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.
- Fungicide -
2-generation reproduction study in Sprague Dawley rats
receiving 0, 100, 1,000 or 10,000 ppm benthiavalicarb-isopropyl
in the diet, the parental noobserved adverse effect level (NOAEL)
was 100 ppm based on hepatocyte hypertrophy
at the next higher dose level. The reproductive NOAEL was 10,000
• 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.
• In a developmental
toxicity study in Sprague Dawley rats
receiving 0, 10, 100 or 1,000 mg/kg/day from day 7 to day 19 of
gestation, the maternal
NOAEL was 10 mg/kg/day based on elevated liver and adrenal
weights at 100 mg/kg/day.
The NOAEL for developmental toxicity was 1,000 mg/kg/day.
March 9, 2005. Petition
for the establishment of Tolerances on Imported Grapes and Tomatoes.
Federal Register: March 9, 2005.
lambda - Insecticide - CAS No. 91465-08-6
Abstract (2003). Icon
is a water miscible type II synthetic pyrethroid insecticide based
on active ingredient lambda cyhalothrin
(10% w/w). It is used in Sri Lanka as an adulticidal indoor spray
against malaria vector mosquitoes. The goal of this study was
to assess the effects of Icon on pregnancy outcome of rats when
exposed during early pregnancy (days 1-7). Icon was gavaged daily
for 7 consecutive days in three different doses; 63, 83, or 125
mg/kg/day (active ingredient; lambda cyhalothrin; 6.3, 8.3, 12.5
mg/kg/day), respectively. Several parameters of reproduction and
pre- and post-natal development were monitored. The
results show that Icon is detrimental to pregnancy outcome (in
terms of quantal pregnancy, number of uterine implants, implantation
index and foetal deaths) but induced no detectable developmental
defects. The anti-reproductive effects of Icon were mainly due
to increased pre-implantation losses. Enhancement of post-implantation
losses played a subsidiary role. These effects resulted from multiple
mechanisms: maternal toxicity, stress, uterotropic activity and
embryo-foetotoxicity. Further progesterone had a protective effect
against Icon induced anti-reproductive actions.
Overall, the results suggest that exposure to Icon during early
gestation may result in a threat to pregnancy.
Ref: Effects of Icon, a pyrethroid
insecticide on early pregnancy of rats; by Ratnasooriya
WD, Ratnayake SS, Jayatunga YN. Hum Exp Toxicol. 2003 Oct;22(10):523-33.
AIM: To assess the effect of ICON (trade name of lambda-cyhalothrin)
on sexual competence and fertility of male rats.
METHODS: Male rats were gavaged daily for 7 consecutive days with
different doses of ICON (63 mg/kg and 100 mg/kg) or vehicle (distilled
water). Their sexual behaviour and fertility were evaluated at
different time points during treatment and post-treatment using
RESULTS: Treatment had no effect on fertility, but sexual
competence was seriously impaired: libido (assessed in
terms of pre-coital sexual behaviour, and numbers of mounting,
intromission and ejaculation), sexual arousability/motivation
(in terms of latencies for mounting, intromission and ejaculation),
sexual vigour (judged by frequencies of mounting and intromission
or copulatory efficiency). In addition,
ICON suppressed intromission ratio, indicating erectile dysfunction.
These effects on sexual function had a rapid onset and was reversible.
ICON-induced sexual dysfunction was mediated by multiple mechanisms,
mainly toxicity, stress, sedation and possibly via GABA and dopaminergic
CONCLUSION: Exposure to ICON may cause sexual
dysfunction in male rats.
Ref: Effects of pyrethroid insecticide ICON
(lambda cyhalothrin) on reproductive competence of male rats;
by Ratnasooriya WD, Ratnayake SS, Jayatunga YN. Asian J Androl.
2002 Mar;4(1):35-41. Full free text available at
21) - Propellant,
EPA List 2 Inert - CAS No. 75-43-4
CFC-21 has produced "pre-implantation" loss in pregnant rats exposed
at 10,000 ppm. After exposure for 6 hr daily, on days 6 to 15
of gestation, 15 or 25 pregnant females had no viable fetuses
or implantation sites on the uterine wall. Pregnancy outcome and
fetal development in the other 10 rats were unaffected.
[American Conference of Governmental Industrial Hygienists, Inc.
Documentation of the Threshold Limit Values and Biological Exposure
Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991.
Ref: TOXNET profile from Hazardous
Substances Data Base for DICHLOROFLUOROMETHANE
Reproductive Hazard. Dichlorofluoromethane
may damage the developing fetus.
Ref: HAZARDOUS SUBSTANCE FACT SHEET. RIGHT
TO KNOW PROJECT.
Produced by: New Jersey Department of Health and Senior Services.
Provided by: Canadian Centre for Occupational Health and Safety.
- Herbicide - CAS No. 55283-68-6
-- Ethalfluralin is
also a developmental toxicant based
on a rabbit study... Dutch Belted rabbits were given 0, 25, 75,
150, or 300 mg/kg/day of ethalfluralin by gavage on gestation
days 6-18. The NOELs for maternal and developmental toxicity were
75 mg/kg/day. The maternal LOEL at 150 mg/kg/day was based on
abortions and decreased food consumption. These effects as well
as decreased weight gain, enlarged liver, and orange urine were
found at 300 mg/kg/day. In this study developmental toxicity was
observed. The developmental LOEL was 150 mg/kg/day, based on slightly
increased resorptions, abnormal cranial
development, and increased sternal variants. (MRID 00129057)...
Since developmental toxicity is the toxicological effect to which
high end exposure is being compared in this analysis, the DRES
subgroup of concern is females (13+ years) which approximates
women of child-bearing age.
Ref: US EPA Reregistration Eligibility Decision
(RED) Ethalfluralin. EPA 738-R-95-001. March 1995.
Acaracide, Insecticide, Wood Preservative -
Reproductive and developmental toxicity. The
developmental toxicity NOELs in the rat
and rabbit were 20 mg/kg/day (HDT) and 1 mg/kg/day (HDT),
Maternal toxicity was observed in the rat at the HDT as evidenced
by decreased body weight gain and
food efficiency. In
the rabbit, the maternal toxicity
NOAEL was less than 0.1 mg/kg/day, based
on reduced body weight gain and food efficiency at all
dose levels tested. In a two-generation
rat study, the NOEL for parental
(systemic) toxicity was 3 ppm (0.26 mg/kg/day for both sexes combined),
based on increased weight of the thyroid glands and liver
in males and females, decreased weight
of the pituitary gland in females, and
an increased incidence of follicular epithelial hypertrophy
in females at 30 ppm. The NOEL for reproductive toxicity
was 30 ppm (2.64 mg/kg/day for both sexes combined), based on
clinical signs of toxicity in pups, decreased
litter size, decreased pup body weights, decreased mating, decreased
fertility index, reduced pre- and postnatal survival, and delays
in physical development at 300 ppm (26.03 and 28.40 mg/kg/day
for males and females, respectively).
a developmental neurotoxicity study in the rat,
the NOAEL for maternal toxicity was 10 ppm
(0.91 mg/kg/day), based on decreased body weights and body
weight gain at 200 ppm (HDT; 15 mg/kg/day).
Considerable maternal toxicity at the HDT prevented adequate
neurotoxicity evaluation of pups at this dose level. There
was no evidence of neurotoxicity at 10 ppm (0.91 mg/kg/day), which
was the NOAEL for developmental neurotoxicity. The
NOAEL for general developmental toxicity was 0.5 ppm (0.05 mg/kg/day),
based on systemic effects consisting of decreases
in pup weights during lactation and increases in time of preputial
separation in males at 10 ppm.
Ref: August 24, 2005. Federal Register.
Fipronil; Notice of Filing a Pesticide Petition to Establish a
Tolerance for a Certain Pesticide Chemical in or on Food.
Abstract: The purpose
of the present study was to investigate possible reproductive
adverse effects of fipronil (Frontline TopSpot)
in female Wistar rats. The pesticide
was topically applied to rats (single dose) at different concentrations
(70, 140 and 280 mg/kg) and hormonal analysis, estrous cycle,
and pregnancy and outcome data were determined. Treatment
with fipronil altered cyclicity of
female rats lengthening the estrous cycle (days) after a single
topic administration of 70 mg/kg (9.7+/-1.18) or 280 mg/kg (14.5+/-1.45)
when compared to control (4.8+/-0.17). In
the mating study fipronil reduced
the pregnancy index (67%) in the highest
dose group (280 mg/kg). Plasma progesterone and estradiol
levels, obtained in different periods after treatment with fipronil
(70 mg/kg), were significantly different 96 h after treatment,
when compared to controls. In summary, the results of the
present study indicate that fipronil may alter the normal functioning
of the endocrine system and cause adverse reproductive effects
in female rats.
Reproductive adverse effects of fipronil in Wistar rats. Ohi M,
Dalsenter PR, Andrade AJ, Nascimento AJ. Toxicol Lett. 2004 Jan
- Herbicide - CAS No. 104040-78-0
• Target / critical effect - Developmental
toxicity: Developmental effects at maternal toxic doses
(foetal mortality, reduced foetal weight,
skeletal variations) in rats. Lowest relevant developmental
NOAEL / 100 mg/kgbw/day.
Insecticide - CAS No. 158062-67-0
In the multigeneration rat reproduction study, the NOAEL
was 300 ppm for both parental animals (13.5-32.8 and 16.3-67.0
mg/kg/day, respectively, for males and females) and their offspring.
The effects at the highest dose of 1,800 ppm included the following:
Increased kidney weights and gross and histopathological alterations
in the kidney. Findings noted in
the top dose females included delayed vaginal
opening and increased liver, kidney and
spleen weights in the F1 generation and reduced
ovary and adrenal weights
in the parental generation and decreased
uterine weights in the F1 female weanlings. There was an
increase in the follicle stimulating hormone
(FSH) and luteinizing hormone (LH) levels in F1 females
tested for these endpoints.
-- Endocrine disruption. No special
studies investigating potential estrogenic or other endocrine
effects of flonicamid have been conducted. Some
suggestions of possible endocrine effects were reported at the
highest dose tested (1,800 ppm) in the multi-generation reproduction
study which showed increased FSH and LH levels, a delay in
the time to vaginal opening in the F1 generation, and reduced
ovary and adrenal weights in the parental generation. However,
there were no effects on reproductive performance
or survival of the offspring in the study. At levels that are
expected to be found in the environment, flonicamid will not cause
any endocrine-related effects.
Federal Register. Jully 7, 2004. Flonicamid; Notice of Filing
a Pesticide Petition to Establish a Tolerance for a Certain Pesticide
Chemical in or on Food. [OPP-2004-0132; FRL-7362-5].
Reproduction and fertility effects (rats).
Offspring NOAEL is 300 ppm (equivalent to 22.3/26.5mg/ kg/day
[M/F]. LOAEL is 1,800 ppm(equivalent to 132.9/153.4 mg/kg/day
[M/ F] based on decreased absolute and relative to body uterus
weights and delayed sexual maturation
in the F1 females
Reproduction rat. Parental LOAEL = 22 mg/kg/day based on increased
kidney weights, kidney
hyaline deposition, increased blood
serum LH (F1 females).
developmental toxicity (rats).
-- Developmental: NOAEL is 100 mg/kg
bw/day. LOAEL is 500 mg/kg bw/day, based on the increased
incidence of cervical rib
is 100 mg/kg bw/day. LOAEL is 500 mg/kg bw/day, based on increased
liver weight, and liver
and kidney pathological changes
(hypertrophy of centrilobular hepatocytes
in liver and vacuolation of proximal tubular cell in kidneys)
August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule.
- Herbicide - CAS No. 79241-46-6
Toxicity Studies: Chronic toxicity studies in rodents
have shown liver changes (cellular hypertrophy). The No Effect
Level (LEL) in rats is 10 ppm (0.5 mg/kg/day). Long term feeding
studies in dogs produced a range of potentially serious effects
at high dose rates (red cell, bone marrow and lymphadenopathy
changes and liver and spleen damage) with a No Effect Level of
25 mg/kg/day. Target Organs: Liver,
skin, kidney, eye, bone marrow, blood, reproductive
Ref: Material Safety Data Sheet for Fusilade
DX (active indredient Fluazifop-P-Butyl). Syngenta. January 21,
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
Euopean Commission. Appendix 5. Substances which may not be included
as active ingredients in approved pesticide products, Chapter
15, Section 2, subsection one.
- Insecticide - CAS No. 272451-65-7
of a reproductive toxicity study in rats (exposure route not stated):
1. Delayed sexual development
(preputial separation) in the 50
(considered incidental), 2000, and 20000 ppm F1 parental males.
2. Decreased sperm head count per testis
in F1 parental males
3. Increased incidence of eyeball enlargement
and dark-colored liver in 2000 and 20000 ppm F1 and F2
4. Thyroid, liver, uterine, thymus, and
spleen weight changes in 2000 and 20000 ppm F1 and F2 pups.
Ref: TSCA Health & Safety Study
Cover Sheet "Public Display Copy"
document was cited at EPA's
site: "TSCA 8(e) and FYI Submissions Received from 11-15-04-11-26-04".
It is important to note this as the document itself does not identify
flubendiamide or its CAS No.
study was conducted in the laboratory of The Institute of Environmental
Toxicology - Japan
•• Source of Data/Study
Sponsor: Bayer Material Science Corporation, 100 Bayer Road, Pittsburg
- Herbicide - CAS No. 2164-17-2
E. Endpoint Selection or Dose/Response
1. Acute Reference Dose For the general population, no study exists
to determine effects from a single dose. Therefore there is no
acute reference dose for the general population. However, for
females age 13+ (women of child bearing years) there is a study
to support this reference dose. In the rat
developmental toxicity study (83-3aYMRID 00163710), dose
levels of 10, 100, and 1000 mg/kg/day were administered via gavage
on days 6-15 of gestation. The NOAEL/LOAEL for developmental toxicity
were 10/100 mg/kg/day, based on delayed
urinary system development (23/83 [28%] vs. 9/82 [11%]
controls). The urinary system of the fetus
forms at specific time points during development and therefore
could be adversely affected from a single exposure during gestation.
Delayed urinary development would not be
recognized until later during growth. Maternal NOAEL/LOAEL
was 10/100 mg/kg/day, based on decreased food consumption (high-dose:
8%-23% from Day 10 to Day 20 of gestation) and an increased
incidence of darkened spleens (mid: 7/27 [26%]; high: 24/27
[89%], controls: 0/27). An uncertainty factor of 100 (1 OX for
interspecies extrapolation and 1OX for intraspecies variability)
February 1, 2005. US EPA: Fluometuron: Revised HED Risk Assessment
for Phase III of the Reregistration Eligibility Decision. Docket
Identification Number: OPP-2004-0372-0008.
on for all fluorinated pesticides)
• Twenty three mated Sprague-Dawley female rats/group were
dosed orally by gavage with 0, 5, 60 or 700 mg/kg/day from gestation
day 7 through gestation day 20. The mean body weight gain of the
700 mg/kg dams was less than that of the control between days
7 and 21. The mean fetal body weight of the 700 mg/kg offspring
was less than the control value (p<0.05). The
mean crown-rump length of the 700 mg/kg fetuses
was less than the control value (p<0.05). No adverse
effect indicated. Maternal NOEL: 60 mg/kg/day (based on the lower
body weight gain of the 700 mg/kg group); Developmental NOEL:
60 mg/kg/day (based on the lower mean body weight and crown-rump
length of the fetuses in the 1000 mg/kg group).
• Four mated female SpragueDawley rats/group
were dosed orally by gavage with 500 or 1000 mg/kg/day from day
7 through day 20 of gestation. The vehicle was aqueous 1% (w/v)
methyl cellulose. The number of live fetuses/litter was inversely
affected with 13.0 for the 500 mg/kg group and 9.3 for the 1000
mg/kg group. The mean fetal weight and crown-rump
length for the 1000 mg/kg offspring were 2.78 g and 32.6
cm as compared to 3.12 g and 34.1 cm for the 500 mg/kg group.
There was an apparent treatment-related effect upon both
the dams and the development of the fetuses in the 1000 mg/kg
• Rabbit Oral Developmental Toxicity (Teratogenicity) Study
(Including Addendum). Twenty three mated female Himalayan rabbits/group
were dosed orally by gavage with 0, 5, 20 or 60 mg/kg/day from
day 6 through day 28 of gestation. Three does in the 60 mg/kg
group died during the study. Fifteen does in the 60 mg/kg group
and 1 doe in the 20 mg/kg group delivered their offspring prematurely.
The mean food consumption of the 5 does in the 60 mg/kg group
which delivered live fetuses was less than that of the control
during the last 6 days of the treatment (p<0.05). The
mean body weight and crown-rump length of the
fetuses in the 60 mg/kg group were less than the respective control
values (p<0.05). Developmental NOEL: 20 mg/kg/day (based
upon the lower mean body weight and the crownrump length of the
fetuses in the 60 mg/kg/day group).
Ref: Fluopicolide: summary of toxicology
data. California EPA, Department of Pesticide Regulation, Medical
Toxicology Branch. May 2, 2007.
Insecticide - CAS
known as Fluoroacetamide or Compound 1081)
AN ORAL DOSAGE OF 15 MG/KG ... INTERFERES
WITH REPRODUCTION IN FEMALE MICE, WHETHER ADMIN 2 DAYS
BEFORE OR 10 DAYS AFTER FERTILIZATION; PREGNANCY
WAS PROLONGED, PRENATAL MORTSEITY WAS INCR, & THE YOUNG SUFFERED
FROM CYANOSIS, RESPIRATORY DISTRESS, REDUCED GROWTH, & DECR SURVIVAL.
[Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide
Toxicology. Volume 3. Classes of Pesticides. New York, NY: Academic
Press, Inc., 1991. 1279]
FLUOROACETAMIDE CASRN: 640-19-7. Hazardous Substances Data Bank.
- Herbicide - CAS No. 61213-25-0
61213-25-0 Withdrawn. Reproductive effects
in experimental animals. 1989.
" 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
insect chemosterilant; now used as a chemotherapeutic drug-
CAS No. 51-21-8
or other effects on newborns were reported in offspring of women
receiving 150 or 240 mg/kg fluorouracil intravenously during weeks
11 to 14 or 20 to 31 of pregnancy. In addition, maternal toxicity
to the reproductive organs, toxicity to the fetus, and developmental
abnormalities have been reported in mice, rats, and hamsters receiving
oral, intraperitoneal, or intramuscular doses of fluorouracil
ranging from 10 to 700 mg/kg.
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.
based dose-response (BBDR) models are a way to incorporate mechanistic
information into dose-response assessment. The chemotherapeutic
drug 5-fluorouracil (5-FU) has been used as a prototypic compound
for the construction of a BBDR model for
developmental toxicity (Shuey et al. 1994). Previous work
(Lau et al. 2000) has provided data and a general mechanistic
framework for the development toxicity of 5-FU when it was administered
to pregnant rats subcutaneously on gestation day 14. Here we develop
a mathematical model relating maternally administered dose to
embryonal thymidylate synthetase (TS) inhibition, and thymidylate
synthetase inhibition to various measures of deoxyribonucleotide
(dNTP) pool perturbation, and estimate parameters and the uncertainty
of subsequent predictions using the previously collected data.
The strategy used was to develop semi-empirical submodels for
5-FU pharmacokinetics, 5-FU metabolism and TS inhibition, and
nucleotide pool perturbation, and to estimate model parameters
from the dose-response data described in Lau et al. (2000). Even
for the relatively simple models described here, not all parameters
could be uniquely estimated using data from dose-response and
time-course studies, and some values had to be assigned based
on plausible guesses. The models developed predict that even minimal
doses of 5-FU should result in some perturbation of dNTP pools.
In particular, the relationship between dNTP pool perturbation
and fetal weight deficit suggests that if there is a biological
threshold for the effect of 5-FU on fetal weight, the responsible
repair or compensation mechanism must be downstream of dNTP pool
perturbation, and saturable at 5-FU doses lower than 10 mg/kg,
the lowest dose examined for developmental effects in these studies.
Ref: Setzer RW et al. (2001). Creating a
biologically-based dose-response model for developmental toxicity
of 5-fluorouracil in the rat. Toxicologist 2001 Mar;60(1):145.
As cited on Toxnet.
- Fungicide - CAS No. 193740-76-0
decreased body weights, delayed
preputial separation*, and incomplete ossification in the
F1 and/or F2 males and females. Parental
premating body weight gain of the P-generation males and females
and decreased premating absolute body weight of
the F1 males and females.
Federal Register. September 16, 2005. Fluoxastrobin; Pesticide
Tolerances. Final Rule.
*Note: Preputial separation is an indicator of sexual maturation
- Fungicide -
CAS No. 85509-19-9
-- Ten developmental toxicity studies were carried out with flusilazole,
six in the rat (one dietary, four gavage, and one dermal) and
four in the rabbit (one dietary and four gavage). In rats, maternal
toxicity included decreased weight gain and food consumption,
increased clinical signs, and increased liver weights. Fetal toxicity
was evidenced by increased incidences of
resorptions, fetal mortality, stunted fetuses, and skeletal variations
(delayed ossifications, supernumerary ribs, and renal pelvis variations)
and decreased fetal weight. Absent
renal papillae occurred at 10 mgkglday and above and cleft palate
occurred at 250 mgkg/day. Taken as
a whole, the NOEL in rats was 0.5 mg/kg/day by the oral route.
By the dermal route 2 mg/kg/day was near a NOAEL based on only
placental, but no fetal effects at this dose. (- In a rabbit dietary
developmental study the NOEL for the dam was 21.2 mg/kg/day and
the developmental NOEL was 2.8 mgkg/day based on decreased litters
and increased resorptions. In the first two rabbit gavage studies,
the maternal and offspring NOELS were both 12 mg/kg/day. In the
second there were increased total resorptions
and one malformation (hydrocephaly) at 35 mg/kg/day. In
the final rabbit gavage study, the maternal NOEL was 7 mgkglday
based on increased clinical signs as 15 mgkglday. The developmental
NOEL was 15 mg/kg/day based on increased resorptions at the high
dose. Taken as a whole, the rabbit maternal NOEL via the gavage
route is 7 mgkg/day and the developmental NOEL is 15 mgikglday.
-- In the feeding study, dietary concentrations were 0,50, 100,
300 and 900 pprn (MRID 00072999). Maternal food consumption was
reduced at ≥300 pprn during treatment and maternal body
weight gains were reduced at 900 ppm. The number
of resorptions was significantly increased at the two highest
doses and litter size was reduced at the highest dose.
There was a significant dose related increase
in stunted fetuses, significant at ≥300 ppm. There
were no dose-related incidences of malformations. The
incidence of variations (supernumerary and delayed ossifications)
was increased at ≥ 100 ppm. The maternal NOEL was
100 pprn - (9 mgkgiday). EPA considered
the developmental NOAEL to be 100 ppm (9.0 mg/kg/day) and li the
NOEL for malformations to be > 900 pprn (79.2 mg/kg/day) the
highest dose tested. (Page
-- In the first of three rat gavage studies, flusilazole was administered
by gavage (in corn oil) at concentrations of 0, 10,50 and 250
mgikgiday (MRID 00161 169). Maternal morality and clinical signs
occurred at 250 mg/kg/day. Weight gain and food consumption were
decreased and liver weight increased at ≥ 50 mg/kg/day group
during dosing. In the 250 mg/kg/day group mean fetal body weight
was reduced; the incidence of resorptions increased; and the number
of live fetuses per litter were reduced. The number of live fetuses
was also decreased in the intermediate group. There was a significant
increase in malformations (cleft palate and absent renal papillae)
at the maternally toxic dose, 250 mg/kg/day. There was
an unusually high incidence of external
hydrocephaly and distended lateral ventricles in all groups (including
controls). However, this finding did not exhibit a definitive
dose response and was not reproduced in another study over a similar
dose range. Increased fetal variations in
all dosed groups were misaligned sternebra, extra ossifications,
rudimentary and extra ribs and delayed development consisting
of partially ossified sternebra and vertebral arch. The
maternal NOEL was 10 rng/kg/day and no fetal NOEL was established
(< 10 mg/kg/day). (Page
-- In the second gavage study, flusilazole was administered to
rats at doses of 0,0.4,2, 10, 50, and 250 mg/kg/day (MRID 00161170).
Maternal findings at 250 mg/kg/day were reduced feed consumption
and weight gain and increased liver weights. At 50 mg/kg/day,
there was a significant decreased food consumption and weight
for the first two days but not thereafter. Relative liver weight
was increased also at 50 mg/kg/day. A non-statistically
significant increase in stunted fetuses occurred at 2 10 mgkglday.
There was a statistically significant increase
in malformations (cleft palate) in the maternally toxic, high-dose
group. The incidence of total malformations
(mostly absent renal papillae) and fetal variations were significantly
increased at ≥ 10 mg/kg/day. The maternal NOEL 10
mgkg was based on reduced weight gain, liver weight increases
and clinical signs. The developmental NOEL
was 2.0 mgkg, based on increased incidence of skeletal variations.
-- The third rat developmental gavage study,
was conducted to resolve the biological significance and potential
reversibility of the changes to the urinary system (small or no
papillae, large renal pelvi and dilated ureter) seen in the previous
study (MRID 40640704). Rats were dosed with 0, 0.2,0.4,2, 10,
and 100 mg/kg/day and either sacrificed at gestation day 21 or
22 to examine fetuses (Phase 1) or dams were allowed to deliver
and raise their young to weaning (Phase 2). Maternal toxicity
was evidenced at the high dose in both phases as decreased food
consumption and reduced weight gain, clinical signs (Phase 1 only),
and death (Phase 2). Minimal maternal toxicity (reduction in weight
gain during Phase 2) occurred 10 mg/kg/day. Fetal
effects consisted of increased incidence of resorptions and stunted
fetuses (100 rng/kg/day), increased numbers of fetuses dead at
birth, and lower neonatal survival. In the fetal examinations
there was an increased incidence of small renal papillae, dilated
ureters and subcutaneous hemorrhage at 2 10 mg/lkg/day and bladder
foci at 100 rng/kg/day. There were no apparent treatment-related
malformations. The maternal and reproductive/developmental
was NOAEL 2.0 mg/kg/day. (Page
-- In the fourth rat gavage study (MRID 45042601), rats were dosed
with 0,0.5,2, 10, or 50 mg/kg/day flusilazole on one of the following
three schedules: days 6-15G (gestation) and sacrificed day 16G,
days 6-15G and sacrificed day 21G, or 6-20G and sacrificed on
day 21G. - Results were generally similar between the three designs.
Maternal weight gain was affected at ≥10 mg/kg/day. Red
vaginal discharge was observed at 2 mg/kg/day. Placental weights
were increased at 22 mg/kg/day. Fetal weights were affected
at 50 mg/kg/day only in the group dosed from 6-15G and sacrificed
at 21G. Fetal resorptions were increased at 210 mgkglday.
Fetal variations were increased at ≥2 mg/kg/day.
At 50 mg/kg/day there was one malformation
(naris atresia). The NOEL
for the study was 0.5 mg/kg/day based on minimally increased incidence
of red vaginal discharge, increased placental weight and increased
fetal variations at 2 mg/kg/day. (Page
-- In a rat dermal developmental toxicity study (MRID 44594201),
flusilazole was applied to the skin of pregnant rabbits for six
hourslday on days 6 to 19 of gestation at doses of 0, 2, 10, 50,
and 250 mg/kg/day. Rats were sacrificed on gestation day 20. Mean
maternal weight gains were greatly reduced in the 250 mg/kglday
group. There were no abnormal clinical signs at any concentration.
Microscopic examination of the dams' livers revealed minimal to
mild centrilobular hepatocellular hypertrophy at ≥ 10 mg/kg/day.
There were enlarged placenta observable at ≥ 10 mg/kg/day
and microscopic placental changes at all dose levels. There
were no other maternal effects at 2 mg/kg/day.
Fetuses of dams treated with ≥ 10 mg/kg/day had enlarged
livers and increased variations (rudimentary ribs and unossified
sternebra). The lowest dose (2 rng/kg/day) was considered
to approximate a NOAEL with the only effect being microscopically
observable placental changes. It was not
established whether the effect on placenta represent an adverse
effect. Since placenta contains a large amount of cytochrome P-450
enzymes, the possibility of a metabolic/adaptive role should be
considered. (Page 22)
the effects of flusilazole on reproductive
parameters were investigated in one single-generation and two
multigeneration studies. In the single-generation study, there
were effects on pup viability and weights. In the first multigeneration
study, there was no parental toxicity demonstrated at doses up
to 250 ppm. Offspring findings, mostly at the high dose level
included reduced number of live pups at birth and reduced viability
during lactation. The NOEL r- for this study was 50 ppm based
on perinatal effects. The same dose levels were used in the second
study. Minimal signs of treatment-related effects seen in the
50 (not significant) and 250 pprn parental animals consisted of
body weight effects in parental females. A
significant increase in gestation length and periparturient deaths
occurred in the high dose group. This finding was consistent
with reduced viability of pups at birth. In addition, pups did
not thrive and reduced weight gain and survival was recorded for
litters of dams fed 250 pprn in all matings. The NOEL for reproductive/offspring
effects was 50 ppm. (Pages 20-21)
DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma
(Active ingredients: Flusilazole and Famoxadone): Summary
of data compiled in support of a Section 18 Emergency Exemption
request for control of Asian soybean rust on soybeans. By DuPont
authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A,
Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck
V. Revision No. 1: February 2, 2005.
fish early life-stage tests provide useful information on sensitive
life stages of fish, for flusilazole
in particular the risk assessment has explicitly identified fish
and other aquatic species to be at risk from agricultural use
of this a.s., and there is evidence that flusilazole may
have specific effects on the reproductive process. Therefore
the SCP cannot conclude that a NOEC based on a fish early life-stage
test for a single species is necessarily adequate in this particular
case to ensure sufficient protection of fish populations from
adverse effects on reproduction.
-- The monograph (volume 3, pp. 230-233) identified aquatic species,
and fish in particular, as possibly at risk from flusilazole.
In addition, a dose-dependent decrease in
serum estradiol levels by flusilazole, considered to be indicative
of aromatase inhibition, was observed in
studies with rats (volume 3, p. 73). Aromatase
inhibition is significant for reproduction since aromatization
of testosterone is the process by which oestrogen is formed in
vertebrates (Trant et al. 1997). This reaction is mediated
by the cytochrome P450 aromatase. It has been shown that oestrogen
(i.e., oestradiol) plays a major role in the reproductive physilogy
of all vertebrates, including gamete development and maturation,
and induces the hepatic synthesis of the yolk precursor, vitellogenin.
Studies in which fish have been exposed to aromatase inhibitors
suggest that aromatase activity, specificity or expression levels
vary with maturation stage and among species (Bl‡zquez et al.
2001, Zerulla et al. 2002).
-- ... Neither of the above tests was designed to investigate
possible effects on reproductive output or mating behaviour of
adult fish. Given that there is evidence that flusilazole is an
aromatase inhibitor, there are specific concerns that reproduction
could be adversely affected by this substance. Therefore potential
effects on mating behaviour, time to sexual maturity, reproductive
output and timing, fertilisation success, and sex ratio of offspring
are also of concern and should be explicitly addressed by a test
designed for this purpose.
Ref: July 2002 - Opinion of the
Scientific Committee on Plants on specific questions from the
Commission concerning the evaluation of flusilazole in the Council
Directive 91/414/EEC. European Commission. Health & Consumer Protection
- Insecticide - CAS No. 76703-62-3
Reproduction - Rat (Cyhalothrin; Lambda cyhalothrin
and Gamma cyhalothrin).
Parental NOAEL: 1.5 mg/kg/day; Parental
LOAEL: 5.0 mg/kg/day
(decreased parental body weight and body weight gain during premating
and gestation periods).
Reproductive NOAEL: 5.0 mg/kg/day; Reproductive LOAEL: Not established.
Offspring NOAEL: 1.5 mg/kg/day
Offspring LOAEL: 1.5 mg/kg/day
(reduced pup weight and weight gain during lactation).
April 8, 2004. Federal Register. Lambda-Cyhalothrin and Gamma-Cyhalothrin.
Tolerances for Residues. FINAL RULE.
- Herbicide, Wood Preservative -
CAS No. 17029-22-0
Developmental or Reproductive Toxin
Note: Hexaflurate is an inorganic Arsenic compound.
Ref: PAN Pesticides Database - Chemicals
- Mutagenicity There
are five acceptable mutagenicity (84-2) studies of hydramethylnon.
The findings of adverse effects on spermatocyte
and/or spermatogonia in the dominant lethal assay are consistent
with the results of the 2-generation reproduction study in rats
showing that hydramethylnon is a reproductive
toxicant which appears to specifically target the germinal cells
and/or tissues in the testes.
- On May 28, 1998, the AgencyÕs Cancer Peer Review Committee
concluded that the dose levels of 100 ppm in males, and 50 ppm
in females were adequate to assess the carcinogenic potential
of hydramethylnon in rats.... The statistically
significant increases in tumors observed in the uterus (adenomatous
polyps) and adrenals (medullary adenomas) were not considered
to be biologically significant since they were seen at excessive
doses (i.e., at 200 ppm). Under the conditions of this study,
the NOAEL was 50 ppm (2.4 mg/kg/day in males, 3.0 mg/kg/day in
females), and the LOAEL was 100 ppm (4.9 mg/kg/day in males, 6.2
mg/kg/day in females) based on small, soft
testes, decreased testicular weights, and testicular atrophy in
males; and decreased body weight gain in females. This
study is classified as acceptable and satisfies guideline requirement
83-5 for a chronic feeding/carcinogenicity study in rodents.
- In a carcinogenicity study, MRID 00101563, groups of 50 male
and 50 female Charles River CD-1 mice received diets containing
hydramethylnon at dose levels of 0, 25, 50, 100, or 200 ppm (0,
3.57, 6.93, 14.2, or 28.6 mg/kg/day in males, and 0, 4.45, 6.87,
17.3, or 33.1 mg/kg/day in females, based on food consumption)
for 18 months. The 200 ppm males and females were sacrificed after
55 weeks because of high mortality. Survival after 18 months at
the 50 and 100 ppm doses was 72% and 46% in males, and 66% and
46% in females (compared to control survival of 86% in males and
76% in females)... Histopathologic findings of testicular degeneration
in the 50, 100, and 200 ppm males displayed a
dose-related pattern of incidence and severity, and included hypospermia,
interstitial cell hyperplasia of Leydig cells, and germinal cell
- Mutagenicity There are five
acceptable mutagenicity (84-2) studies of hydramethylnon. The
findings of adverse effects on spermatocyte
and/or spermatogonia in the dominant lethal assay are consistent
with the results of the 2-generation reproduction study in rats
showing that hydramethylnon is a reproductive
toxicant which appears to specifically target the germinal cells
and/or tissues in the testes.
Ref: US EPA. Reregistration Eligibility
Decision (RED) Hydramethylnon. EPA 738-R-98-023. December 1998.
- Insecticide - CAS
-- Developmental neurotoxicity - rat. Acceptable/non-guideline
0, 0.5, 1.0, 1.5, or 3.0 mg/kg/day.
Maternal systemic/neurotoxicity NOAEL
= 1.5 mg/kg/day LOAEL = 3.0 mg/kg/day, based on the adverse
clinical signs observed, decreased body-weight gain and food consumption
NOAEL= 1.5 mg/kg/day LOAEL = 3.0 mg/kg/day, based on an increased
incidence of stillbirths, decreased mean pup body weight at birth
and increased pup mortality during PND 1-4 in males and
females, and increase in number of learning
trials to reach criterion and increased latency in males.
Ref: USEPA. May 23, 2007. Indoxacarb. Health
Effects Division (HED) Risk Assessment for Grapes; Vegetable,
Brassica, Leafy, Group 5; Turnip Greens; Vegetable, Leafy, Except
Brassica (Group 4); Pome Fruits (Group 11, except pear); Tuberous
and Corm Vegetables (Subgroup 1C); Cucurbit Vegetables (Group
9); Stone Fruits (Group 12); Cranberry; Mint; Okra; Southern Pea;
and Fire Ant Bait.
- Herbicide - CAS No. 77501-63-4
and fertility effects
Parental/Systemic NOAEL = 2.6 mg/kg/day.
Parental/Systemic LOAEL = 26.2 mg/kg/day based on mortality and
decreased male fertility.
Reproductive NOAEL = 2.6 mg/kg/day.
Reproductive LOAEL = 26.2 mg/kg/day based on decreased
Ref: Sept 24, 2004.
Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
and its potassium and diethanolamine salts - Herbicide,
Plant growth regulator - CAS Nos. 53780-34-0,
Developmental effects of Mefluidide in rats included increased
number of early resorptions and mean postimplantation
loss. These effects were observed at the same dose that
caused maternal toxicity indicating there was no increased susceptibility
to fetuses. The maternal toxicity included tremors, decreased
body weight, weight gain and mortality. In rabbit, the LOAEL/NOAEL
for developmental toxicity were above the highest dose tested
(60 mg/kg/day). In the 2-generation reproduction toxicity study,
the offspring toxicity was characterized by decreased body weights
in both sexes and both litters in all generations. The reproductive
LOAEL was not observed (NOAEL = 346/604 mg/kg bw/day).
USEPA. Mefluidide - Toxicology
section for the Reregistration Eligibility Decision Document (RED)
(January 31, 2007)
(BAS 320 I) - Insecticide
Reproductive and developmental
a 2-generation reproduction toxicity study in Wistar
rats by oral gavage administration. Originally, the highest
dose tested (HDT) by oral gavage was 75 mg/kg b.w./day, which
induced both excessive maternal toxicity
(very high incidences of poor general health in females during
premating, gestation, and lactation; and statistically decreased
food consumption, body weights, and body weight gain) as well
as excessive developmental toxicity (statistically
impaired pup body weights and body weight gain), which altogether
resulted in high pup mortality. Consequently, a meaningful
assessment of the potential reproductive toxicity of the test
compound at this excessively toxic dose level was not possible.
Thereafter, for the next two successive parental generations of
rats, which were originally derived from the parents treated at
75 mg/kg b.w./day, the HDT was 50 mg/kg b.w./day. Subsequently,
the no observable adverse effect level (NOAEL) for parental toxicity
was 20 mg/kg b.w./day, based on the following effects for females
at 50 mg/kg b.w./day (HDT for two consecutive generations) increased
incidences of poor general health in females during premating,
gestation, and lactation; 3 of 25 dams with complete litter losses;
and statistically significantly reduced
body weights during premating, gestation, and lactation.
The NOAEL for offspring/pup toxicity was 20 mg/kg b.w./day, based
on a slight increased incidence of pup mortality at 50 mg/kg b.w./day.
Whereas the NOAEL for fertility in this study was 50 mg/kg b.w./day
(HDT for two generations), the NOAEL for
reproductive performance was considered to be 20 mg/kg b.w./day,
based on 3 of 25 dams with complete litter losses, of which
2 of these 3 dams had indications of poor nursing for their first
generation of pups.
Ref: October 27,
2004. Federal Register. Pesticide
- Insecticide - CAS No. 116714-46-6
Excerpt from Table 1.--Subchronic, Chronic, and
-- Reproduction and
fertility- rat. NOAEL (M/F)= 74.2>=1009.8
mg/kg/day; LOAEL= 297.5 mg/kg/ day based
on decreased epididymal sperm counts and
increased age of preputial separation in the F1 generation,
reproductive LOAEL for females was not established.
June 2, 2004. Novaluron; Pesticide Tolerance. Final Rule. Federal
The NOAEL for developmental toxicity was also less than 74.2
mg/kg bw/day on the basis of decreased lactational
body weight gain, and increased spleen and liver weight in both
F1 and F2 pups observed at this dose level. When adult
and offspring spleen weights were compared, adults appeared to
be more sensitive to the effects of treatment. However, the offspring
would have received the treatment (via milk and a small portion
in diet during the latter portion of the lactation phase) for
21 days only, compared to the parental treatment duration of 17
weeks. The NOAEL for reproductive toxicity was set at 74.2 mg/kg
bw/day on the basis of decreased epididymal sperm count and delayed
sexual maturation in the F1 males at 297.5 mg/kg bw/day. Overall,
Novaluron was not considered to cause selective toxicity to the
developing young. (PAGE 13)
Ref: Proposed Registration Decision. PRD2006-05.
Health Canada Pest Management Regulatory Agency. December 22,
- Insecticide - CAS No. 121451-02-3
-- “XDE-007: One-Generation Dietary
Reproduction Toxicity Study With CrossFostering in CD Rats,”
(Marty, M.S., Zablotny, C.L., Liberacki, A.B., Yano, B.L.;Toxicology
& Environmental Research and Consulting, The Dow Chemical
Company, Midland, MI; Laboratory Project Study ID: 011221; 3/23/04).
XDE -007 (97.9% pure) was fed in diet to Crl:CD (SD) IGS BR rats
(30/sex/dose) at 0, 0.5, 5 and 100 mg/kg/day continuously from
pre-mating (10 weeks) of parental generation, through breeding
(2 weeks), gestation (3 weeks) and lactation through weaning of
F1 offspring. Although designed as a 2 generation
reproduction study, it was terminated after 1 generation due to
excessive F1 pup mortality at 100 mg/kg/day. Subsequently
a Cross-fostering Study was performed to determine whether the
decreased survival in pups from XDE-007 treated P1 rats resulted
from in utero or lactational exposure. Parental Systemic NOEL
= 0.5 mg/kg/day (Tonoclonic convulsions were observed in 2/30
males and 1/24 females at 100 mg/kg/day. Males had statistically
significantly decreased food consumption from day 8 until termination
at 100 mg/kg. Females had statistically significantly decreased
food consumption during lactation. Male
P1 premating body weights were statistically significantly decreased
at 100 mg/kg/day. Mean gestational body
weight gain in females was statistically significantly decreased
GD 0 - 7 (but not GD 0 - 21) and lactation days 7 - 13 at 100
mg/kg/day.) Reproduction and Fertility NOEL = 0.5 mg/kg/day (P1
female gestation survival was decreased and gestation length was
increased at 100 mg/kg. Pup NOEL = 0.5 mg/kg (F1
survival was drastically decreased throughout lactation at 100
mg/kg. Clinical effects were increased in pups at 100 mg/kg,
primarily tonoclonic convulsions, no milk in stomach, entire litter
loss and death. Pup weights were statistically
significantly decreased at 100 mg/kg. Cross-fostering data
indicate the proximate toxicant (either XDE-007 and/or its metabolites)
led to decreased pup survival through the maternal milk and not
through exposure in utero. Possible adverse effect indicated:
excessive neonatal/pup mortality and increased
tonoclonic convulsions in pups (17/24 litters) at 100 mg/kg.
These data are supplemental. M. Silva, 7/20/04
-- “XDE-007: Two-Generation Dietary
Reproduction Toxicity Study in CD Rats,” (Carney,
E.W., Zablotny, C.L., Liberacki, A.B., Yano, B.L.;Toxicology &
Environmental Research and Consulting, The Dow Chemical Company,
Midland, MI; 3/22/04). XDE -007 (97.9% pure) was fed in diet to
Crl:CD (SD) IGS BR rats (30/sex/dose/generation) at 0, 0.5, 5
or 25 mg/kg/day continuously from pre-mating of parental generation
1 (P1) through weaning of offspring through 2 generations (2 matings
for P2 generation) to F2b weaning. Parental Systemic NOEL = 5.0
mg/kg/day (There were increased absolute
and relative liver weights in both sexes of P1 and P2 adults at
25 mg/kg and in P1 female liver weights at 5.0 mg/kg. P1
male relative kidney weights, P2 female absolute kidney weights,
P2 male relative spleen and thyroid weights and P2 female absolute
and relative adrenal weights were increased at 25 mg/kg.) Reproduction
and Fertility NOEL = 5.0 mg/kg/day (There
was an increased proportion of abnormal P2 sperm at 25 mg/kg.
Although not statistically significant, there were decreased mating
and fertility indices in both sexes of P2a and P2b adults at >
5.0 mg/kg.) Pup NOEL = 5.0 mg/kg (There was a decrease
in F1 survival (not statistically significant) on lactation days
14 and 21 at 25 mg/kg. F2a pups had statistically
significantly decreased survival of lactation days 7, 14 and 21at
25 mg/kg. Mean F2a litter size was statistically significantly
decreased on lactation days 14 and 21 at 25 mg/kg. Mean
F1 pup weights were statistically significantly decreased at 25
mg/kg on lactation days 1, 14 and 21. Mean
F2a male pup weights were statistically significantly decreased
on lactation days 1 and 21 and F2a female pup weights were
decreased on lactation day 21 at 25 mg/kg.
F2a male weanlings had statistically significantly decreased body
weights, relative brain and absolute spleen weights at 25 mg/kg.
Neonates at 25 mg/kg in both F1 and F2 generations showed tonoclonic
convulsions, as well as in 1 litter of F2a at 5.0 mg/kg.
P2 females (1, 1, 5 and 7 at 0, 0.5, 5.0 and 25 mg/kg, respectively)
failed to litter, so the female is considered to be an affected
sex.) Possible adverse effects on reproduction, fertility and
pup survival, along with numerous other toxicologically relevant
effects. M. Silva, 6/18/04
August 2005 - Summary of toxicological data. California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
- Insecticide - CAS No. 179101-81-6
reproductive toxicity study
Male: 2.80 mg/kg bw/day
3.11 mg/kg bw/day
3.40 mg/kg bw/day
Female: 3.62 mg/kg bw/day
sexual maturation in females
Report. PYRIDALYL. January 14, 2004. Japan Food Safety
Commission. Pesticides Expert Committee.
- Acaracide, Insecticide - CAS No. 4151-50-2
-- Action Requested: Please define what constitutes human exposure
to an amount of Sulfluramid via this product that may produce
serious personal injury or illness to a 25 lb. child... In the
classical sense, Sulfluramid is not an acute toxin; however, some
of the endpoints observed in the developmental
toxicity studies may result from a one-time exposure;
e.g., the amount of Sulfluramid in one bait
ingested by a child has the potential to cause adverse reproductive
and/or developmental effects as the child develops. Since
the calculated dose to a child is comparable to the LEL's and
greater than all but one NOEL in the oral toxicity studies, no
margin of safety exists in this case.
Ref: August 10, 1994. US EPA memorandum,
"Sulfluramid - Amount of A.I. in Raid Max Roach Bait."
To Mike Mendelsohn, PM Team Reviewer, Registration Division (7505C).
From Linda L. Talor, Ph.D., Toxicology Branch II, Health Effects
Division (7509C) and Marcia van Gemert, Ph.D., Chief, Toxicology
Branch II/HED (7509C). (Copy of this memorandum was requested
and received by Ellen Connett in October 2002 from Michael H.
Surgan, Ph.D., Chief Scientist, Environmental Protection Bureau,
State of New York, Office of Attorney General Eliot Spitzer to
-Fungicide - CAS No. 112281-77-3
Reproduction Study. Rats received
0, 10, 70 or 490 ppm of tetraconazole in the diet for two generations.
F0 and F1 females at 490 ppm had reduced food consumption, and
lower body weights during premating
and gestation, as did F1 males of this group. Increased mortality
(due to dystocia) and
higher liver, kidney and ovary weights were seen in adults of
both generations at 490 ppm. Mating performance and pregnancy
rate for both F0 and F1 generations were not affected. A prolonged
gestation period was associated with dystocia, and total
litter loss in some F0 and F1 females at 70 and 490 ppm. Increased
post-implantation loss and/or fetal deaths and consequently reduced
litter size at birth, and lower pup
weight gain during lactation were observed in F1 and F2
pups at 490 ppm. Offspring at 70 and 490 ppm had a slight
retardation of growth and sexual maturation (delayed vaginal opening
and balanopreputial cleavage). Increased
liver weights were seen in F1 and F2 pups at 490 ppm as well as
female pups at 70 ppm at weaning. No external and internal
abnormalities were found for both F1 and F2 pups. The NOEL was
10 ppm (0.4 mg/kg bw/day) for reproduction and postnatal toxicity.
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
Effects were also seen on reproductive organs in both sexes, most
notably ovaries (in rats) and testes (in rats and mice),
in both the reproductive toxicity and subchronic toxicity studies....
Health Aggregate Risk Assessment for Triazole-derivative Fungicide
Compounds (1,2,4-Triazole, Triazole Alanine, Triazole Acetic
Acid). US EPA, February 7, 2006.
toxicity study-- Rats.
In the 2-generation reproductive toxicity study in rats, the maternal
(systemic) NOAEL was 0.7 mg/kg/day, based on
dystocia, delayed vaginal opening, and increased
liver weight at the LOAEL of 5.9 mg/kg/day. The developmental
(pup) NOAEL was 0.7 mg/kg/day, based on
increased time to observation of balanopreputial skin fold [foreskin]
and liver weight at the LOAEL of 5.9 mg/ kg/day. At the
high dose of 35.5 mg/kg/day, there was a decrease in the mean
number of live pups per litter on lactation days 0 and 4 (precull)
in the presence of significant maternal toxicity.
Ref: Federal Register: December 6, 1999.
Tetraconazole; Pesticide Tolerances for Emergency Exemptions.
Note from EC:
Dystocia. Literally, it
means difficult labor and practically means abnormally slow
progress of labor. The word comes from the Greek 'dys' meaning
'difficult, painful, disordered, abnormal' and 'tokos' meaning
'birth'. Four potential factors may cause difficult labor characterized
by abnormally slow progress. They may occur separately or together.
1) Uterine contractions may be either too weak or too uncoordinated
to open up the cervix. There may also be inadequate pushing
with voluntary muscles during the second stage of labor. 2)
The baby may be lined up wrong to easily pass through the birth
canal. Alternatively, there may be other problems with the baby
that also retard passage of the baby through the birth canal.
3) The maternal bony pelvis may be too
narrow to allow the baby to pass through the birth canal.
4) Abnormalities of the birth canal other than those of the
bony pelvis may obstruct fetal descent. The
most common cause of dystocia is a small bony pelvis and/or
insufficiently strong and coordinated uterine contractions.
- Balanopreputial skin fold-
• Developmental Studies Pregnant
rats received 0, 5, 22.5 or 100 mg/kg bw/day of tetraconazole
by gavage on gestation days 6-15. Post-dosing salivation was noted
in dams at 22.5 and 100 mg/kg bw/day. Increased water consumption
at 100 mg/kg bw/day, and decreased food
consumption and body weight gain at 22.5 and 100 mg/kg
bw/day were observed. Liver and kidney weights
were increased in dams at 100 mg/kg bw/day. There were
no treatment-related effects on embryo/fetal loss, litter size
and sex ratio of pups. Variable fetal weights
within each group at 22.5 and 100 mg/kg bw/day might be associated
with variation in degrees of skeletal ossification. Incidences
of hydronephrosis and hydroureter at
100 mg/kg bw/day were increased. The number
of fetuses with supernumerary rib(s) was higher, and ossification
in skeletons tended to be advanced at 100 mg/kg bw/day.
The NOEL was 5 mg/kg bw/day for maternal toxicity, and was 22.5
mg/kg bw/day for fetal development.
-- Pregnant rabbits received 0, 20, 40 or 80 mg/kg bw/day of tetraconazole
in a preliminary study, and 0, 7.5, 15 or 30 mg/kg bw/day in the
main study, by gavage on gestation days 6-18. Rabbits at 80 mg/kg
bw/day showed minimal to nil food intake, body
weight loss and deteriorated condition, and were sacrificed
on day 7 of dosing showing increased early fetal loss. At 40 mg/kg
bw/day, reduced food intake, body weight
loss, lower fecal output and emaciation occurred during
the dosing period, and increased liver and
kidney weight were observed at necropsy. Abortion, death, post-implantation
loss, and reduced fetal weight were seen in this group.
Food consumption and body weight gain of dams were lower at 30
mg/kg bw/day. Incidences of malformation,
anomalies and skeletal variants were low in all groups. The
NOEL was 15 mg/kg bw/day for maternal toxicity, and was 30 mg/kg
bw/day for fetal growth/development. (page 6)
2005 - Evaluation of Tetraconazole in the product Domark 40ME
Fungicide. Australian Pesticides and Veterinary Medicines Authority.
- Fungicide - CAS No. 731-27-1
-- Prenatal developmental
in nonrodents (rabbit). Developmental NOAEL = 25 mg/kg/day LOAEL=
70 mg/kg/day, based on increased malformations
[see definition below•]
of front extremities and small orbital cavity/folded
retina) and variations (floating
rib and accelerated ossification).
-- 2-Generation reproduction and fertility effects (rat). Parental/systemic
NOAEL not established LOAEL = 15.9-21.5 mg/ kg/day, based on
hardened crania of P generation animals Reproductive NOAEL
not established LOAEL = 15.9-21.5 mg/ kg/day, based on increased
clinical signs of toxicity Offspring NOAEL > 15.9-21.5 mg/kg/day
(HDT) LOAEL not established
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL
= 18.1/21.1 mg/ kg/day (M/F); LOAEL = 90.1/105.2 mg/ kg/day (M/F),
based on skeletal changes. Evidence
of thyroid follicular cell adenomas and/or carcinomas in high-
dose males and females.
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL
= 20/20 mg/kg/ day (M/F); LOAEL = 80/110 mg/kg/day (M/F),
based on bone hyperostosis in males and females. Evidence
of thyroid follicular cell adenomas and/or carcinomas in high-
dose males and females.
Federal Register: September 25, 2002. Tolylfluanid; Pesticide
Tolerance. Final Rule. Federal Register.
WHAT IS ARTHROGRYPOSIS?
Published by AVENUES A National Support Group for Arthrogryposis
Multiplex Congenita - http://www.sonnet.com/avenues/pamphlet.html
"Arthrogryposis" (Arthrogryposis Multiplex Congenita)
is a term describing the presence of multiple joint contractures
at birth. A contracture is a limitation in the range of
motion of a joint. In some cases, few joints maybe affected
and the range of motion may be nearly normal. In the "classic"
case of Arthrogryposis, hands, wrists, elbows, shoulders,
hips, feet, and knees are affected. In the most severe
cases, nearly every body joint may be involved, including
the jaw and back. Frequently, the joint contractures are
accompanied by muscle weakness which further limits movement.
Arthrogryposis is relatively rare, occurring in perhaps
one in 3,000 births... There is a wide variation
in the degree to which muscles and joints are affected
in those with Arthrogryposis. In
some cases, Arthrogryposis may be accompanied by other
conditions, such as central nervous system disorders,
which complicate the picture... In general, there are
four causes for limitation of joint movement before birth:
(1) Muscles do not develop properly (atrophy). In most
cases, the specific cause for muscular atrophy cannot
be identified. Suspected causes include muscle diseases
(for example, congenital muscular dystrophies), maternal
fever during pregnancy, and viruses which may damage cells
which transmit nerve impulses to the muscles.
(2) There is not sufficient room in the uterus for normal
movement. For example, the mother may lack normal amount
of amniotic fluid, or have an abnormally shaped uterus.
(3) Central nervous system and spinal cord are malformed.
In these cases, Arthrogryposis is usually accompanied
by a wide range of other conditions.
(4) Tendons, bones, joints or joint linings may develop
abnormally. For example, tendons may not be connected
to the proper place in a joint.
- Antifoulant, Fungicide, Microbiocide - CAS No. 1983-10-4
-- Lee and Xu
(1984) reported that exposure to 25 mgl TPT acetate or TPTF
caused 46-47% reduction in 1-methyladenine induced germnal vesicle
breakdown for oocytes of the starfish Patiro pectinefera.
Having recorded such an effect on mitosis, it is postulated that
fertilization and developmental effects would be induced in this
species (page 46)
-- Cotta-Ramusino and Doci (1987) conducted tests using TPT acetate
to assess the sensitivity of some aquatic organisms. The least
senstive of those tested was Asellus aquaticus, which gave
a 48 h TLm of 1100 ugl. In contrast to this, Linden et al (1979)
found that the harpacticoid Nitrocra spinipes was very
sensitive to TPT. The authors established
a 96 hr LC50 of 8 ugl TPTF (page 55).
Evaluation on: A Review of the Environmental Effects of Triorganotin
Compounds. October 1994. Issue No. 111. Prepared by: The Health
and Safety Executive, Biocides & Pesticides Assessment Unit.
Available from: Department for Environment, Food and Rural Affairs,
Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme
Greene, York YO1 7PX.
Available online at http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm
Excellent "Mitosis animation" available at (scroll
- Fungicide - CAS No. 68694-11-1
-- Two three-generation
reproduction studies in rats (when considered together) with a
reproductive toxicity NOEL of 30 ppm (1.5 mg/kg/day) and a reproductive
toxicity LEL of 70 ppm (3.5 mg/kg/day). Triflumizole
is considered a reproductive toxicant.
Ref: Federal Register: November 16, 1994.
Pesticide Tolerances and Feed Additive Regulations for Triflumizole.
-- In a 3-generation
rat reproduction study, dose levels of 0, 70, 170 and 420 ppm
in feed resulted in a NOEL greater than 70 ppm (LDT) based on
increased gestation length. At 170
ppm there was pup mortality. At 420 ppm, there was reduced body
weight gain, increased length of estrous
cycles, reduced vaginal cornification,
extended gestation length and high pup mortality.
Ref: EPA Pesticide Fact Sheet September
1991. Triflumizole (Terraguard, Procure).
-- Endocrine disruption.
In the rat reproduction study there was an increase in placental
weight in females at the high dose level of 170 ppm. There was
also a biologically significant increase
in gestation length in high dose F0 and F2 females (F1a
and F3a intervals). The NOAEL for endocrine effects is 70 ppm
Ref: [Federal Register: July 6, 2001 [Notices]
[Page 35623-35628]. Notice of Filing a Pesticide Petition to Establish
a Tolerance for a Certain Pesticide Chemical in or on Food. http://www.fluoridealert.org/pesticides/triflumizole.fr.july6.2001.htm
- Herbicide - CAS No. 1582-09-8
REPRODUCTIVE TOXICITY... The relevant NOAEL for reproduction
was set to 4.5-5.8 mg/kg bw/day in the rat based on haematological
changes, decreased maternal body weight
during gestation and decreased offspring growth and survival,
respectively at 40.7-50.8 mg/kg bw/day (Rubin et al., 1987). (page
11).... In order to examine teratogenic
or developmental effects of trifluralin
four studies in rat and rabbit were submitted in the dossier and
two (one rat and one rabbit) were not accepted according to the
rapporteur Member State, since it was of very old date (1966)
and thus there were many deficiencies and deviation
according to test guideline. One dog study
was submitted in the dossier but was not considered acceptable
according to same statement as above.
From these studies it is concluded that trifluralin did not induce
teratogenic or fetotoxic effects at non-maternally toxic doses.
March 14, 2005. European
Food Safety Authority: Conclusion
regarding the peer review of the pesticide risk assessment of
the active substance trifluralin. EFSA Scientific Report (2005)