| See short description and defintions on bone
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
Food and Agricultural Organization of the United Nations
This is not an exhaustive list.
When time allows more information will be added.
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.
Ref: November 10, 1999. Toxicology Chapter
for RED. MEMORANDUM SUBJECT: ACIFLUORFEN: TOXICOLOGY CHAPTER FOR
- Acaracide, Insecticide - CAS No.
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).
- CAS No. 1341-49-7
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.
Analytyka. Material Safety Data Sheet. Online as of September
- 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
Ref: 1999 Material Safety Data Sheet prepared
by Mallinckrodt Baker, Inc.
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,
weakness and stiffness of joints.
Internal bleeding may develop. First aid procedures should be
followed even in cases of suspected contact.
Ammonium fluorosilicate Material Safety Data Sheet from LCI, Ltd.
- Fungicide -
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.
- Insecticide - CAS No. 68359-37-5
Beta-cyfluthrin (96.5- 97.3%).
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.
- 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
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.
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.
Herbicide - CAS No. 134605-64-4
Some excerpts from Table 2.--Subchronic,
Chronic, and Other Toxicity
Butafenacil; Pesticide Tolerance. Final Rule.
Federal Register. September 19, 2003.
oral (dietary) toxicity rodents
(rat) - [870.3100]
= 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
excerpts from Table 3.--Toxicological Dose and Endpoints
- a summary of the toxicological endpoints used for human
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
and Toxicological Effects
inhalation (1 to 30 days)
-- Oral NOAEL = 18.8 mg/kg/ day
LOC for MOE = 100
-- Occupational = 100
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
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
inhalation (1 to 30 days)
-- Intermediate-term inhalation (1 to 6 months)
-- Oral NOAEL = 18.8 mg/kg/day
LOC for MOE = 100
-- Occupational = 100
- CAS No. 128639-02-1
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.
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.
available at http://www.apvma.gov.au/publications/prscar.pdf
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)
24, 2001 - Summary
of Toxicological Data. California EPA.
Department of Pesticide Regulation. Medical Toxicology Branch.
available at: http://www.cdpr.ca.gov/docs/toxsums/pdfs/3938.pdf
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.
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;
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,
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
- 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
-- 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)]
-- FROM ANALYSIS OF BONES OF 2 /CRYOLITE/
WORKERS ... /IT WAS/ ESTIMATED THAT THEIR SKELETAL
SYSTEMS CONTAINED 50 AND 90 G OF FLUORINE, RESPECTIVELY. THE LATTER
AMT HAD BEEN DEPOSITED DURING 7500 WORKING DAYS, CORRESPONDING
TO AN AVG DEPOSITION OF 12 MG/DAY. [Patty,
F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology.
2nd ed. New York: Interscience Publishers, 1963. 841]
-- 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,
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.
Ref: 1995 - Summary of Toxicology Data.
California EPA, Department of Pesticide Regulation, Medical Toxicology
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
--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.
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
Note: FAN has requested a copy of this study from inter-library
(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.
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
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.
Cytogenetic effects of lambda-cyhalothrin on Wistar rat bone marrow;
A, Mazmanci B, Camlica Y, Askin A, Comelekoglu U. Mutat Res. 2003
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)...
Table 3.9 : Fluoride Content Of Bones And Teeth At Study Termination
mg fluoride/g ash
3.10 : Incidence And Severity Of Cranial Osteosclerosis
3.12 : Incidence Of Skull And Nasal Turbinate Thickness And
Tooth Alveolitis Reported On Necropsy
fluoride content of teeth and bone was found to be significantly
increased at all doses and time points for both sexes. See Table
: Fluoride Content of Bones and Teeth (mg g -1 ash)
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:
- Propellant, EPA List 2 Inert - CAS
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,
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
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
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.
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.
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,
- 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.
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:
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
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
compensated hemolytic anemia observed in the 1- year dog feeding
study with a NOAEL of 26 mg/kg/day and an uncertainty factor of
Ref: Federal Register: December 12, 2001
(Volume 66, Number 239)] [Notices] [Page 64257-64262].
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.
**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. http://www.fluorideaction.org/pesticides/diflufenzopyr.ca.epa.2000.pdf
Fungicide - CAS No. 135319-73-2 (formerly
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.
- 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.
-- 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.
INITIAL SUBMISSION: A TERATOLOGY STUDY WITH ETHALFLURALIN IN DUTCH-BELTED
RABBITS WITH COVER LETTER DATED 08-21-92. ELI LILLY & CO.
The National Technical Information Service.
Report Number: NTIS/OTS0545085.
- Rodenticide - CAS No. 371-62-0
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
Ref: TOXNET profile from Hazardous Substances
- Miticide, Ovicide - CAS No.
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.
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
29, 2004. Review report for the active substance etoxazole. European
Commission. SANCO/4054/2001 - rev. 3.