Teratogen:
• 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.
Ref: 1992.
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.
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.
http://www.fluoridealert.org/pesticides/fluazifop-p-butyl.msds.pdf
Fluazifop-P-butyl
- Herbicide - CAS No. 79241-46-6
--
Reproductive Effects: In a 3-generation reproductive study in
rats, effects included reductions in weight gain, fetal weight,
ossification, testicular weight, spleen weight, increased prostate
weight and gestational length. No Effect Level (NEL) was 1 mg/kg/day.
Fetotoxic effects seen in the rabbit, including reduced fetal
weight and reduced ossification at higher doses. No Effect Level
(NEL)
was 30 mg/kg/day in rabbits. The NEL for teratogenic
effects is at least 10/mg/day in the rat, with diaphragmatic
hernia at higher doses. Not teratogenic at highest dose
tested in rabbits (90 mg/kg/day). While
fluazifop-p-butyl is fetotoxic
when fed to
pregnant rats, human exposure data has concluded that female formulation
workers are not at increased risk of fetotoxic effects when skin
protection measures are applied.
Ref: Material Safety Data Sheet for
Fusilade DX (active indredient Fluazifop-P-Butyl). Syngenta. January
21, 2002.
http://www.fluoridealert.org/pesticides/fluazifop-p-butyl.msds.pdf
"Fluazifop-P-butyl
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
4.2.3.8 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
http://www.fluorideaction.org/pesticides/f-p-b.opp-2004-0347-0003.pdf
Definitions:
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.
http://www.fluorideaction.org/pesticides/flumioxazin.abstracts.htm
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.
http://www.fluoridealert.org/pesticides/fluorouracil.toxnet.hsdb.htm
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:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15913947&query_hl=19
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.
•
Definitions:
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
http://www.fluoridealert.org/pesticides/flusilazole.pubmed.abstrcts.htm
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
http://www.fluoridealert.org/pesticides/flusilazole.scot.eye.2000.htm
•
Definitions:
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.
Ref: 1992 - INITIAL SUBMISSION: EMBRYO-FETAL
TOXICITY AND TERATOGENICITY STUDY OF INH-6573-39 BY GAVAGE IN
THE RAT (FINAL REPORT) WITH ATTACHMENTS AND COVER LETTER DATED
03-27-92. HASKELL LAB [E I DUPONT DE NEMOURS & CO]. Report
No. NTIS/OTS0535920 from The National Technical Information Service.
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
http://pmep.cce.cornell.edu/profiles/extoxnet/haloxyfop-methylparathion/haloxyfop-ext.html
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.
http://www.epa.gov/opprd001/factsheets/lithium.pdf
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.
http://www.fluoridealert.org/pesticides/noviflumuron.ca.epa.2002.pdf
[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. http://edcenter.med.cornell.edu/CUMC_PathNotes/Neuropathology/Neuropath_II/dev2.html
-- "... 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."
- http://128.100.71.82/neurosurgery/developmental.html
-- "Trisomy 13 Syndrome is
a genetic disorder with onset before birth. It occurs approximately
1/5000 live births. Infants affected with Trisomy 13 tend
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."
-
http://www.trisomy.org/html/trisomy_13_facts.htm
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.
Ref: http://www.kumc.edu/instruction/medicine/pathology/ed/keywords/kw_nephroti.html
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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12963002&dopt=Abstract
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]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10684086&dopt=Abstract
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.
http://www.fluorideaction.org/pesticides/sulfentrazone.ca.epa.2006.pdf
tau-Fluvalinate
- Acaricide, Insecticide - CAS No. 102851-06-9
Teratogenicity studies
on tau fluvalinate in rabbits showed incidences of delayed ossification,
and visceral and skeletal malformations at an overt maternotoxic
dose (125 mg/kg bw). This dose also caused increased numbers of
resorptions and poorer viability of fetuses. No teratogenic effects
occurred at lower doses. No reproduction studies with tau fluvalinate
in other species were submitted and the
compound has to be classified as possibly teratogenic.
No teratogenic effects of the less toxic racemic fluvalinate were
seen in rats. Doses of 10 and 50 mg/kg bw/day were materno- and
fetotoxic.
Ref:
Revised
Summary Report. EMEA/MRL/021-REV1/95. Committee for Veterinary
Medicinal Products. The European Agency for the Evaluation of
Medicinal Products.
http://www.fluorideaction.org/pesticides/tau.fluvalinate.1995.review.pdf
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.
http://www.epa.gov/EPA-PEST/2000/October/Day-20/p27036.htm
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