Bone - Adverse Effects
Fluorinated and Fluoride Pesticides

beginning with
A-E • F-G H-P Q-Z
See short description and defintions on bone

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

-- Food and Agricultural Organization of the United Nations

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

Acifluorfen, sodium - Herbicide - CAS No. 62476-59-9

-- Developmental toxicity in rats... A significant increase (p < 0.0001) in resorptions in the high-dose group and significant reduction (p< 0.01) in mean fetal weights for both the mid- and high-dose groups were observed. A significant increase (p< 0.05 or 0.01) in anatomical variations was seen in the mid- and high-dose groups. The variations included slightly dilated lateral ventricles of the brain, hemorrhage in the eyeball, slight dilation of the renal pelvis, hemorrhage in either the peritoneal cavity or subcutaneous spaces, and minor changes in ossification (such as incomplete ossification of supra-occipital sternebra or thoracic centra). The NOAEL for developmental toxicity is 20 mg/kg/day; the LOAEL for developmental toxicity is 90 mg/kg/day based on the decreased fetal body weight and the increase in anatomical variations.

Acrinathrin - Acaracide, Insecticide - CAS No. 103833-18-7

-- Rat Teratology Study Acrinathrin suspended in corn oil was administered at the dose levels of 0, 2, 6 and 18 mg/kg/day to groups of 25 mated females in SD rats from days 6 to 15 of pregnancy. On day 20 of pregnancy, females were sacrificed and fetuses were removed by caesarean section... Maternal findings:.. The incidence of minor skeletal abnormalities was increased at the highest dose level [18 mg/kg/day] but these abnormalities were essentially represented by a delay in the ossification process. The rate of fetuses affected with external, skeletal or visceral abnormalities was comparable between the control and the 2 and 6 mg/ kg/day groups. In conclusion, the dose of 2 mg/kg/day was considered to be the NOEL in terms of maternal toxicity. The dose of 6 mg/kg/day was considered as the NOEL in terms of embryofetal development. Acrinathrin revealed no evidence of teratogenicity even at the highest dose level of 18 mg/kg/day.
Ref: Summary of Toxicological Studies on Acrinathrin Market Development, AgrEvo Japan Limited (Received January 26, 1998 ; Accepted March 20, 1998).

Ammonium bifluoride - Wood Preservative - CAS No. 1341-49-7

Chronic Exposure: Chronic exposure may cause mottling of teeth and bone damage (osteosclerosis) and fluorosis. Symptoms of fluorisis include brittle bones,weight loss, anemia, calcified ligaments, general ill health and joint stiffness.
Ref: Analytyka. Material Safety Data Sheet. Online as of September 15, 2003.

Ammonium fluoride - Wood Preservative - CAS No. 12125-01-8

Chronic Exposure: Chronic exposure may cause mottling of teeth and bone damage (osteosclerosis) and fluorosis. Symptoms of fluorisis include brittle bones, weight loss, anemia, calcified ligaments, general ill health and joint stiffness.
Ref: 1999 Material Safety Data Sheet prepared by Mallinckrodt Baker, Inc.

Ammonium silicofluoride - Insecticide, Miticide Wood Preservative, EPA List 3 Inert - CAS No. 16919-19-0

Chronic: Causes severe skin irritation and burns. Ingestion or inhalation may be harmful and possibly fatal depending on severity and length of over-exposure. Chronic over- exposure may cause fluorosis. Product may be absorbed through the skin and produce signs of fluorosis such as weight loss, brittleness of bones, anemia, weakness and stiffness of joints. Internal bleeding may develop. First aid procedures should be followed even in cases of suspected contact.
Ref: Ammonium fluorosilicate Material Safety Data Sheet from LCI, Ltd.

Benthiavalicarb-isopropyl - Fungicide - CAS No. 177406-68-7

-- In a developmental toxicity study in New Zealand White rabbits receiving 0, 10, 20 or 40 mg/kg/day benthiavalicarb-isopropyl from day 6 to 28 of gestation, the maternal NOAEL was 20 mg/kg/day based on abortion and increased liver weights at the 40 mg/kg/day dose. The developmental NOAEL was 20 mg/kg/day based on increased incidence of small fetus and delayed ossification of the hindlimb talus at 40 mg/kg/day.
Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Beta-cyfluthrin - Insecticide - CAS No. 68359-37-5

-- Beta-cyfluthrin (96.5- 97.3%). Prenatal developmental toxicity study--rats. Maternal NOAEL = 3 Developmental NOAEL = 10 Maternal LOAEL = 10 based on reduced body weight gain and reduced food consumption with post-treatment recovery. Developmental LOAEL = 40 based on reduced fetal body weights and increased skeletal variations.
Ref: Federal Register. September 27, 2002. Cyfluthrin; Pesticide Tolerance. Final Rule.

Boron Trifluoride - Fumigant - CAS No. 7637-07-2

-- Target Organs: Lungs, blood, bones and teeth.
-- Signs and Symptoms of Exposure: Acute exposure: coughing, shortness of breath, headache, vertigo, chills and nausea. Subchronic: dental fluorosis, increased bone, serum and urinary fluoride levels, hypocalcemia.
-- Chronic and Subchronic Data: Two of forty rats exposed to 6 ppm for 6 hours/day, 5 days/week for 13 weeks exhibited renal toxicity and signs of respiratory irritation. Six month exposures of rats, rabbits and guinea pigs produced dental fluorosis and pneumonitis at similar levels. This material is listed in the Registry of Toxic Effects of Chemical Substances (RTECS), but no information on its carcinogenicity is available.
Ref: Material Safety Data Sheet for Boron Trifluoride (BF3). May 2001.

• Note: Dental fluorosis hasn't been included in the bone category even though it was noted in many studies for this and other pesticides. However, we will keep this study in to remind us that this category was omitted.- EC
... Exposure of six animal species to 0.28 mg/L of boron trifluoride for 4 to 7 hours a day, 5 days a week killed all animals within 30 days. Rats, rabbits, and guinea pigs were exposed to boron trifluoride via inhalation. Guinea pigs died of respiratory failure after being exposed to 0.036 mg/L for 19 days; rats experienced fluorosis of the teeth at this concentration.
Ref. USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. 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.

-- Boron trifluoride is primarily a respiratory irritant which predisposed the exposed /guinea pigs/ to respiratory infection. Exposure at 100 ppm (277 mg/cu m) was fatal to all animals. Physiological responses prior to death included respiratory irritation and infection, kidney damage, retarded growth, and severe progressive fluorosis in rat teeth...
Ref: TOXNET profile from Hazardous Substances Data Bank for Boron Trifluoride.

Butafenacil - Herbicide - CAS No. 134605-64-4

Some excerpts from Table 2.--Subchronic, Chronic, and Other Toxicity
Ref: Butafenacil; Pesticide Tolerance. Final Rule. Federal Register. September 19, 2003.
Study type
[Guideline number]
90-Day oral (dietary) toxicity rodents
(rat) - [870.3100]
NOAEL = 300 ppm (18.8/20.6 mg/kg/ day M/F). LOAEL = 1,000 ppm (62.3/69.3 mg/kg/ day M/F) based on decreased body weight gains, decreased hemoglobin, hematocrit, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), increased red cell volume, increased bone marrow hypercellularity; increased bilirubin and urobilinogen; increased alanine aminotransferase; hepatocyte necrosis; inflammatory liver cell infiltration

Some excerpts from Table 3.--Toxicological Dose and Endpoints for Butafenacil
- a summary of the toxicological endpoints used for human risk assessment
Ref: Butafenacil; Pesticide Tolerance. Final Rule. Federal Register. September 19, 2003.

-- Exposure Scenario
-- Dose Used in Risk Assessment, UF
-- Special FQPA SF* and Level of Concern for Risk Assessment
Study and Toxicological Effects
-- Short-term inhalation (1 to 30 days)
-- Oral NOAEL = 18.8 mg/kg/ day
-- Residential LOC for MOE = 100
-- Occupational = 100
90-day rat feeding study.
The LOAEL for this study is 62.3 mg/kg/ day based on decreased hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular volume, increased red cell volume distribution width, and increased incidence of bone marrow hypercellularity
-- Short-term incidental oral (1 to 30 days)
-- Intermediate-term incidental oral (1- 6 months)
-- LOAEL = 18.8 mg/kg/day
-- Residential LOC for MOE = 100
-- Occupational = NA
-- Short-term inhalation (1 to 30 days)
-- Intermediate-term inhalation (1 to 6 months)
-- Oral NOAEL = 18.8 mg/kg/day
-- Residential LOC for MOE = 100
-- Occupational = 100

Carfentrazone-ethyl - Herbicide - CAS No. 128639-02-1

Developmental toxicity study - rat... Examination of fetuses for alterations of external, visceral, and skeletal development revealed significantly increased litter incidences of wavy and thickened ribs in the 1,250 mg/kg/day treatment group. The developmental LOAEL is 1,250 mg/kg/day (based upon a significant increase in the litter incidences of wavy and thickened ribs); the developmental NOAEL is 600 mg/kg/day.
Ref: Federal Register. August 1, 2001. Carfentrazone-ethyl; Pesticide Tolerances for Emergency Exemptions. Final Rule.

-- Reproduction and Developmental Studies... Carfentrazone-ethyl was orally administered to pregnant female rabbits, at doses of 0, 10, 40, 150 or 300 mg/kg bw/day from day 7 to day 19 of gestation. Slight increases in abdominogenital, and pink or red pan liner staining were recorded at doses •150 mg/kg bw/day. Skeletal variations in rabbits (angulated hyoids, unilateral and floating ribs, and non-ossified 6th sternabrae in rabbit litters), were slight and not dose-related at materno-toxic doses. Maternal and foetal NOELs were 40 and 10 mg/kg bw/day respectively, in rabbits.
Ref: April 2000 - Australia. Evaluation of the new active CARFENTRAZONE-ETHYL in the product AFFINITY 400 DF HERBICIDE. National Registration Authority for Agricultural and Veterinary Chemicals. NRA Ref. 51555.
Also available at

Chlorfenapyr - Acaricide, Insecticide - CAS No. 122453-73-0

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

1-chloro-1,1-difluoroethane - Solvent, EPA List 2 Inert - CAS No. 75-68-3

Damske et al. (1978) exposed 20 pregnant CRL:COBS CD (SD) BR rats to 0, 3259, or 9420 ppm HCFC-142b (0, 13,460, or 38,905 mg/cu.m, respectively) for 6 hours/day on gestation days 6-15. Dams were sacrificed on day 20, and the fetuses were weighed, sexed, and examined for external malformations... Some skeletal variations described by the study authors were classified as "commonly encountered" or "unusual skeletal variations", but no further information is given. Reduced ossification was described for several areas, including the interparietal and supraoccipital bones of the skull and the hyoid bone.."
Ref: US EPA IRIS, CASRN 75-68-3.

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

In a developmental toxicity study in rats, the highest dose level of 160 mg/kg resulted in reduced body weight gain of the dams and signs of retarded fetal body weight and incomplete ossification of vertebrae and sternebrae... The EPA's Hazard Identification Assessment Review Committee (HIARC) concluded that based on an increase in bilateral distension and torsion of the ureters and delayed ossification in the fetuses, the developmental LOAEL was 40 mg/kg/day and the NOAEL was 5 mg/kg/day.
Ref: Federal Register. Arpil 26, 2000. [PF-938; FRL-6554-2]

Study # 870.3700a. Prenatal Developmental Toxicity in Rats. Maternal NOAEL = 160 mg/kg/day Maternal LOAEL > 160 mg/kg/day based on lack of effect. Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 40 mg/kg/day based on increased incidences of bilateral distension and torsion of the ureters, unilateral 14th ribs, and incomplete ossification of the metacarpals and various cranial bones (parietals, interparietals, occipital, and squamosal).
Ref: US EPA Pesticide Fact Sheet. Reason for Issuance: Conditional Registration. June 6, 2000.

Cryolite - Insecticide - CAS No. 15096-52-3

6. A developmental toxicity study conducted in female mice with cryolite at dose levels of 0, 30, 100 and 300 mg/kg/day (gavage). The NOEL for maternal toxicity is 30 mg/kg/day and the LOEL is 100 mg/kg/day based on the occurrence of dark red contents of the stomach. Fetuses at 300 mg/kg/day exhibited bent ribs and bent limb bones. The NOEL for developmental toxicity is 100 mg/kg/day. The LOEL is 300 mg/kg/day based on an increase in bent ribs and bent limbs.
Ref: Federal Register: May 8, 1996. Fluorine Compounds; Pesticide Tolerance and Feed Additive Regulation. Proposed Rule.

-- Exposure to cryolite dust may result in skeletal fluorosis. Eight male workers at a cryolite concentrator participated in a 4 day study after 5 days of vacation. Dust exposures were 0.16 to 21.2 mg/cu m. Urine was collected before work began and during two 4 hr periods. Preshift urine fluoride concentrations increased during the week. Fluoride concentrations in postshift urine and serum both correlated with the dust exposures. Serum fluoride concentrations decreased with a half-life of 3.3 to 6.9 hr after work. Fluoride clearance was 40.5 ml/min at urinary flow rates of 0.89 to 2.21 ml/min. Serum aluminum concentrations varied without relation to the exposure, but the urinary aluminum excretion correlated with the fluoride levels. Preshift serum phosphate concentrations increased significantly during the week, possibly indicating changes in mineral metabolism. For monitoring of individual uptake of cryolite dust, serum fluoride measurements are most useful. [Grandjean P et al; J Occup Med 32 (10: 58-63 (1990)]
-- Fluoride levels in urine should be checked periodically and all workers should be subjected to periodical skeletal X-ray exam particularly of the pelvis. /Fluoride and cmpd/ [International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983. 894]
Ref: TOXNET from Hazardous Substances Data Bank for ALUMINUM SODIUM FLUORIDE, CAS No. 15096-52-3

-- 145-045 139642 Nemec, M.D., "Developmental toxicity study of Kryocide* in mice", WIL Research Laboratories, Inc. Study No. WIL-160004, Jan. 6, 1992. Kryocide*, purity of 97.3%, was administered via gavage at concentrations of 0 (0.5% Methylcellulose), 100, 300 or 1000 mg/kg/day to 30 mated Crl:CD-1* (ICR) BR mice/group during gestation days 6 through 15. Maternal toxicity NOEL = 100 mg/kg/day. Mortality was 40% and 10% for high and mid dose groups, respectively, with occasional necropsy reporting of "red stomach contents" or "reddened adrenals". Food consumption and body weight gains were reduced at 1000 mg/kg/day. Survival was too low at 1000 mg/kg/day to meaningfully assess treatment effects on fetuses, however a small increase in incidences of cleft palate and a single incident of open eyelid contributed toward a general increase in malformations in this group. There were no definitive developmental effects at or below 300 mg/kg/day, however a single incident of the variation "bent ribs" was considered an equivocal indication of a treatment effect, so that 100 mg/kg/day is the developmental NOEL. This study is not independently acceptable, however it provides useful data, and justifies dose levels used in the teratology study which followed (Record No. 112070). Kishiyama and Aldous, Nov. 1, 1995.
-- 031 071324 "Cryolite Animal Metabolism," (Pennwalt Corporation, 10/28/88), Summary of in-house and literature studies on cryolite. Cryolite serves as a source of fluoride and is essentially metabolized as free fluoride. Released in aqueous solution, the fluoride is deposited primarily in teeth and bone. Teeth striations have been observed in rat (3 to 13 ppm fluorine in diet) and cryolite in new bone of rabbit mandible (12 to 50 mg fluorine/day). Osteomalacia was produced in sheep with cryolite (60 mg fluorine/day). These effects are in response to fluoride's interference with normal calcium metabolism. Cryolite hydrolyzes in vitro to produce fluoride anion instantaneously under acidic (pH 5: 15.5%), neutral (pH 7: 36.8%) or basic (pH 9: 43.3%) conditions. The same effect probably also occurs in vivo, based upon the rapid assimilation into the bone as well as it’s efficient membrane permeability. Hydrolysis products of cryolite may re-associate to form similar salts. Differences in acute toxicity between cryolite and other fluoride salts is potentially due to solubility. Inefficient absorption occurs at levels necessary to cause acute fluoride toxicity symptoms. Chronic effects, however, are similar to those produced by simple fluoride salts. M. Silva, 8/22/89.
-- 031 071325 "The Comparative Toxicity of Fluorine in Calcium Fluoride and in Cryolite," (University of Illinois, 3/29,39). Cryolite (synthetic product), marketed as an insecticide, consisted of 47% fluorine and calcium fluoride were fed in diet and drinking water to albino rats (10 females and 14 males/treatment group) at 0.58 mg/kg for 14 weeks. Several of the rats, irrespective of treatment groups showed hematuria lasting 1 or 2 days in the first week. Striations in tooth enamel began to appear during the 8th week of treatment and were visible in all rats by the end of the 10th week. Data demonstrate that the action of fluorine from cryolite is indistinguishable from that of calcium fluoride when both are administered in aqueous solutions at the rate of 0.58 mg/kg daily. Approximately 96% of the fluorine retained (13 ppm in food) is deposited in the skeleton, while the rest is equally divided between teeth and soft tissues. M. Silva, 8/10/89.
-- 031 071330 "The Assimilation of Fluorine by Rats From Natural and Synthetic Cryolite and From Cryolite-Sprayed Fruits," (University of Illinois, 6/30/41). Twelve pairs or trios of rats, depending upon the number on rations to be compared, were selected on the basis of sex, litter membership and body weight and fed equal amounts within the pairs or trios. Initially, 1-4 animals/litter were sacrificed for base level of fluorine. Experiment I: Domestic synthetic cryolite (particle size < 1 mm, 44.9% fluorine) and natural Greenland cryolite (commercial form < 5 mm, 46.2% fluorine; specially ground form < 1 mm, 50.5% fluorine) was fed (9.4 ppm fluorine). Results showed that fluorine of synthetic cryolite is retained significantly more than fluorine from natural cryolite, probably due to solubility...M. Silva, 8/14/89.
Ref: 1995 - Summary of Toxicology Data. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

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

-- Rat developmental studies via inhalation: In the second study, the dams were exposed to analytical concentrations of 0, 0.09, 0.25, 0.59 or 4.2 mg/m3 of the test material. The dams were sacrificed on day 20 and their pups removed by caesarian section. The maternal NOEL was 1.1 mg/ m3 and the maternal LOEL was 4.7 mg/m3 (reduced motility, dyspnea, piloerection, ungroomed coats and eye irritation. The developmental NOEL was 0.59 mg/m3 and the developmental LOEL was 1.1 mg/m3 (increases in the incidence of runts and skeletal anomalies in the sternum (1.1 mg/m3 and above); increases in post-implantation losses and decreases in pup weights (4.7 mg/m3 and above) and increased incidences of late embryonic deaths, in skeletal anomalies in the extremities, pelvis and skull and in microphthalmia (23.7 mg/m3).
--Two rat developmental toxicity studies via the inhalation route of exposure were also conducted... In the second study, the maternal NOAEL and LOAEL were < 0.46 mg/ M3, based on decreased body weight gain and reduced relative food efficiency. The developmental NOAEL was 0.46 mg/M3 and the developmental LOAEL was 2.55 mg/M3, based on reduced fetal and placental weight,
and reduced ossification in the phalanx, metacarpals, and vertebrae.
Ref: Federal Register: November 26, 1997. Cyfluthrin; Pesticide Tolerances. Final Rule.

Cyhalothrin, lambda - Insecticide - CAS No. 91465-08-6

Mutagenesis. 2005 May;20(3):235.
Induction of micronuclei by lambda-cyhalothrin in Wistar rat bone marrow and gut epithelial cells.
No abstract available.
Authors: Celik A, Mazmanci B, Camlica Y, Askin A, Comelekoglu U.

Note: FAN has requested a copy of this study from inter-library loan.

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 Çömelekogölu, 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.

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

-- In the chronic studies, the most consistent findings were cranial osteosclerosis in the rat, and findings consistent with fluorosis in a 2-year mouse study. Clinical chemistry findings with supportive histopathology were observed in a 1-year study in the dog which were indicative of renal and liver damage. A detailed assessment of cranial osteosclerosis was performed in a 2-year study in the rat; a LOEL was established at 10-14 mg kg -1 d -1 . There was a clear increase in the incidence of cranial osteosclerosis in the low- and middle-dose groups, with almost all animals affected at the top dose. These findings are likely to be secondary to fluorosis in these animals. In terms of interspecies comparisons, in a mouse 2-year study, thickening of both the appositional bone of the cranial vault and nasal turbinates, and tooth alveolitis were observed at the top dose of 1,731-1,873 mg kg -1 d -1 . These findings are also considered to be a secondary consequence of fluorosis in these animals. No evidence of fluorosis was observed in the dog studies. . In this study a NOAEL of 2.5 mg kg -1 d -1 was established with nephropathy reported at 12.5 mg kg -1 d -1 .
-- It is considered that cranial osteosclerosis is likely to represent a fluoride mediated perturbation of bone metabolism but is not considered to be of concern for human health. It is also considered that the observed renal and liver damage is of concern to human health. For professional operators the ACP considered that the most appropriate NOAEL to use in risk assessments was the figure of 2.5 mg kg -1 d -1 taken from the one year dog study. Professional operators would not be expected to use products for prolonged periods, therefore a value from a one year study would be suitable. The other reported end points (thyroid tumours and osteosclerosis were associated with chronic exposure and much higher doses. Acceptable risk assessments would require a safety margin of about 100 over the NOAEL 2.5 mg kg -1 d -1 . Consequently these would also offer a high margin of safety against the longer term end points.

-- One-year Study. A repeat-exposure study using Beagles (4/dose/sex) is available; it was GLP and OECD Annex V compliant. Animals were administered either vehicle or 2.5, 12.5 or 37.5/62.5 mg kg -1 d -1 of dichlofluanid (90 % purity) in capsule form for one year. The top dose was reduced at week 15 to 37.5 mg kg -1 d -1 because of excessive toxicity. As a NOEL could not be established with the initial dosing regime, a subsequent study was carried out in which 0 or 1.25 mg kg -1 d -1 dichlofluanid was used... The pathology report on the interim kills revealed "a whitish hardening" of the cranium (still present at study termination). At the interim kill, the absolute heart weight was significantly decreased in both sexes at the top dose only (18 % and 14 % males and females respectively). The increases in relative liver weight in both sexes, and relative kidney and brain weight in females, reported at 4500 ppm reflected the previously noted decreases in body weight. In males at study termination the absolute organ weights of the kidney (5 %) and testes (5.6 %) were significantly increased at the top dose. At study termination the relative testes weight was increased in the top-dose group (18 %). The reported increases in relative organ weights reflected the decreases in body weights noted earlier. Histopathology of the satellite groups revealed a dose-dependent increase in cranial osteosclerosis in females, achieving statistical significance in the middle (8/10) and top-dose groups (9/10) when compared to control animals (1/10). In males however a significant increase in cranial osteosclerosis was only found in the low- (7/10) and top-dose groups (9/10); control (1/10). An increase in cranial lamellar growth patterns was also reported in males at the top dose (7/10, and controls 0/10). The forestomachs of males from the top-dose group were found to have a higher incidence of hyperkeratosis and acanthosis (0/10 and 5/10 controls and 4500 ppm respectively). The thyroids of males exhibited follicular cell hypertrophy; 0/50 (control), 2/10 (180 ppm), 1/10 (900 ppm) and 3/10 (4500 ppm). Histopathology of the main groups (24 months) revealed a significant increase in hyperkeratosis and acanthosis of the forestomach in males (2/49 and 21/49 controls and 4500 ppm respectively) and females (0/49 and 12/49 controls and 4500 ppm respectively). A significant increase in the incidence of cranial osteosclerosis was apparent in males of all treatment groups and in females at the top dose. These data also suggest an increase in severity with increasing dose. See Table 3.10. A significant decrease in sternal chondrodystrophy reported in females of the top-dose group. A significant increase in cranial lamellar growth patterns was reported in both sexes at the top dose (45/49 and 37/50 males and females respectively) compared to the controls (1/49 and 0/50 males and females respectively)... [Unpublished, 1993(b)]

Dichlofluanid: Table 3.9 : Fluoride Content Of Bones And Teeth At Study Termination
site 0 ppm 180 ppm 900 ppm 4500 ppm
teeth* 0.12 0.27 1.17 3.92
bones* 0.43 0.97 2.91 13
site 0 ppm 180 ppm 900 ppm 4500 ppm
teeth* 0.11 0.32 1.12 5.36
bones* 0.66 1.44 3.53 11.46
* mg fluoride/g ash

Dichlofluanid: Table 3.10 : Incidence And Severity Of Cranial Osteosclerosis
- males (dose ppm) females (dose ppm)
grade 0 180 900 4500 0 180 900 4500
minimal 0 6 4 0 12 1 1 1
slight 11 14 24 4 0 7 13 8
moderate 0 11 6 18 0 10 2 22
marked 0 3 0 26 0 2 0 9
severe 0 0 0 1 0 0 0 6
total 11 34* 34* 49* 12 20 16 46*
* statistically significant

Dichlofluanid: Table 3.12 : Incidence Of Skull And Nasal Turbinate Thickness And Tooth Alveolitis Reported On Necropsy
5000 ppm
pathology males females males females
skull thickness 0/45 0/46 39/42 40/40
turbinate thickness 0/45 0/46 23/42 35/40
tooth alveolitis 0/45 1/46 17/42 19/40

The fluoride content of teeth and bone was found to be significantly increased at all doses and time points for both sexes. See Table 3.13.

Dichlofluanid: Table 3.13 : Fluoride Content of Bones and Teeth (mg g -1 ash)
week 53
week 104
week 53
week 104
dose male female male female male female male female
0 0.4 0.4 0.2 0.3 1.1 0.9 1.1 1.2
200 0.7 0.6 0.7 0.8 2.4 1.5 3.6 2.9
1000 2.2 2.1 2.4 2.2 6 4.3 8.3 7.3
5000 10.9 9.9 15.7 13.8 17.4 14.5 18.7 17.5
Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Also available at:

Dichlorofluoromethane (CFC-21) - Propellant, EPA List 2 Inert - CAS No. 75-43-4

Aerosol sprays containing fluorocarbon propellants are another source of solvent intoxication. Prolonged exposure or daily use may result in damage to several organ systems. Clinical problems include cardiac arrhythmias, bone marrow depression, cerebral degeneration, and damage to liver, kidney, & peripheral nerves. Death occasionally has been attributed to inhalant abuse, probably via the mechanism of cardiac arrhythmias, especially accompanying exercise or upper airway obstruction. /Fluorocarbon propellants/ [Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 575]
Ref: TOXNET profile from Hazardous Substances Data Bank for DICHLORODIFLUOROMETHANE

Diflubenzuron - Chemosterilant, Insecticide - CAS No. 35367-38-5

At all dose levels, histopathological examinations indicated dose related increases of hemosiderosis and congestion of the spleen, hemosiderosis and chronic hepatitis of the liver, and mild erythroid hyperplasia of the bone marrow... Male rats at 6 and 18 mg/kg/day and female rats at 18 mg/kg/day had blue extremities indicative of cyanosis. Histopathological examinations indicated non-neoplastic treatment-related effects in the spleen, liver, bone marrow and adrenal gland...
Ref: US EPA RED. August 1997.

Groups of 49 or 50 rats and mice of each sex (7 to 8 weeks old) were administered PCA at dose levels of 2, 6 or 18 mg/kg (rats) or 3, 10, or 30 mg/kg (mice) on 5 days per week for 103 weeks. Vehicle control groups of 50 males and 50 females received deionized water by gavage. ... The combined incidences of uncommon splenic sarcomas (fibrosarcomas, osteosarcomas or haemangiosarcomas) were increased in male rats but not in females (males: 0/49, 1/50, 3/50, 38/50; females: 0/50, 0/50, 1/50, 1/50)... Bone-marrow hyperplasia was also observed.
Ref: Diflubenzuron. Environmental Health Criteria Report 184. WHO International Programme on Chemical Safety. 1996.

• One of the metabolites of Diflubenzuron is 4-chloroaniline (PCA).
-- ... PCA is carcinogenic in male rats, with the induction of unusual and rare tumours of the spleen (fibrosarcomas and osteosarcomas), which is typical for aniline (EU, 2002) and related substances. In the NTP (1989) study, PCA was found to be carcinogenic in male rats, based on the increased incidence of splenic sarcoma, osteosarcoma, and haemangiosarcoma in high-dose (18 mg/kg body weight) rats. The dose-response was non-linear, the incidence of sarcomas at 2 and 6 mg/kg body weight being marginal.

Uses of PCA: PCA is used as an intermediate in the production of several urea herbicides and insecticides (e.g., monuron, diflubenzuron, monolinuron), azo dyes and pigments (e.g., Acid Red 119:1, Pigment Red 184, Pigment Orange 44), and pharmaceutical and cosmetic products (e.g., chlorohexidine, triclocarban [3,4,4'-trichloro- carbanilid], 4-chlorophenol) (Srour, 1989; BUA, 1995; Herbst & Hunger, 1995; Hunger et al., 2000; IFOP, 2001). In 1988, about 65% of the global annual produc- tion was processed to pesticides (Srour, 1989). In Germany, in 1990, about 7.5% was used as dye precur- sors, 20% as intermediates in the cosmetics industry, and 60% as pesticide intermediates. The use for the remain- ing 12.5% of the production quantity was not specified (BUA, 1995). More recent data on the use pattern of PCA are not available.
Ref: Concise International Chemical Assessment Document 48. 4-CHLOROANILINE. World Health Organization Geneva, 2003.

Diflufenican - Herbicide - CAS No. 83164-33-4

-- Reproductive toxicity studies. In a teratogenicity study in the rat, the minimum effect level for maternal toxicity was 50 mg/kg bw/day based on reductions in weight gain at all dose levels. The NOEL for foetotoxicity and teratogenicity was 5000 mg/kg bw/day. In a teratogenicity study in the rabbit, the NOAEL for maternal toxicity was 50 mg/kg bw/day based on clinical signs of toxicity and the NOEl for foetotoxicity and teratogenicity 2500 mg/kg bw/day. A dose-related increase in the incidence of supernumerary ribs was considered to be within the historical control range. It was noted that the incidence in controls was low, whilst the statistical significance was marginal at the highest dose level.
Ref: September 1995. Evaluation on Diflufenican. 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 7PX, UK. Available at:

Diflufenzopyr - Herbicide - CAS No. 109293-97-2

-- In a developmental toxicity study, technical diflufenzopyr was administered by gavage to female Sprague Dawley rats at dose levels of 0, 100, 300, or 1000 mg/kg/day from days 6 through 15 of gestation... Developmental effects, characterized as significantly lower fetal body weights in males( 5%) and skeletal variations, exhibited as incompletely ossified and unossified sternal centra and reduced fetal ossification sites for caudal vertebrae, were observed at 1000 mg/kg/day. The developmental LOAEL is 1000 mg/kg/day, based on decreased fetal body weights and skeletal variations. The developmental NOAEL is 300 mg/kg/day...
-- In a developmental toxicity study, technical diflufenzopyr was administered by gavage to female New Zealand White rabbits at dose levels of 0, 30, 100, or 300 mg/kg/day from days 6 through 19 of gestation. The maternal LOAEL is 100 mg/kg/day, based on minimal reductions in body weight gain with no reduction in food consumption and clinical signs of toxicity (abnormal feces). The maternal NOAEL is 30 mg/kg/day. Developmental effects, characterized as significant increases in the incidence of supernumerary thoracic rib pair ossification sites occurred at the 300 mg/kg/day dose. No treatment-related developmental effects were noted at the low and mid doses. The developmental LOAEL is 300 mg/kg/day based on increased skeletal variations (supernumerary rib ossification sites). The developmental NOAEL is 100 mg/kg/day.
Ref: US EPA Fact Sheet. Reason for Issuance: Conditional Registration Date Issued: January 28, 1999.

Dietary exposure. EPA has established the reference dose (RfD) for diflufenzopyr at 0.26 milligrams/kilogram/day (mg/kg/day). This RfD is based on bone marrow compensated hemolytic anemia observed in the 1- year dog feeding study with a NOAEL of 26 mg/kg/day and an uncertainty factor of 100.
Ref: Federal Register: December 12, 2001 (Volume 66, Number 239)] [Notices] [Page 64257-64262].

Chronic Toxicity/Carcinogenicity. In a chronic toxicity study in dogs, diflufenzopyr was administered to beagle dogs in the diet at dose levels of 0, 750, 7500, or 15,000 ppm for 52 weeks. The LOAEL for this study is 7500 ppm (299 mg/kg/day for males and 301 mg/kg/day for females), based on erythroid hyperplasia in the bone marrow in bone sections, reticulocytosis, and increased hemosiderin deposits in the liver, kidneys, and spleen. The NOAEL is 750 ppm (26 mg/kg/day for males and 28 mg/kg/day for females).
Ref: US EPA. Diflufenzopyr Pesticide Fact Sheet. Conditional Registration. January 28, 1999.

TERATOLOGY, RABBIT **52843-020; 173136; “Developmental Toxicity (Embryo-Fetal Toxicity and Teratogenic Potential) Study of SAN 835 H Administered Orally via Stomach Tube to New Zealand White Rabbits” (Sharper, V., Argus Research Laboratories, Inc., Horsham, PA, Project ID No. 1819-008, 2/23/95). Twenty pregnant New Zealand White rabbits (strain Hra:[NZW]SPF) were administered a suspension of SAN 835 H (Lot No. 5904-4, 98.1% pure) via oral intubation at 0 (0.5% methylcellulose), 30, 100 and 300 mg/kg/day during days 6-19 of gestation, until sacrifice... The incidences of supernumerary thoracic ribs (12.47/12.36/12.61/12.74**), thoracic vertebrae (12.54/12.42/12.67/12.79*) and lumbar vertebrae (6.45/6.56/6.32/6.20*, * p<0.05, ** p<0.01) were altered in high dose fetuses. However, the small magnitude of these changes, and the prior findings that these variations commonly occur at maternally toxic doses, cast doubt on their biological significance as developmental defects. No adverse effects indicated. Maternal NOEL = 30 mg/kg/day (based on abortions in does administered 100 and 300 mg/kg/day). Developmental NOEL = 300 mg/kg/day (based on similar incidences of malformations and variations in fetuses from control does and does administered 300 mg/kg/day). Study acceptable (Vidair 4/20/00).
Ref: July 13, 2000. Summary of Toxicology Data for Diflufenzopyr. CA EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

Epoxiconazole - Fungicide - CAS No. 135319-73-2 (formerly 106325-08-0)

A developmental study was conducted via oral gavage in rats resulted in dosages of 0, 5, 15, and 45 mg/kg/day HDT with a developmental toxicity NOAEL of 5 mg/kg/day and a maternal toxicity of 5 mg/kg/day based on the following:.. d. A significant number of fetuses with skeletal variations (especially rudimentary cervical and/or accessory 14th rib(s)) in the high dose group tested were observed. However, no malformations were observed in any pups in this study. iii. In a second developmental study in rats via dermal exposure for 6 hours/day on intact skin with dosages of 0, 100, 400, and 1,000 mg/kg/day (HDT) with a development toxicity NOAEL of 400 mg/kg/day and a maternal toxicity of 400 mg/kg/day based on increased placental weights and a slight increase in the number of fetuses with skeletal variations was observed at the highest dose tested."
Ref: Federal Register. September 22, 2000. [PF-961; FRL-6737-8].

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

Beagle dogs were given 0, 4, 20, or 80 mg/kg/day orally, by capsule, for 1-year. The NOAEL was 4 mg/kg/day. The LOAEL was 20 mg/kg/ day, based on increased urinary bilirubin, variations in erythrocyte morphology, increased thrombocyte count, and increased erythroid series of the bone marrow. Elevated alkaline phosphatase levels were found at the two higher doses and siderosis of the liver at the high dose.
Ref: Federal Register. November 14, 2001. [PF-1052; FRL-6808-9]

-- Oral developmental toxicity study in rabbits. NOAEL = 75 mg/kg/day. LOAEL = 150 mg/kg/day based on an increased number of resorptions and increased sternal and cranial variations.
-- In the developmental toxicity study in rabbits, the maternal (systemic) NOAEL was 75 mg/kg/day, based on abortions and decreased food consumption at the LOAEL of 150 mg/kg/day. The developmental (fetal) NOAEL was also 75 mg/kg/day, based on a slightly increased number of resorptions, abnormal cranial development, and increased sternal variants at the LOAEL of 150 mg/kg/day.
-- Prenatal and postnatal sensitivity. There is qualitative evidence of increased susceptibility following in utero exposure to ethalfluralin in the developmental toxicity study in rabbits demonstrated by abortions and a slightly increased number of resorptions, abnormal cranial development, and increased sternal variants in the pups. There was no indication of increased susceptibility following in utero exposure to ethalfluralin in the prenatal developmental toxicity study in rats.
Ref: Federal Register: August 8, 2001. Ethalfluralin; Pesticide Tolerances for Emergency Exemptions. Final Rule.

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

REPRODUCTIVE HAZARDS: An increase in sternebral ossification defects, hydronephrosis, runting (pup weight less than 2.7 g), variant rib ossifications, extra vertebral ossification centers, cardiac septal defects, and intrauterine growth retardation were noted in rats.
Ref: TOXNET profile from Hazardous Substances Data Base.

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

Rabbit developmental study. Etoxazole did not produce developmental toxicity in rabbits... A statistically significant increased incidence of 27 presacral vertebrae with 13th ribs was observed in fetuses at 1,000 mg/kg/day compared with controls. This finding was within historical control range for fetal incidence but above the historical control range for litter incidence. No dose response was evident and the variation is considered to be equivocally treatment related. The NOAEL for maternal and developmental toxicity was 200 mg/ kg/day based on decreased body weight and body weight gain, decreased food consumption, and liver enlargement at 1,000 mg/kg/day. The NOAEL for developmental toxicity was 200 mg/kg/day based on statistically significant increased incidence of 27 presacral vertebrae with 13th ribs in fetuses at 1,000 mg/kg/day.
Ref: August 13, 2003. [Federal Register: August 13, 2003 (Volume 68, Number 156)] [Notices]. Etoxazole; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

Hyperplasia of bone tissue in rats at high doses (≥5000 ppm)
Ref: November 29, 2004. Review report for the active substance etoxazole. European Commission. SANCO/4054/2001 - rev. 3.

Fluoride Action Network | Pesticide Project | 315-379-9200 |