Lithium Perfluorooctane sulfonate (LPOS). August 1990. EPA-730-F-99-009.
http://www.fluoridealert.org/pesticides/lithium.per..epa.facts.1999.pdf

 Metaflumizone (BAS 320 I) - Insecticide - CAS No. 139968-49-3

Genotoxicty. In a battery of three in vitro and two in vivo mutagenicity assays consisting of all required end-points (point mutation, chromosomal damage, and DNA damage and repair), the weight of the evidence for BAS 320 I indicates a lack of potential genotoxicity.
Specifically, for the battery of three in vitro mutagenicity assays with BAS 320 I, no positive responses were observed for increased revertant frequencies with and without metabolic activation bacterial reverse mutation assay or for increased mutant frequencies with and without metabolic activation Hypoxanthine guanine phophoribosyl
transferase (HGPRT) locus assay. Although there was a positive result for a statistically increased number of structurally aberrant metaphases in the chromosomes, which indicates clastogenic potential under in vitro conditions, this result was only observed without metabolic activation cytogenicity study with V79 cells.
Importantly, the potential biological significance of this apparent chromosome damage observed in vitro only without metabolic activation, was evaluated in vivo using the mouse micronucleus assay. Testing in the in vivo micronucleus study with NMRI mice was conducted at a high dose level (2,000 mg/kg b.w.) that demonstrated clinical symptoms of toxicity, including piloerection and poor general state, in 5 of 5 animals. No significant or dose-related increases in chromosomal damage were observed in this in vivo test, indicating that BAS 320 I does not cause chromosomal aberrations in intact animals.
Moreover, it has also been recognized by EPA that more weight should be placed on in vivo systems than in vitro systems as expressed in the Agency's weight of evidence for genotoxic evaluation of a chemical included in the ``Guidelines for Mutagenicity Risk
Assessment'' (Federal Register, September 24, 1986, Vol. 51: 34006-34012). Thus, the negative in vivo results (non-clastogenicity for chromosomal aberrations) observed in the mouse micronucleus assay and the rat hepatocytes assay, should override the positive results obtained in the in vitro assay only without metabolic activation. Furthermore, it has been noted that in vitro systems may simulate abnormal physiological conditions from prolonged exposure to a chemical in the absence of S-9 metabolic activation (Brusick, D.J. (editor) 1987. Genotoxicity Produced in Cultured Mammalian Cell Assay by Treatment Conditions. Mutation Research, Vol. 189, No.1: 1-69 and Sofuni, T. 1993. Japanese Guidelines for Mutagenicity Testing. Environmental and Molecular Mutagenesis, Vol. 21, No.1: 2-7). Consequently, based on the weight of the evidence presented above, BAS 320 I does not pose a genotoxic concern.
Ref: October 27, 2004. Federal Register. Pesticide tolerance petition.
http://www.fluorideaction.org/pesticides/metaflumizone.fr.oct.27.04.htm

PFOA - Insecticide, US EPA List 3 Inert

Abstract excerpt: The effects of perfluorooctanoic acid (PFOA), a potent hepatocarcinogen and peroxisome proliferator in rodents, on human cells have not yet been examined. In the present study we demonstrate that treatment of human hepatoblastoma HepG2 cells with PFOA induces apoptosis, as well as perturbs the cell cycle... Simultaneous flow cytometric analysis of apoptosis-associated DNA strand breaks using the TUNEL procedure and of propidium iodide staining of cellular DNA revealed DNA breaks in HepG2 cells exposed to 150 microM PFOA, prior to nuclear fragmentation.
Ref: 1999. Carcinogenesis Dec;20(12):2237-46. Effects of the rodent peroxisome proliferator and hepatocarcinogen, perfluorooctanoic acid, on apoptosis in human hepatoma HepG2 cells; by Shabalina IG, Panaretakis T, Bergstrand A, DePierre JW. Full report available free at:
http://carcin.oupjournals.org/cgi/content/full/20/12/2237

Abstract: To elucidate the relationship between peroxisome proliferation by perfluorinated compounds and oxidative DNA damage, perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), perfluorobutyric acid (PFBA) and perfluorooctane (PFO) were administered to 6-week-old F-344 male rats. After a single intraperitoneal (i.p.) injection of PFOA, PFBA or PFO in corn oil at a dose of 100 mg/kg, significant increases of liver weight and 8-hydroxydeoxyguanosine (8-OH-dG) levels in liver DNA were observed in PFOA-treated rats. Oral administration of powdered diet containing 0.02% PFOA or 0.01% PFDA for 2 weeks resulted in significant increases of liver weight and 8-OH-dG levels in liver DNA in rats given both chemicals. On the other hand, no increase in 8-OH-dG levels in kidney DNA was found in either of the studies. Our results demonstrate that, as with other peroxisome proliferators (phthalic ester plasticizers and hypolipidemic drugs), PFOA and PFDA induced peroxisome proliferation also leads to organ specific oxidative DNA damage.
Ref: 1991. Cancer Lett Apr;57(1):55-60. Short-term exposure to the peroxisome proliferators, perfluorooctanoic acid and perfluorodecanoic acid, causes significant increase of 8-hydroxydeoxyguanosine in liver DNA of rats; by Takagi A, Sai K, Umemura T, Hasegawa R, Kurokawa Y.

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

Abstract: The L5178Y mouse lymphoma cell forward-mutation assay was used to test for the mutagenic activity of sodium and potassium fluoride at the thymidine kinase locus. Mutants were detected by colony formation in soft agar in the presence of trifluorothymidine. Mutagenic and toxic responses were observed in the concentration range of 300-600 micrograms/ml with both sodium and potassium fluoride. Approximately 3-fold increases in mutant frequency were observed for concentrations in the 500-700 micrograms/ml range that reduced the relative total growth to approximately 10% in the absence or presence of a rat-liver S9 activation system. A sample of 30% sodium fluoride-70% sodium bifluoride (NaHF2) induced a similar mutagenic response but was more toxic with respect to the fluoride concentration. A specificity for fluoride ions in causing mutagenesis was indicated by the fact that much higher concentrations of sodium or potassium chloride were necessary to cause toxicity and increases in the mutant frequency. The possible involvement of chromosomal changes was signaled by the predominant increase in the small colony class of mutants.
Ref: Caspary WJ et al. (1987). Mutagenic activity of fluorides in mouse lymphoma cells. Mutat Res. Mar;187(3):165-80.

Sodium bifluoride - Insecticide, Former US EPA List 3 Inert - CAS No. 1333-83-1

Abstract: The L5178Y mouse lymphoma cell forward-mutation assay was used to test for the mutagenic activity of sodium and potassium fluoride at the thymidine kinase locus. Mutants were detected by colony formation in soft agar in the presence of trifluorothymidine. Mutagenic and toxic responses were observed in the concentration range of 300-600 micrograms/ml with both sodium and potassium fluoride. Approximately 3-fold increases in mutant frequency were observed for concentrations in the 500-700 micrograms/ml range that reduced the relative total growth to approximately 10% in the absence or presence of a rat-liver S9 activation system. A sample of 30% sodium fluoride-70% sodium bifluoride (NaHF2) induced a similar mutagenic response but was more toxic with respect to the fluoride concentration. A specificity for fluoride ions in causing mutagenesis was indicated by the fact that much higher concentrations of sodium or potassium chloride were necessary to cause toxicity and increases in the mutant frequency. The possible involvement of chromosomal changes was signaled by the predominant increase in the small colony class of mutants.
Ref: Caspary WJ et al. (1987). Mutagenic activity of fluorides in mouse lymphoma cells. Mutat Res. Mar;187(3):165-80.

-- GENOTOXICITY - DNA damage and chromosome aberrations have been reported in insect studies.
Ref: Hazardous Substances Data Bank for SODIUM HYDROGEN DIFLUORIDE CASRN: 1333-83-1 http://www.fluorideaction.org/pesticides/sodium.bifluoride.toxnet.htm

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

Abstract: 1080 has been used in New Zealand to control vertebrate pests since 1954, and although a large historical database exists, little is known about the developmental toxicity of this pesticide. This investigation was intended to evaluate the developmental toxicity and teratogenic potential of 1080 in Sprague-Dawley rats following oral intubation. A pilot study was performed to help select doses for the subsequent study and consisted of groups of 5 time-mated females. Animals received 1080 at concentrations ranging from 0.1 to 1.0 mg/kg/day from Days 6 to 17 of gestation. A 60% mortality rate and reductions in maternal body weight and body weight gain as well as decreased litter size and increased resorptions were observed at 1.0 mg/kg/day. Consequently, the doses selected for the main study were 0.1, 0.33 and 0.75 mg/kg/day. Groups of 26 time-mated females received 1080 from Days 6 to 17 of gestation. On Day 20 of gestation, litters were delivered via laparohysterectomy. The results of this study have not been fully evaluated, but visceral and skeletal evaluation results will be presented. Significant reductions in maternal body weight, body weight gain and food consumption were noted at 0.75 mg/kg/day. No changes in litter size or resorptions were observed, but fetal body weight was significantly reduced at 0.75 mg/kg/day. No external fetal abnormalities were noted. Available data indicate that 1080 is maternally toxic at 0.75 mg/kg/day and higher. Embryolethality was noted at 1.0 mg/kg/day, but not at 0.75 mg/kg/day. At this stage, there is no evidence of developmental toxicity. Reductions in fetal body weight at 0.75 mg/kg/day are probably linked to maternal toxicity rather than a direct effect on the fetus.
Ref: Turck PA et al. (1998). Assessment of the developmental toxicity of sodium monofluoroacetate (1080) in rats. Toxicologist 1998 Mar;42(1-S):258-9.

Sulfluramid - Acaricide, Insecticide - CAS No. 4151-50-2

Abstract: Oral administration of sulfluramid, an insecticide, has been shown to produce transient sterility in dogs. The present study in rabbits was designed to evaluate the potential adverse effects of maternal exposure to sulfluramid during late gestation on the growth, viability, development and sperm quality of the F1 generation. Sulfluramid, suspended in 1% CMC/0.1% Tween 80, was administered by gavage to three groups of 22 timed-pregnant, "litter-experienced" New Zealand White rabbits from gestation days 19-28 at levels of 0.3, 1.0 and 3.0 mg/kg/day. The F0 females were allowed to deliver naturally and rear their bunnies to PND (postnatal day) 42. Selected F1 bunnies were evaluated for developmental landmarks, and a longitudinal quantitative assessment of spermatogenesis was performed on semen from all selected F1 males. The number of bunnies stillborn or found dead on PND 0 was increased, and the viability on PND 1 was decreased in the 3.0 mg/kg/day group. In addition, postnatal viability indices in all treated groups were decreased throughout the pre-weaning period (PND 4-42). No treatment-related effects were noted on the age at which balanopreputial separation or vaginal patency occurred. The numbers of sperm/ejaculate, percentages of motile sperm, numbers of motile sperm/ejaculate and percentages of sperm with normal morphology were apparently unaffected by treatment during the 4-week longitudinal assessment of spermatogenesis. No adverse effects were apparent on mean testicular and epididymal sperm numbers, and no treatment-related histopathological findings were noted in the reproductive organs at any dose level. Although significant neonatal toxicity (mortality) was noted in all treatment groups, no treatment-related effects were noted on sexual maturation or testicular function of the F1 generation in this study.
Ref: Stump DG et al. (1997). Study of the effects of sulfluramid on pre- and postnatal development, maturation and fertility in the rabbit. Toxicologist Mar;36(1 Pt 2):357.

tau-Fluvalinate - Acaricide, Insecticide - CAS No. 102851-06-9

-- Teratogenicity studies on tau fluvalinate in rabbits showed incidences of delayed ossification, and visceral and skeletal malformations at an overt maternotoxic dose (125 mg/kg bw). This dose also caused increased numbers of resorptions and poorer viability of fetuses. No teratogenic effects occurred at lower doses. No reproduction studies with tau fluvalinate in other species were submitted and the compound has to be classified as possibly teratogenic. No teratogenic effects of the less toxic racemic fluvalinate were seen in rats. Doses of 10 and 50 mg/kg bw/day were materno- and fetotoxic.
Ref: Revised Summary Report. EMEA/MRL/021-REV1/95. Committee for Veterinary Medicinal Products. The European Agency for the Evaluation of Medicinal Products.
http://www.fluorideaction.org/pesticides/tau.fluvalinate.1995.review.pdf

Teratogenicity studies on tau fluvalinate in rabbits showed incidences of delayed ossification, and visceral and skeletal malformations at an overt maternotoxic dose (125 mg/kg bw). This dose also caused increased numbers of resorptions and poorer viability of fetuses. No teratogenic effects occurred at lower doses. No reproduction studies with tau fluvalinate in other species were submitted and the compound has to be classified as possibly teratogenic. No teratogenic effects of the less toxic racemic fluvalinate were seen in rats. Doses of 10 and 50 mg/kg bw/day were materno- and fetotoxic.
Ref: Revised Summary Report. EMEA/MRL/021-REV1/95. Committee for Veterinary Medicinal Products. The European Agency for the Evaluation of Medicinal Products.
http://www.fluorideaction.org/pesticides/tau.fluvalinate.1995.review.pdf

TFM (3-Trifluoro-Methyl-4-Nitro-Phenol) - Lampricide, Piscicide - CAS No. 88-30-2

Mutagenicity. In an in vitro cytogenetic assay (MRID 40999201), cultured CHO cells were exposed to TFM (86%) at concentrations of 49.6, 99.2, 149, or 198 Fg/ml for 17.25 hrs. in absence of the S9 metabolic activation. In the presence of the S9 activation, the CHO cells were exposed to TFM at concentrations of 115, 384, 769, 1150, or 1540 Fg/ml for 2 hrs. After exposure to TFM, the treated cells were washed with buffered saline, and complete McCoyÕs a medium containing 0.1 Fg/ml Colcemid was added to the washed cells. The cells were then incubated for 2.5 hrs (without S9) or 7.5 hrs (with S9). The metaphase cells were then harvested, and slides prepared for analysis. The results showed that, without S9 activation, TFM at concentrations of 149 and 198 Fg/ml induced chromosomal aberrations, consisting mainly of simple chromatid breaks. In the presence of S9 activation, 1150 and 1540 Fg/ml of TFM caused a statistically significant and dose-related increase in chromosomal aberrations, consisting of simple chromatid and chromosome breaks. (pp 10--11)
Ref: November 1999 US EPA's Reregistration Eligibility Decision (RED) for 3-Trifluoro-Methyl-4-Nitro-Phenol and Niclosamide).
http://www.fluoridealert.org/pesticides/tfm.red.1999.pdf

Tolylfluanid - Fungicide - CAS No. 731-27-1

-- Bacterial gene mutation assay. Tolylfluanid was cytotoxic to all strains at = 8 [mu]g/plate +/ - S9 and precipitated from solutions in all strains at 5,000 [mu]g/plate +/- S9. There were no reproducible, dose- related differences in the number of revertant colonies in any strain or dose over the background. Positive controls induced appropriate response.
-- Metabolite--WAK 6698. Bacterial gene mutation assay. Metabolite was cytotoxic at doses £=158 [mu]g/plate in the initial assay and 1,581 [mu]g/plate in the repeat assay. There was no evidence of a significant increase in mutant colonies over background in any strains tested in the initial or repeat mutagenicity assays. Positive controls induced appropriate response.
-- Technical. In vitro mammalian cell gene mutation assay. Cytotoxicity was observed at concentrations 1 to 10 [mu]g/milliliter (mL) -S9 and 5 to 10 [mu]g/mL +S9. Over the ranges tested clastogenic effects included increased incidences of metaphases with aberrations including gaps, metaphases excluding gaps, metaphases with exchanges, and metaphases with polyploidy were observed. Tolyfluanid is clastogenic both in the presence and in the absence of S9 activation.
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/tolylfluanid.fr.sept25.2002.htm

Transfluthrin - Insecticide - CAS No. 118712-89-3

Abstract: ... Our study describes the genotoxic effects of PCP, lindane, transfluthrin, cyfluthrin, and natural pyrethrum on human mucosal cells of the inferior and middle nasal conchae.
METHODS: Epithelial cells were isolated from nasal mucosa, which was removed in the surgical treatment of chronic sinusitis and nasal concha hyperplasia. After the cells had been tested for vitality using the trypan blue exclusion test, the short-term culture method was used. The material was incubated with PCP (0.3, 0.75, and 1.2 mmol), lindane (0.5, 0.75, and 1.0 mmol), transfluthrin (0.05, 0.1, 0.5, 0.75, and 1.0 mmol), cyfluthrin (0.05, 0.1, 0.5, 0.75, and 1.0 mmol), natural pyrethrum (0.001, 0.005, 0.01, 0.05, and 0.1 mmol), and N-methyl-N'-nitro-N-nitrosoguanidine for 60 minutes. Substance-induced DNA damage (single-strand and double-strand breaks) were determined using single-cell microgel electrophoresis. A fluorescence microscope was used together with an image processing system to analyze the results obtained.
RESULTS: After exposure to all tested substances, a high percentage of the cells of the middle nasal concha in particular were found to have severely fragmented DNA as a result of strong genotoxic effects. Although the reaction of the cells of the inferior nasal concha was significantly less strong (p < 0.001), the tested substances were nevertheless found to have a notable genotoxic effect on these cells too.
CONCLUSION: Our study strongly suggests that exposure to PCP, lindane, transfluthrin, cyfluthrin, and natural pyrethrum has a genotoxic effect on the epithelial cells of human nasal mucosa. In addition, we have shown that nasal structures differ in susceptibility to the various pesticides used in the tests. Thus, the study provides new evidence supporting the biological plausibility of PCP- and lindane-induced effects, thereby helping evaluate potential PCP- and lindane-induced mucous membrane carcinomas of these parts of the nose. In addition, our study shows that other substances that today are widely used for controlling pests have a considerable genotoxic effect on human target cells. The results obtained indicate the need for additional studies on the genotoxicity of these substances and their adverse effects on human health.
Ref: Genotoxic effects of pentachlorophenol, lindane, transfluthrin, cyfluthrin, and natural pyrethrum on human mucosal cells of the inferior and middle nasal conchae; by Tisch M, Faulde MK, Maier H. Am J Rhinol. 2005 Mar-Apr;19(2):141-51.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15921213&query_hl=2

3-Trifluoromethyl aniline - Intermediate for herbicides (eg, Fluometron & Norflurazon); Intermediate for pharmaceuticals; Breakdown product - CAS No. 98-16-8

-- GENOTOXICITY. m-Trifluoromethylaniline induced dominant lethal mutations in flies.
-- ACUTE EXPOSURE. m-Trifluoromethylaniline is toxic by the oral, inhalation, dermal, or IP routes.
-- Non-Human Toxicity Excerpts: WHEN ADDED TO FOOD OF LARVAL & IMAGO DROSOPHILA, M-TRIFLUOROMETHYLANILINE INCR INCIDENCE OF DOMINANT LETHAL MUTATIONS AMONG OFFSPRING & INCR PERCENTAGE OF UNFERTILIZED EGGS. [ILICHKINA AG ET AL; MOL MEKH GENET PROTSESSOV 291 (1976)].
Ref: TOXNET profile from Hazardous Substances Data Bank.
http://www.fluoridealert.org/pesticides/3-trifluoromethyl.an.toxnet.htm

Trifluralin - Herbicide - CAS No. 1582-09-8

Abstract: The genotoxicity of trifluralin (1582098) was examined in human lymphocytes. Lymphocyte cultures were established from blood samples drawn from two healthy young male donors. These were treated with 0 to 200 micrograms per milliliter (microg/ml) trifluralin with or without metabolic activation from S9 mix for up to 72 hours (hr). Induction of sister chromatid exchanges (SCEs) was assessed after 2 or 48hr of incubation with trifluralin. Micronuclei induction was evaluated after 72hr of trifluralin treatment. Induction of chromosome aberrations was assessed after 30hr of incubation with trifluralin. Cytotoxicity was assessed by measuring changes in the proliferative rate index (PRI), determined by examination of the first three metaphases, and the cytokinesis block proliferative index (CBPI). Trifluralin treatment for 48hr in the absence of S9 mix caused a slight, but statistically significant increase in SCE frequency in lymphocytes from both donors at 50microg/ml, the highest concentration tested. Treatment with 25microg/ml trifluralin in the absence of S9 mix also caused a significant increase in SCE frequency in lymphocytes from one donor. Treatment with 200microg/ml trifluralin for 2hr in the presence of S9 mix caused a significant increase in SCE frequency in lymphocytes from both donors. These effects were accompanied by slight decreases in the PRI and CBPI. Trifluralin did not increase the frequency of chromosome aberrations or micronuclei above the background level. The authors conclude that trifluralin is able to exert weak cytotoxic and genotoxic effects in cultured human lymphocytes. The SCE assay seems to be more sensitive for detecting these types of effects than the chromosome aberration or micronucleus assays.
Ref: Ribas G et al. (1996). Genotoxic Evaluation of the Herbicide Trifluralin on Human Lymphocytes Exposed In Vitro. Mutation Research, Vol. 371, Nos. 1/2, pages 15-21, 30 references, 1996.

Abstract: In the present study, the herbicides bentazone, molinate, thiobencarb and trifluralin were evaluated for mutagenic and recombinagenic effects using the wing spot test of Drosophila melanogaster (somatic mutation and recombination test, SMART). Both standard (ST) and high-bioactivation (HB) fly crosses were used, the latter cross is characterised by a high sensitivity to promutagens and procarcinogens. Three-day-old larvae, transheterozygous for the multiple wing hairs (mwh, 3-0.3) and flare-3 (flr(3), 3-38.8) genes, were chronically fed with six different concentrations of each herbicide. Feeding ended with pupation of the surviving larvae and the genetic changes induced in somatic cells of the wing's imaginal discs lead to the formation of mutant clones on the wing blade. Point mutation, chromosome breakage and mitotic recombination produce single spots; while twin spots are produced only by mitotic recombination. Bentazone, usually considered as a non-mutagen, gave positive results in the wing spot test with the high-bioactivation cross. Molinate, about which information on mutagenic effects is inconclusive, gave positive responses in both the standard and the high-bioactivation crosses, while the other thiocarbamate, thiobencarb, gave positive results only in the standard cross and at the highest concentration tested (10 mM). Finally, trifluralin, one of the most widely studied herbicides for genotoxic effects, gave positive results in the wing spot test with both crosses. Apart from the interest of the results found in the genotoxic evaluation of the four selected herbicides, our results also contribute to extend the existing database on the Drosophila wing spot test, and corroborate the utility of the use of high-bioactivation strains for the genotoxic evaluation of xenobiotics.
Ref: Evaluation of the genotoxicity of four herbicides in the wing spot test of Drosophila melanogaster using two different strains; by Kaya B, Marcos R, Yanikoglu A, Creus A. Mutat Res. 2004 Jan 10;557(1):53-62.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14706518

2.4 GENOTOXICITY. In the DAR, 11 in vitro studies and five in vivo studies have been evaluated and presented. There was evidence of aneuploidy induction from an in vitro chromosome aberration study, positive effects in a comet tail test, as well as weak positive effects in an in vivo micronucleus study. In order to clarify these effects, the need of performing of a new micronucleus study was requested by the rapporteur Member State. This was stated as a data requirement in level 4 of the DAR “An in vivo bone marrow micronucleus assay in mice with kinetochore or centromeric staining in order to ascertain the nature of the micronuclei induced”. The new study was performed and submitted by the notifier and the rapporteur Member State has evaluated and presented it in the Addendum. No increase in the incidence of micronuclei formation or the aneuploidy was recorded, when it was administered as a single dose to male and female mice. Hence, trifluralin is considered negative for clastogenic and aneugenic potential in the present study (page 10)
Ref: March 14, 2005. European Food Safety Authority: Conclusion regarding the peer review of the pesticide risk assessment of the active substance trifluralin. EFSA Scientific Report (2005) 28, 1-77.
http://www.fluoridealert.org/pesticides/trifluralin.eu.long.2005.pdf

Triflusulfuron-methyl - Herbicide - CAS No. 126535-15-7

-- A human lymphocyte cytogenetic assay was performed using 0.5, 1.5, 1.7, 1.85, or 2.0 mg/mL DPX-66037-59 (98.7%) with and without metabolic activation. Cytotoxicity was observed at 1.85 mg/mL, indicated by a lower mitotic index than controls. Triflusulfuron-methyl, with metabolic activation, was clastogenic at 2.0 mg/mL under the conditions of this test.
-- A human lymphocyte cytogenetic assay was performed using 0.1Ð2.0 mg/mL DPX-66037-24 (95.6%) with and without metabolic activation. Cytotoxicity was observed at 2.0 mg/mL, indicated by a lower mitotic index than controls. Triflusulfuron-methyl, with metabolic activation, was clastogenic at $1.7 mg/mL in a dose-dependent manner under the conditions of this test.
-- ... It was genotoxic in mammalian in vitro chromosomal aberrations assays (same assay performed twice), but not in a mammalian in vivo assay.
Ref: Dec 3, 1999 - Report on Triflusulfuron methyl. Regulatory Note REG99-03. Pest Management Regulatory Agency, Health Canada, Ottawa.
http://www.fluorideaction.org/pesticides/triflusulfuron.methy.canada.pdf