Fluorinated and Fluoride Pesticides


an agent that has the potential to cause birth defects if exposure to a fetus occurs at a critical time in pregnancy. 
• any agent that interferes with normal embryonic development: alcohol or thalidomide or X-rays or rubella are examples
• a chemical that can cause birth defects by adversely altering the development of an embryo or fetus without necessarily altering the organism's genetic structure.
anything which produces nonheritable birth defects is said to be teratogenic.

The use of high doses increases the likelihood that potentially significant toxic effects will be identified. Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans. From a conservative risk assessment perspective however, adverse findings in animal species are assumed to represent potential effects in humans, unless convincing evidence of species specificity is available.

-- Food and Agricultural Organization of the United Nations

Note: This is not an exhaustive list.

As time allows more information will be added.

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

Ethalfluralin was evaluated for developmental toxicity. Fourteen, 11, and 14 pregnant Dutch-Belted rabbits were administered 0, 75, and 250 mg/kg/day of the test substance respectively, on days 6-18 of gestation. An increase in the number of anorectic rabbits occurred at 250 mg/kg/day. Four and 3 rabbits of the 75 and 250 mg/kg/day dose group, respectively, died or aborted. The abortions were preceded by anorexia and weight loss. Nine, 9, and 12 rabbits of the 0, 75, and 250 mg/kg/day dose groups were available for evaluation. Live litter size, resorption occurrence, fetal viability, and sex distribution were unaffected by treatment. Mean fetal weights of the treatment groups were lower than controls but the differences were not statistically significant. An increase in the incidence of skeletal abnormalities, including cleft palate and crooked ribs, was observed at 250 mg/kg/day. No treatment related visceral abnormalities were observed. The 250 mg/kg/day dose was maternally toxic but not teratogenic since the increased incidence of fetal defects was associated with anorexic dams. The 75 mg/kg/day dose was a no-effect level.

Ethylene fluorohydrin - Rodenticide - CAS No. 371-62-0

Abstract: The 2 substituted halo ethanols (e.g., 2-chloro ethanol-ethylene chlorohydrin-ECH, 2-bromo ethanol-ethylene bromohydrin-EBH, 2-fluoro ethanol-ethylene fluorohydrin-EFH) are contaminants of gas-sterilized foods and medical devices (EBH, ECH) and common industrial reagents (ECH, EBH, EFH). In a continuing effort to define the teratogenic potential of substituted ethanols, pregnant Long-Evans rats were given EFH (0.06, 0.36, and 0.6 mg/kg -I.G.) or water (20 ml/kg-isovolumetric vehicle control) from day 6 to day 15 of gestation. All dams were given lab chow and water ad libitum. Body weights were monitored during gestation. On gestation day 20, the dams were euthanized by halothane overdose and the products of conception examined according to Manson and Kang (1989). Soft tissue defects were evaluated by the free hand slice technique of Wilson (1965) and defects in skeletal development were assessed by the simultaneous double staining technique of McLeod (1980). Significance was set at P less than 0.05 (Yates X2 test). An increase in sternebral ossification defects were present in all experimental groups. Hydronephrosis was evident in the two highest doses. The high dose group had significant incidences of runting (pup weight less than 2.7 g) and variant rib ossifications. Cardiac septal defects appeared in the hearts of pups of the 0.36 mg/kg group. Pups of dams given 0.06 mg/kg of EFH revealed the presence of extra vertebral ossification centers. In the high dose group alone, intrauterine growth retardation was evident based on decreased pup weight (P less than 0.05, corrected T-test). There were no significant changes in either dam or gestational weight gain observed. Overall, the percentage of implantations resulting in malformed or dead pups in response to oral administration of EFH increases significantly in a dose-related manner with increasing alcohol concentrations.
Ref: Mankes RF et al. (1992). Teratogenic effects of the halogenated ethanol 2-fluoro ethanol in Long Evans rats. Teratology 1992 May;45(5):463 as cited by Toxnet.

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

In a teratogenicity study in Sprague-Dawley rats exposed via oral gavage, delayed ossification and an increased incidence of hydroureter were observed in fetuses (the fetotoxic LOEL was 5 mg/kg/day; the NOEL 1 mg/kg/day) and a teratogenic LOEL of 200 mg/kg/day (the NOEL was 10 mg/kg/day) was determined based on the incidence of diaphragmatic hernia.
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.

-- 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.
-- In a teratogenicity study in Sprague-Dawley rats exposed via oral gavage, delayed ossification and an increased incidence of hydroureter were observed in fetuses (the fetotoxic LOEL was 5 mg/kg/day; the NOEL 1 mg/kg/day) and a teratogenic LOEL of 200 mg/kg/day (the NOEL was 10 mg/kg/day) was determined based on the incidence of diaphragmatic hernia.
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.

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.
Ref: Material Safety Data Sheet for Fusilade DX (active indredient Fluazifop-P-Butyl). Syngenta. January 21, 2002.

"Fluazifop-P-butyl 79241-46-6 Withdrawn. Teratogenic and suspected reproductive effects in experimental animals. 1991." Definition: "Withdrawn. A substance which the manufacturer has either withdrawn from the market, or for which he has withdrawn his application for registration, approval, or renewed approval and when it is clear that these measures were undertaken due to the health or environmental properties of the substance."
Ref: Euopean Commission. Appendix 5. Substances which may not be included as active ingredients in approved pesticide products, Chapter 15, Section 2, subsection one.
http://www.kemi.se/lagar_eng/pdf/app5_8.pdf Fluazifop-P-butyl - Rabbit In a developmental toxicity study [MRID 46082904] [fluazifop-p-butyl (90.1% a.i., batch/lot # P12)] was administered to [(20 females) New Zealand White] rabbits/group by gavage in corn oil vehicle [1 ml/kg] at dose levels of 0, 2, 10 or 50 mg a.i./kg bw/day from days 8 through 20 of gestation. Day sperm was found was designated as day 1. On day 30 of gestation, dams were killed and the uterine contents examined for live and dead fetuses. Fetuses were weighed, examined for external and visceral abnormalities, sexed, eviscerated and stained for skeletal examination. ... Treatment related effects on development were seen in the 50 mg/kg/day group only. Statistically significant extra 13 th rib and delayed ossification was seen in sternebrae 2 and 5. An increase in partially ossified 5 sternebrae was seen at 10 mg/kg/day, but the litter incidence was not increased. A nominal increase in malformations were seen at 50 mg/kg/day, such as acephaly [1 fetus/1 litter], cebocephaly [1 fetus/1 litter], cleft palate [1 fetus/1 litter], microphthalmia [1 fetus/1 litter], gastroschisis [1 fetus/1 litter], and multiple anomalies in 1 fetus/1 litter. None were duplicated and all could have occurred 1 to 3 times in the same litter, with 0 in control. Since individual animal data was not submitted, this incidence in litters could not be verified. For developmental toxicity, the NOAEL is 10 mg/kg/day and the LOAEL is 50 mg/kg/day based on increased 13 th rib and increased incidence of delayed ossification of sternebrae 2 and 5. (page 39).
Ref: December 10, 2004. US EPA> Fluazifop-P-butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Decision (TRED) Document. EPA Docket number: OPP-2004-0347-0003


Acephaly: literally means absence of the head. The acephalic fetus is a parasitic twin attached to an otherwise intact fetus. The acephalic fetus has a body but lacks a head and a heart; the fetus’s neck is attached to the normal twin. The blood circulation of the acephalic fetus is provided by the heart of the twin. The acephalic fetus can not exist independently of the fetus to which it is attached.
Ref: http://www.icomm.ca/geneinfo/acep.htm

Cebocephaly: A facial anomaly, characterized by a small, flattened nose with a single nostril situated below incomplete or underdeveloped closely set eyes.
Ref: http://www.icomm.ca/geneinfo/cephaly.htm

Gastroschisis: is an abdominal wall defect located to the side of the umbilical cord (umbilicus). The infant is born with intestines protruding through this defect and no protective sac is present.
Ref: http://www.nlm.nih.gov/medlineplus/ency/article/002924.htm

Microphthalmia - small eye syndrome. Microphthalmia is a disorder in which one or both eyes are abnormally small.

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

1999 PubMed Abstract:
(1) Follow-up studies of approximately 1,000 women exposed to quinolones during pregnancy show no increase in the risk of malformations, miscarriage, prematurity, intrauterine growth retardation or postnatal disorders, but there are not enough data to draw firm conclusions.
(2) Teratogenic effects have been observed in animals treated with the oldest quinolones (flumequine, nalidixic acid and pipemidic acid) and also with sparfloxacin, a fluoroquinolone.
(3) Cartilage damage after postnatal exposure to quinolones in animals and humans has been reported.
(4) Alternatives to quinolones can almost always be found for pregnant women.
(5) Accidental exposure to quinolones during pregnancy does not warrant termination.
Ref: Prescrire Int 1999 Feb;8(39):29-31.
Quinolones and pregnancy: worrying animal findings, few clinical data. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10557576&dopt=Abstract

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

Abstract: An N-phenylimide herbicide, S-53482, inhibits protoporphyrinogen oxidase, an enzyme common to chlorophyll and heme biosynthesis, and produces embryolethality, teratogenicity [mainly ventricular septal defects (VSD) and wavy ribs], and growth retardation in rats. In order to elucidate the mechanism of the developmental toxicity, in particular VSD, effects of the herbicide on rat embryonic blood cells were investigated histologically at the light and electron microscopic levels at 6, 12, 24, 36, and 48 h after oral administration of the chemical to pregnant rats on day 12 of gestation, the most sensitive day for toxicity. Electron and light microscopy demonstrated mitochondrial lesions, including abnormal iron deposits that were probably due to inhibition of heme biosynthesis, in erythroblasts derived from the yolk sac. Subsequently, degeneration of these erythroblasts occurred followed by erythrophagocytosis. Histologically hearts from exposed embryos had a thin ventricular wall, which may reflect a compensatory reaction to a loss of embryonic blood cells. Thus, the herbicide may induce VSD due to hematological dysfunction caused by the inhibition of heme biosynthesis rather than by direct injurious effects on the heart.
Ref: Kawamura S et al (1996). Histological changes in rat embryonic blood cells as a possible mechanism for ventricular septal defects produced by an N-phenylimide herbicide. Teratology. Nov;54(5):237-44.


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

REPRODUCTIVE HAZARDS. Fluorouracil is known to be teratogenic in animals, as well as causing degenerative effects in male test animals' reproductive system.
Ref: TOXNET profile from Hazardous Substances Data Base for Fluorouracil.


Flusilazol / Flusilazole - Fungicide - CAS No. 85509-19-9

Abstract: Triazole-derivatives alter the pharyngeal apparatus morphogenesis of rodent embryos cultured in vitro. The hindbrain segmentation and the rhombencephalic neural crest cell (NCCs) migration are altered by Fluconazole exposure in vitro. The aim of the present work is to identify if a common pathogenic pathway is detectable also for other molecules of this class of compounds. 9.5 days post coitum (d.p.c.) old rat embryos were exposed in vitro to the teratogenic concentrations of Flusilazole, Triadimefon and Triadimenol and cultured for 24, 48 or 60 h. The expression and localisation of Hox-b1 and Krox-20 proteins (used as markers for hindbrain segmentation) were evaluated after 24 h of culture. The localisation and distribution of NCC was evaluated after 24, 30 and 48 h of culture. The morphology of the embryos was analysed after 48 h, while the branchial nerve structures were evaluated after 60 h of culture. Hindbrain segmentation and NCC migration alteration as well as pharyngeal arch and cranial nerve abnormalities were detected after exposure of the tested molecules. A common severe teratogenic intrinsic property for the tested molecules of this chemical class has been found, acting through alteration of the normal hindbrain developmental pattern.
Reference: Menegola E, Broccia ML, Di Renzo F, Massa V, Giavini E (2005). Study on the common teratogenic pathway elicited by the fungicides triazole-derivatives. Toxicol In Vitro. Sep;19(6):737-48.
Abstract available at:


abnormalities at the level of the branchial apparatus; disorganisation and fusions at the level of the cranial nerves; abnormalities in the migration of NCC, not able to form 3 distinct migration stripes from the rhomboencephalon to the branchial apparatus; alteration of the hindbrain segmentation, with reduced and scattered immunolocalised stripes.
Reference: Massa et al. Mechanisms Involved In Triazole-Induced Teratogenesis: In Vitro Study. Toxicol Lett 2003 Sep ;144 (Suppl 1 ):S107

Abstract: This report describes the first part of a study which was undertaken to examine the teratogenic potential of triazole compounds used as fungicides in agriculture. Pregnant Wistar rats were given single oral dosages of flusilazole or bitertanol on days 9, 10, 11 or 13th of gestation (positive vaginal smear=day 1) at levels of 1/5, 1/10 and 1/50 LD50. The dosages were calculated from the reported LD50 values of 1272 mg/kg for flusilazole and 5000 mg/kg for bitertanol. The results of the study demonstrated that both compounds induce congenital anomalies when given on days 9, 10 or 11th at levels corresponding to 1/5 and 1/10 LD50. The types of the registered malformations after flusilazole treatment were exophthalmus, hypognathia, macroglossia and cleft palate and after bitertanol treatment micro- and acaudia and in rare cases exophthalmus, hypognathia and cleft palate. A clear dose effect relationship was established for both compounds.
Ref: Vergieva T (1990). Teratology 1990 Aug;42(2):27A-28A. Triazoles teratogenicity in rats. Abstract from Toxnet.

Exophthalmia (n.) The protrusion of the eyeball so that the eyelids will not cover it, in consequence of disease.
Hypognathus - Unequal conjoined twins in which the rudimentary parasite is attached to the mandible of the autosite.
Macroglossia - Excessively large tongue.

PubMed abstract: Triazole-derivatives are antimycotics used in agriculture as well as in clinical and veterinary therapy. The aim of the present work is the in vitro comparative study of the teratogenic activity of triazole (the parental compound), flusilazole (an agricultural triazole mono-derivative fungicide), and fluconazole (a clinically used bis-triazole derivative). Rat embryos, 9.5 days old (1 to 3 somites) were exposed in vitro to triazole 500 to 5000 microM, flusilazole 3.125 to 250 microM, or fluconazole 62.5 to 500 microM. After 48 h in culture, the embryos were morphologically examined and processed for histologic and biochemical analysis. Flusilazole and fluconazole [antifungal drug] showed similar teratogenic effects (abnormalities at the branchial apparatus level and cell death at the level of the branchial mesenchyme) at concentration levels of 6.25 microM and higher for flusilazole and of 125 microM and higher for fluconazole. By contrast, only slight developmental retardation and blood discoloration were observed at the highest concentrations of triazole, suggesting no teratogenic activity for the triazole group.
Ref: Antifungal triazoles induce malformations in vitro; by Menegola E, Broccia ML, Di Renzo F, Giavini E. Reprod Toxicol 2001 Jul-Aug;15(4):421-7


Much of what is known about the possible dangers of flusilazole is considered a trade secret -- unavailable even to state agents investigating health complaints. What is known about the fungicide -- which is not approved for use in the United States -- offers little comfort to those who applied it to Florida farmland as an undisclosed ingredient in some lots of Benlate 50 DF. According to a study conducted in Bulgaria, oral doses of flusilazole given to pregnant rats produced congenital defects such as protruding eyes, twins of unequal size joined at the jaw and grossly enlarged tongues...
Ref: Jan Hollingsworth. Fungicide studies offer little comfort. Memo: BURIED SECRETS PURSUING A MEDICAL MYSTERY. December 18, 1995. Tampa Tribune (Florida). page 4.

Parents believe that exposure to Flusilazol during pregnacy resulted in severe eye deformities such as microphthalmia (small eyes) and coloboma, a defect in the structure of the eyes.
Ref: Scottish Daily Record & Sunday Mail Ltd. - Sunday Mail. October 15, 2000

Coloboma - A defect of the iris caused by a failure of the eyeball to fuse properly during fetal development. These are developmental anomalies and do not worsen as the child grows older.
Microphthalmia - An unnatural smallness of the eyes, occurring as the result of disease or of imperfect development.

Abstract. Silane,[Bis(4-Flouorophenyl)] (Methyl)(1H,1,2,4-Triazol-1-ymethyl-INH-6573 (CAS# 85509-19-9) was evaluated to determine its embryo-fetal toxicity and teratogenic potential when administered by oral gavage to twenty-five rats (Charles River CD strain) per treatment group on days 7 through 16 of gestation at doses of 0, 10, 50, and 250 mg/kg body weight. At 250 mg/kg maternal deaths occurred and overt toxicity expressed as decreased body weight gain and feed consumption and by a significant increase of chromodacryorrhea, chromorhinorrhea, wet and stained underbodies, and alopecia. Slight maternal toxicity at 50 mg/kg was expressed as a significant decrease in feed consumption. The mean relative liver weight was significantly increased in the 250 and 50 mg/kg treatment groups. No maternal toxicity was noted at 10 mg/kg and below. Embryo-fetal toxicity was noted at all treatment levels. At 250 mg/kg a decrease in fetal body weight and an increase in fetal deaths were reported. The incidence of skeletal variations were increased significantly above controls at all treatment levels. An increase in fetal head malformations were reported in all groups, including controls. Male to female sex ratios of litters were not reported. Due to the incidence of fetal head malformations across all groups, no NOEL was reported in this study.

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

Reproductive Effects: In rats, oral doses of 10 and 50 mg/kg/day of haloxyfop-ethoxyethyl from days 6 to 16 of pregnancy reduced the number of live offspring per litter and caused vaginal bleeding in the mother (5). Teratogenic Effects: Oral doses of 50 mg/kg/day of haloxyfop-ethoxyethyl in rats between days 6 and 16 of pregnancy caused developmental abnormalities in the offspring's urogenital system and death to the fetus (5). Oral doses of 7.5 mg/kg/day of haloxyfop-methyl given to rats from days 6 to 15 of pregnancy caused delayed bone formation in the offspring (6).
Ref: EXTOXNET Pesticide Information Profile


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.

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

-- 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 Fact Sheet. Lithium perfluorooctane sulfonate (LPOs). August 1999.

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

-- 52905-009 186501, "XR-007: Whole Embryo Culture Teratogenicity Screen", (E. W. Carney, Health and Environmental Research Laboratories, The Dow Chemical Company, Midland, MI, Report # 971083, 31 July 1997). Seven non-pregnant female rats (serum donors) received 1000 mg/kg/day of the test article (XR-007, 98%) in 0.5% Methocel by gavage for 3 consecutive days. Four hours after the last dose, rats were exsanguinated and their blood centrifuged to obtain serum. Six control rats were similarly treated with vehicle and bled... Statistically significant increases in crown-rump length and somite number for treated embryos were reportedly due to a lower than usual growth rate in control embryos. Morphological abnormality was limited to an abnormal curvature of the anterior neural tube which distorted the head in one treated embryo (8.3%). No historical control data. This is supplemental information. (Green and Gee, 10/3/02).
Ref: September 26, 2002. Summary of Toxicology Data for Noviflumuron ((XDE-007) or N-(((3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl)amino)carbonyl)-2,6- diflurobenzamide. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

[Note from FAN- some definitions:
"Predominately anterior neural tube defects, occuring early in gestation. The anterior neural tube fails to close properly, or does not divide into two hemispheres. The generic name for this category of malformations is arrhinencephaly. Ref: Developmental and Perinatal Disorders of the CNS. Weill Medical College of Cornell University.
-- "... trisomy 13 is closely linked to midline malformations, including
arrhinencephaly, agenesis of the corpus callosum, and holoprosencephaly, and is the single most common chromosomal defect underlying holoprosencephaly." -
-- "Trisomy 13 Syndrome is a genetic disorder with onset before birth. It occurs approximately 1/5000 live births. Infants affected with Trisomy 13 ten
d to be small at birth. Spells of interrupted breathing (apnea) in early infancy are frequent, and mental retardation is usually severe. Many affected children appear to be deaf. A moderately small head (microcephaly) with sloping forehead, wide joints and openings between parietal bones of the head are present. Gross anatomic defects of the brain, especially failure of the forebrain to divide properly (holoprosencephaly) are common. A hernial protrusion of the cord and its meninges through a defect in the vertebral canal (myelomeningocele) is found in almost 50% of cases. The entire eye is usually small (microphthalmia), and a defect of the iris tissue (coloboma), and faulty development of the retina (retinal dysplasia) occur frequently. The supraorbital ridges are shallow and palapebral fissures are usually slanted. Cleft lip, cleft palate, or both are present in most cases. The ears are abnormally shaped and unusually low-set." -


PFOS - PFOA - Insecticide, US EPA List 3 Inert

" DuPont tested for and found PFOA in the blood of female plant workers in Parkersburg. The company followed and documented pregnancy outcomes in exposed workers. Two of seven children born to female plant workers between 1979 and 1981 had birth defects, one an “unconfirmed” eye and tear duct defect, and one a nostril and eye defect. [Dupont Document] In 1981 fifty women were reassigned in the plant."
Ref: Environmental Working Group.
2003 report: PFCs: a family of chemicals that contaminate the planet. Part 4: PFC Health Concerns

Abstract: The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluoride and substituted perfluorooctane sulfonamido components found in many commercial and consumer applications. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1, 5, 10, 15 and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). Maternal weight gain, food and water consumption, and serum chemistry were monitored. Rats were killed on GD 21, and mice on GD 18. PFOS levels in maternal serum, maternal and fetal livers were determined. Maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately 4-fold higher than serum. Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated rat dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid-stimulating hormone (TSH) was observed. A similar pattern of reduction in T4 was also seen in the pregnant mice. Maternal serum triglycerides were significantly reduced, particularly in the high dose groups, although cholesterol levels were not affected. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver, but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively. Our results demonstrate both maternal and developmental toxicity of PFOS in the rat and mouse.
Ref: Toxicol Sci 2003 May 28; Exposure to Perfluorooctane Sulfonate During Pregnancy in Rat and Mouse. I. Maternal and Prenatal Evaluations; by Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Barbee BD, Richards JH, Butenhoff JL, Stevenson LA, Lau C. Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.

• Note from FAN:

Anasarca refers to generalized edema, in its most severe form. There is an accumulation of fluid in subcutaneous tissues, internal organs, and body cavities. It typically occurs during the course of nephrotic syndrome, but severe cardiac failure could result in anasarca.
Ref: http://www.kumc.edu/instruction/medicine/pathology/ed/keywords/kw_anasarca.html

The nephrotic syndrome is caused by a massive loss of protein in the urine, due to an abnormality of the glomerulus (see page 456, Rubin). The losss of protein, particularly albumin, leads to a decreased oncotic pressure of plasma, and subsequent non-inflammatory edema. The edema is usually generalized, and effusions may also occur.

Sodium fluoride - Wood preservative, EPA List 4B Inert - CAS No. 7681-49-4

Abstract: Fluoride was first associated with fetal malformation shortly after water fluoridation was initiated in the 1940s. Since many chemicals can interact directly with the embryo to cause malformation, the effects of fluoride on embryonic and fetal development were investigated. The effects of sodium fluoride on the development of frog embryos were studied under conditions described by the Frog Embryo Teratogenesis Assay-Xenopus (FETAX), a screening assay for teratogens. The most prominent malformations caused by sodium fluoride are reduction in the head-tail lengths and dysfunction of the neuromuscular system of the tadpoles. The values for LC(50), EC(50), and minimal concentration to inhibit growth (MCIG) of sodium fluoride met the limits established for a teratogen in frog embryos, showing that sodium fluoride is a direct acting teratogen on developing embryos. Since FETAX has a high degree of success in identifying mammalian teratogens, the observed teratogenic action of sodium fluoride on frog embryos would indicate a strong possibility that sodium fluoride may also act directly on developing mammalian fetuses to cause malformation.
Ref: Goh EH and Neff AW (2003). Effects of fluoride on Xenopus embryo development. Food Chem Toxicol. 2003 Nov;41(11):1501-8.


Abstract: The effect of fluoride on differentiation and proliferation of rat and mouse embryo limb bud cell were studied with micromass cultures in vitro. Embryo limb bud cells of rat (13-day) and mouse (12-day) were subjected to culture for 5 days. The results showed that fluoride could inhibit differentiation of cells without affecting cells proliferation. The concentrations of 50% inhibition of cell differentiation (ID50) were 6.8 micrograms/ml(rat) and 7.3 micrograms/ml(mouse). The concentrations of 50% inhibitions of cell proliferation (IP50) were 44.1 micrograms/ml (rat) and 63.6 micrograms/ml (mouse). The IP/ID50 values 6.4(rat) and 8.7 (mouse) were both greater than 5. According to the assessment criteria of Flint and Cheng Wanrong, the fluoride may be an embryo limb bud cells specific inhibitor. It could have potent teratogenicity.
Ref: Hua Xi Yi Ke Da Xue Xue Bao 1998 Sep;29(3):256-8, 268.
[Effect of fluoride on proliferation and differentiation in rat and mouse embryo bud cell in vitro]; by Zhang B, Wu D. [Article in Chinese]

Abstract: In this paper, the hydra polyps regeneration assay was used to screen and predict the teratogenicity of sodium benzoate, sodium pyruvate, sodium fluoride, sodium penicillin, and sodium nitrite. The results showed that sodium nitrite, sodium fluoride and sodium benzoate are teratogens, while sodium penicillin and sodium pyruvate are not teratogens. These experimental results accord with the results of mammalian teratogenicity assay. The test is valuable to screen and predict teratogenicity of chemicals.
Ref: [Predication of teratogenicity of chemicals using hydra regeneration assay]; by Cheng QY et al. Huan Ching Ko Hsueh; Mar;18(2):49-51, 1994. [Language: Chinese] - as cited in Dart Special at Toxnet.

Abstract Summary:
1) The teratogenic effects of sodium fluoride on the ankle joint and toe bones of white leghorn chick embryos are reported.
2) Due to endochondrial osteofluorosis, the excessive growth of trabeculae in the epiphyses of distal tibiotarsus and proximal tarsometatarsus obliterated the ankle synovial joint space.
3) An increase occurred in the volume of bones, such as tibiotarsus, tarsometatarsus and phalanx.
4) Toe bones, namely phalanx and their articular surfaces with fibrocartilage containing spherical chondrocytes, were observed in control embryos. In fluoride-treated embryos, the distal and proximal regions of the phalanx grew enormously and irregularly, leaving little space for articulation.
5) Blackening and falling of feathers occurred in the fluoride-treated chick embryos.
Ref: Teratogenic effects of fluoride on chick embryo; by
S Krupanidhi and TM Dhanarajan. Fluoride 1994; 27(1):25-33

Abstract: Down syndrome (DS) birth rates (BR) as a function of maternal age exhibit a relatively flat linear regression line for younger mothers and a fairly steep one for older mothers with the second line intersecting the first line a little above maternal age 30. Consequently, overall DS-BR for all maternal ages are not a very reliable parameter for detecting environmental influences, since they may be strongly affected by the ratio of the number of younger to older mothers. For this reason, data for mothers under age 30 were selected to detect an association between water fluoridation and DS for which the lower maternal age regression would be a much smaller contributing factor. The early research of I Rapaport indicating a link between fluoride in drinking water and Down syndrome was followed by studies claiming there was no such association. Application of sound methodology to the data in those later investigations shows that none of the criticisms against Rapaport's work are valid. For example, in the data of J D Erickson on maternal age-specific DS births in Metropolitan Atlanta, Georgia, when the three youngest maternal age subgroups are reasonably combined into single groups for areas with and without water fluoridation, a highly significant association (P less than 0.005) is revealed between fluoridated water and DS births. It also appears that the dose-response line (DRL) or DS-BR for daily fluoride intake may have no allowable level that does not induce fluoride-linked DS births. Therefore fluoride may be one of the major causes of DS other than aging of mothers. The number of excess DS births due to weffects.spleen.f.pesticides.htmater fluoridation is estimated to be several thousand cases annually throughout the world.
Ref: Takahashi K (1998). Fluoride-linked Down syndrome births and their estimated occurrence due to water fluoridation. Author Address: Department of Internal Medicine and Biostatistics, Tokyo University Medical School, Tokyo, Japan. Source: Fluoride 1998 May;31(2):61-73.
As cited on Toxnet DART.

• Note from FAN: Uncertain of classification for Down syndrome.
Until clarified, we will include it in this section. - EC.

Sulfentrazone - Herbicide - CAS No. 122836-35-5

52988-0047 220351 (EPA MRID#: unknown), Freeman, C., “F6285 Technical: Teratology study in rats (oral),” FMC Corporation Toxicology Laboratory, Princeton, NJ; and Argus Research Laboratories, Inc., Horsham, PA, Aug. 4, 1993. Laboratory Study #: FMC Study No. A91-3410. Pregnant Crl:CD®BR VAF/Plus® dams, 25/group, were dosed by gavage (5 ml/kg corn oil vehicle) with 0, 1, 10, 25, or 50 mg/kg/day Sulfentrazone (F6285 Technical), purity 94.2%, during gestation days 6-15 in a standard developmental toxicity study. Maternal NOEL = 25 mg/kg/day. At 50 mg/kg/day there were decreased maternal body weight gains during late gestation, attributable to decreased gravid uterine weights due to increased resorptions (6.0 resorptions/dam in the 50 mg/kg/day group, compared to a range of 0.3 to 0.9/dam in controls and lower dose groups). About 22% of 50 mg/kg/day group resorptions were late resorptions, which normally occur only in about 0.02% of implantations (based on historical control data). There were three fetal deaths at 50 mg/kg/day, also an uncommon occurrence in historical controls. Vaginal bleeding was observed in ten 50 mg/kg/day dams compared to 0 controls (considered by investigators as associated with the increased resorptions). Also, 50 mg/kg/day dams had increased spleen weights and increased severity of splenic extramedullary hematopoiesis compared to controls and lesser dose groups. Developmental toxicity NOEL = 10 mg/kg/day. Dose related findings at 25 and 50 mg/kg/day included diminished body weights of fetuses (reductions of 7% and 19%, respectively, compared to concurrent controls). Statistically significant skeletal observations at 25 and 50 mg/kg/day were reduced ossification sites of caudal vertebrae and metacarpals. Developmental toxicity at 50 mg/kg/day was marked by malformations [whole body edema (anasarca) in 4 fetuses (4 litters), short ribs in 2 fetuses (1 litter), and bent radius and ulna in 3 fetuses (2 litters): all of these considered treatment-related because of low concurrent and historical control incidences]. Also common at 50 mg/kg/day were wavy ribs [30 fetuses (16 litters), compared with 1 or 0 fetuses per group in controls and lower dose groups] and wide-spread additional ossification delays. This study indicates a “possible adverse effect” and was flagged as such by investigators under 40 CFR 158.34, because the fetal NOEL is lower than the maternal NOEL. Overall, developmental toxicity findings at 25 mg/kg/day were modest, and the dose-response between 25 and 50 mg/kg/day was quite sharp. Study is acceptable. Aldous, 11/29/05.
Ref: January 13, 2006: Summary of toxicology data: Sulfentrazone (F2685). California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.

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.

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

TERATOLOGY, RAT. 51974-030; 119842; "Teratogenic Study of DPX-66037-24 in Rats" (Author: C.A. Mebus; E.I. du Pont de Nemours & Company, Inc., Newark, DE, Project No. HLR 525-91, 11/1/91); DPX-66037-24 (95.6% Triflusulfuron-methyl); 0, 30, 120, 350, 1000 mg/kg/day oral gavage; 25 Crl: CD BR female rats/dose; observations- maternal effects; five animals died due to dosing injuries; significant decreases in maternal weight changes and feed consumption were observed; fetal effects; significantly increased average number of malformed fetuses were observed, the majority of fetal malformations occurred in one fetus, when individual end points of developmental evaluation criteria were grouped a significant increase was noted in the 350 and 1000 mg/kg dose groups primarily due to retarded renal development and partial ossification of skulls, sternebra or vertebra; no adverse effect; Maternal NOEL = 120 mg/kg (based on decreased maternal weight gain and feed consumption), Developmental NOEL = 120 mg/kg (based on increased average number of malformed fetuses, retarded fetal development).

Triphenyltin fluoride - Antifoulant, Algaecide, Herbicide - CAS No. 379-52-2

2. Comment. American Hoechst Corporation disagrees with the Agency's [US EPA] position that TPTH produces teratogenic effects and that a NOAEL has not been determined in the two previously reviewed rat
teratogenicity studies [Refs. 5 and 46]. American Hoechst and M&T Chemicals had the rat teratology study by Battelle Columbus Laboratories [Ref. 3] peer reviewed by two independent sources and submitted the results of those reviews. One reviewer found that 2.8 mg/ kg/day was clearly a NOAEL for teratogenicity while the second reviewer was unable to identify a no effect level from the data available. In addition, American Hoechst submitted the results of a teratology study of triphenyltin fluoride (TPTF) that had been previously submitted to EPA. The NOAEL for this study was 3.0 mg/kg/day.
Response. The submissions from American Hoechst Corporation do not satisfactorily eliminate concerns regarding the teratogenicity of TPTH because no new information was presented to the Agency. Although these studies provided sufficient data to assure that TPTH is not teratogenic in rats at dose levels up to and including 8.0 mg/kg/day, these studies did result in developmental and maternal toxicity. Second, the
registrant did not provide new information indicating that a NOAEL exists in the two rat studies. Third, the teratology study with TPTF also indicated hydroureter as a fetal lesion. The initial reviewer of this study classified this compound as a teratogen.
Ref: Federal Register: October 20, 2000. Triphenyltin Hydroxide; Proposed Determination To Terminate Special Review.

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