| See short description and defintions on bone
use of high doses increases the likelihood that potentially
significant toxic effects will be identified. Findings of
adverse effects in any one species do not necessarily indicate
such effects might be generated in humans. From a conservative
risk assessment perspective however, adverse findings in
animal species are assumed to represent potential effects
in humans, unless convincing evidence of species specificity
Food and Agricultural Organization of the United Nations
This is not an exhaustive list.
When time allows more information will be added.
- Herbicide - CAS No. 87237-48-7
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
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).
Pesticide Information Profile
Abstract: The developmental
toxicity of haloxyfop-ethoxyethyl-ester (87237487) (HEE) was studied
in rats. Pregnant Wistar-rats were gavaged with 5, 10, or 50mg/kg
HEE on days six to 16 of gestation. They were observed for clinical
signs of toxicity and sacrificed on gestational day 21. The uteri
were removed, examined, and the number of implantations, live
and dead fetuses, and resorption sites recorded. The live fetuses
were weighed and examined for malformations. HEE
at 10 and 50mg/kg caused vaginal bleeding in 40 and 50% of the
dams, respectively. The 10 and 50mg/kg doses significantly increased
the number of resorptions per litter and decreased the number
of live fetuses per litter. The 50mg/kg dose caused a significant
decrease in fetal weight. HEE caused a significant dose related
increase in the number of cachectic fetuses. The proportion of
cachectic fetuses following exposure to 5, 10, and 50mg/kg was
2.0, 6.8, and 20.3%, respectively. Ureterohydronephrosis was the
most frequently observed soft tissue malformation, the prevalence
of this defect following the 10 and 50mg/kg doses being
42.9 and 54.8%, respectively. The 10 and 50mg/kg doses caused
skeletal malformations such as retarded
ossification of the sternum and absence of rib 13. The
author concludes that haloxyfop-ethoxyethyl-ester
is embryotoxic and teratogenic. The no observable effect level
is expected to be below 5mg/kg.
Ref: Machera K (1993). Developmental Toxicity
of Haloxyfop Ethoxyethyl Ester in the Rat. Bulletin of Environmental
Contamination and Toxicology, Vol. 51, No. 4, pages 625-632. As
cited at Toxnet.
- Herbicide - CAS No. 69806-40-2
-- 5) Developmental
toxicity - rat: Dose levels tested: 0, 0.1, 1.0, 7.5, 10, and
25 mg/kg/day; Groups of pregnant Fischer 344 rats (10/dose) were
administered haloxyfop-methyl orally during days 6 through 15
of gestation. At the 7.5 mg/kg/day dose
a decrease in weight gain and food consumption accompanied by
an increase in water intake during gestation was observed. Additional
maternal toxicity was observed at 10 and 25 mg/kg/day, including
a decrease in weight gain and food consumption accompanied by
an increase in liver weight. An increase in the incidence of resorptions
was also observed at 10 and 25 mg/kg/day. At
7.5 mg/kg/day, a significant incidence of delayed ossification
of the centra of the thoracic vertebra was observed. The
NOEL and LEL for maternal toxicity are 1 and 7.5 mg/kg/day, respectively.
The NOEL and LEL for developmental toxicity are 1 and 7.5 mg/kg/day,
respectively; core grade guideline (Dow Chemical U.S.A., 1983a)
Health Assessment. US EPA Integrated Risk Information System (IRIS).
- Insecticide - CAS No. 67485-29-4
weight was observed in the offspring of rats administered 30 mg/kg/day
(LOEL). The NOEL was 10 mg/kg/day. Increased post implantation loss
and decreased fetal viability were observed in the offspring of
rabbits administered 15 mg/kg/day (LOEL). The NOEL was 5 mg/kg/day.
Vertebral anomalies were seen in the
offspring of rabbits administered 10 mg/kg/day (LOEL). The NOEL
was 5 mg/kg/day.
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:
Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition
of Certain Chemicals; Toxic Chemical Release Reporting; Community
Right-to-Know; Proposed Rule.
In a prenatal developmental
toxicity study, MRID 00061790, groups of 26 pregnant female Sprague-Dawley
rats were given oral administration of hydramethylnon at doses
of 0, 3, 10, or 30 mg/kg/day on gestation days 6-15. The vehicle
controls were dosed with corn oil. The dams were sacrificed and
examined on gestation day 20... Skeletal variations were generally
comparable in all groups, although the high-dose
fetuses had an increase in the incidence of rudimentary structures
and \incompletely ossified supraoccipitals... At 30 mg/kg/day,
a 16% decrease in maternal body weight, increased incidence of
clinical signs (nasal mucus, alopecia, soft stool, staining of
the ano-genital fur), yellowish discoloration of the fat, and
small thymus were observed. For developmental toxicity, the NOAEL
was 10 mg/kg/day and the LOAEL was 30 mg/kg/day, based on decreased
mean fetal weights, increased incidence
of rudimentary structures, and increased incidence of incompletely
ossified supraoccipital. This study is classified as acceptable
and satisfies guideline requirement 83-3(a) for a developmental
toxicity study in rats.
Ref: US EPA. Reregistration Eligibility
Decision (RED) Hydramethylnon. EPA 738-R-98-023. December 1998.
- Insecticide - CAS No. 173584-44-6
-- 90-Day oral toxicity
in dogs: NOAEL = 5.0 mg/kg/day nonrodents-- LOAEL = 19 mg/kg/
day based on hemolytic anemia, as indicated by decreased in HGB,
RBCs; increases in platelets, increased reticulocytes; and secondary
histopathologic findings indicative of blood breakdown (pigment
in Kupffer cells, renal tubular epithelium, and spleen and bone
marrow macrophages); increased in splenic EMH; and RBC
hyperplasia in bone marrow in dogs.
-- Chronic toxicity- dogs. NOAEL = M 2.3, F 2.4 mg/ kg/day LOAEL
= M 18, F 19 mg/kg/day based on decreased. HCT, HGB and RBC; increased
Heinz bodies and reticulocytes and associated secondary microscopic
changes in the liver, kidneys, spleen, and bone
marrow; increased absolute and relative liver weights.
-- Prenatal developmental in nonrodents--rabbitts. Developmental
NOAEL = 500 mg/kg/ day LOAEL = 1,000 mg/kg/day based on decr.
fetal body weights and reduced ossification
of the sternebrae.
Register. September 29, 2000. Indoxacarb; Pesticide Tolerance.
COMBINED, RAT **52425-054
Chronic Toxicity/Oncogenicity Study with DPX-JW062-106 (50% DPX-KN128,
50% DPX-KN127) Two-Year Feeding Study in Rats”
(Frame, S. 835-E. I. du Pont de Nemours and Company, Haskell Laboratory,
Elkton Road, Newark, Delaware, Study HLR 1174-96, 11/19/97). DPX-JW062-106
technical (Batch DPX-JW062-106, 47.5% DPX-KN128) was given
in the diet daily to males at 0, 20, 40, 60, 125 or 250 ppm and
females at 0, 10, 20, 40, 60 or 125 ppm for 24 months. Deaths
of one female at 60 ppm and seven at 125 ppm during the first
year were associated with bone marrow atrophy,
splenic lymphoid depletion and thymic necrosis. Decreases in mean
body weight/weight gain in males at 125 and 250 ppm and females
at 60 and 125 ppm correlated with decreased food consumption.
Hemolytic anemia at 60 ppm and above (males) and 40 ppm and above
(females): RBC mass, hemoglobin and hematocrit were decreased
and linked with increased reticulocyte counts and increased MCV.
Bone marrow regenerative response was increased
bone marrow hyperplasia in the one-year interim sacrifice
125 ppm females. Spleen weights were increased in both sexes at
the respective high-dose levels and other non-neoplastic changes
were secondary physiological responses to test substance-related
hemolysis; increased pigment observed within the Kupffer cells
of female livers (125 ppm) and the macrophages of the spleen (both
sexes at 60 ppm and above) indicated increased RBC turnover. Increased
hematopoiesis was reported in the spleen of interim sacrifice
males at 125 ppm and above and in the bone
marrow of high-dose males and females. After two years,
secondary changes were seen in the
liver, spleen, bone marrow, kidneys
and thymus in high dose groups. Increased pigment was observed
in the Kupffer cells of female livers at 40 ppm and above; in
males, increases were noted at 250 ppm only. Increased splenic
pigment was seen in all compound-treated male groups and in females
at 60 ppm and above; a slight increase in splenic congestion was
seen in 250 ppm males. No evidence of an oncogenic effect was
reported. NOEL(M)= 40 ppm; (F)=20 ppm (M: 1.59 mg/kg/day; F: 1.04
mg/kg/day based on hemolytic anemia). Acceptable. Kellner, 1/29/99.
-- -- **52425-047 162215 “Chronic
Toxicity Study of DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127)
One Year Feeding Study in Dogs” (Mertens,
J. 831-WIL Research Laboratories, Inc. Ashland, Ohio. Study HLO
885-96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062- 106,
47.5% DPX-KN128) was administered orally (via the feed) to 5 Beagle
dogs/sex/dose at levels of 0, 40, 80, 640 and 1280 ppm for 52
weeks. There was a treatment-related decrease in body weight,
body weight gain and food consumption in 1280 ppm dogs during
the first three months of the study. Reduced mean hemoglobin,
RBC count and hematocrit was noted in the 80, 640 and 1280 ppm
groups during all periods tested; increased Heinz bodies in these
groups indicated hemolysis. Increased mean reticulocyte counts
and MCV and decreased corpuscular hemoglobin concentration, erythrocyte
morphologic changes and increased mean platelet counts indicated
responses to hemolytic anemia. Significantly decreased RBC counts
were also reported in 40 ppm males at week 25 and 51. Females
at 40 ppm also showed reductions in RBC, but the differences were
not statistically significant. Mean liver weights were increased
in males (640 and 1280 ppm groups) and females (1280 ppm only).
Microscopic changes in groups 40 ppm and above included increased
pigment (hemosiderin) in liver Kupffer cells, kidney tubule epithelium,
spleen and bone marrow and increased
extramedullary hematopoiesis in the spleen and bone
marrow hyperplasia. NOEL (M/F)=40
ppm (males: 1.1 mg/kg/day; females: 1.3 mg/kg/day based on biologically
significant hemolytic anemia at 80 ppm and above). Acceptable.
-- -- ** 036; 162201; “Subchronic Oral Toxicity:90-Day Study with
DPX-JW062-106 (Approximately 50% DPX-KN128, 50% DPX-KN127) Feeding
Study in Dogs” (Mertens, J.J.W.M., WIL Research Laboratories,
Inc., Ashland, OH, Haskell Laboratory Project ID: HLO 494-95,
Performing Laboratory Project ID: WIL-189016, 11/19/97). 821.
DPX-JW062 Technical (Batch No. DPX-JW062- 106, 47.5% DPX-KN128)
was admixed to the feed at concentrations of 0, 40, 80, 160, or
640 ppm (0, 1, 2, 5, or 18 mg/kg/day, respectively, for males,
and 0, 1, 3, 5, or 17 mg/kg/day, respectively, for females) and
fed to 4 outbred beagle dogs per sex per dose level for 13 weeks.
No animals died during the study interval. No treatment-related
clinical signs were observed. Statistically significant and treatment-related
decreases in mean red blood cell and hemoglobin levels in males
at 160 and 640 ppm, and females at 640 ppm and statistically significant
and dose-related increases in mean cell volume in males beginning
at 160 ppm and in females beginning at 80 ppm and percent reticulocytes
in males at 640 ppm and in females at 160 and 640 ppm were observed.
Treatment-related increases in Heinz bodies and mean total bilirubin
levels were observed in males and females at 160 and 640 ppm.
Microscopic examination revealed a treatment-related increase
in pigment in the spleen beginning in males at 40 ppm and in females
at 80 ppm, increased extramedullary hematopoiesis in the spleen
beginning in males and females at 160 ppm, treatment-related erythrocytic
hyperplasia and an increase in pigment in
the bone marrow in males beginning at 80 ppm and in females beginning
at 40 ppm, and a treatment-related increase in pigment
in the liver in males and females beginning at 80 ppm. No adverse
effects. NOEL (M/F)< 1 mg/kg/day (40 ppm) (based on a treatment-related
increase in pigment in the spleen in males, and on a treatment-related
increase in extramedullary
hematopoiesis in the spleen,
and treatment-related erythrocytic hyperplasia and a treatment-related
increase in pigment in the bone marrow in
females). Acceptable. (Corlett, 2/10/99)
11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
The haemosiderin deposits
in spleen and liver, and spleen and
bone marrow hyperplastic response should
be considered to be secondary physiological responses to the increased
RBC turn over. The very shallow dose-response curve also indicates
that the compensatory mechanism of the haemopoietic system was
not overcome (except at high doses in the dog) and the effect
of indoxacarb in rats and dogs can be described as a compensated
18, 2002: Opinion of the Scientific Committee on Plants on specific
questions from the Commission concerning the evaluation of Indoxacarb.
European Commission. Health & Consumer Protection Directorate-General.
conducted in rats and rabbits demonstrated that the
rat was more susceptible than the rabbit to the maternal and fetal
effects of DPX-
MP062. Developmental toxicity was observed
only in the presence of maternal toxicity. The NOAEL for maternal
and fetal effects in rats was 2 mg/kg/day based on body weight
effects and decreased food consumption at 4 mg/kg/day. The NOAEL
for developmental effects in fetuses was >4 mg/kg/day.
In rabbits, the maternal and fetal NOAELS were 500 mg/kg/day
based on body weight effects, decreased food consumption in dams
and decreased weight and delayed ossification
in fetuses at 1,000 mg/kg/day.
Ref: Federal Register: January
25, 2002 [Page 3700-3706]. Notice of Filing a Pesticide Petition
to Establish a Tolerance for a Certain Pesticide Chemical in or
- Herbicide - CAS No. 141112-29-0
-- In a developmental
toxicity study in rats, maternal toxicity was observed at 500
mg/kg/day, manifested as an increased incidence of salivation,
decreased body weight, weight gain, and food consumption during
the dosing period. The maternal LOAEL is 500 mg/kg/day, based
on increased incidence of clinical signs and decreased body weights,
body weight gains, and food consumption. The maternal NOEL is
100 mg/kg/day. Developmental toxicity, observed at 100 and 500
mg/kg/day, were manifested as increased incidences of fetuses/litters
with various anomalies: growth
retardations (decreased fetal body weight;
increased incidence of delayed ossification of sternebrae, metacarpals
In addition, an increased incidence of vertebral
and rib anomalies and high incidence of
subcutaneous edema were observed at 500 mg/kg/day.
of these anomalies were higher than the
concurrent control values and in some cases exceeded the range
for historical controls. The LOAEL for developmental toxicity
is 100 mg/kg/day, based on decreased fetal
body weights and increased incidences
of skeletal anomalies. The developmental NOEL is 10 mg/kg/day.
-- In a developmental toxicity study in rabbits, maternal toxicity
was observed at 100 mg/kg/day, manifested as increased incidence
of clinical signs (little diet eaten and few feces) and
decreased body weight gain and food consumption during the dosing
period. The maternal LOAEL is 100 mg/kg/day, based on increased
incidence of clinical signs, decreased body weight gains and food
consumption. The maternal NOEL is 20 mg/kg/day. Developmental
toxicity, observed at 5 mg/kg/day, consisted of increased
incidence of 27th pre-sacral vertebrae. Additional findings
noted at 20 and 100 mg/kg/day were manifested as increased number
of postimplantation loss and late resorptions, as well as growth
retardations in the form of generalized reduction in
skeletal ossification, and increased incidence of 13 pairs of
ribs. At 100
mg/kg/day, an increased incidence of fetuses
with incisors not erupted was also observed.
Incidences of these anomalies, on a litter basis, were higher
than the concurrent control values and in some cases exceeded
the range for historical controls. The LOAEL for developmental
toxicity is 5 mg/kg/day, based on increased
incidence of fetuses with 27th pre-sacral vertebrae. The
developmental NOEL was not established.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole
Reason for Issuance: Conditional Registration Date Issued: September
- Herbicide - CAS No. 77501-63-4
-- Prenatal developmental-- rodents (rat). Developmental NOAEL
= 50 mg/kg/day.
Developmental LOAEL = 150 mg/kg/day based on decreased
fetal weight and skeletal abnormalities
(increased incidence of bent ribs and/or
limb bones) and reduced ossification of vertebral arches.
-- Rat Developmental Toxicity
Study. LOAEL = 150 mg/kg/day based on decreased fetal weight and
Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal
Rats. Pregnant rats were administered oral doses of 0, 15, 50
and 150 mg/kg/day Lactofen Technical on days 6- 19 of gestation.
Maternal toxicity (death, abortion and reduced body weight gain)
was observed at 150 mg/kg/day. Developmental toxicity (reduced
fetal weight, slightly reduced ossification,
bent ribs and bent limb bones)
was also observed at 150 mg/kg/day. The NOEL for this study was
Ref: Federal Register, February 25, 1998.
(LPOS) - Insecticide, Adjuvant - CAS
In the developmental study in rabbits, maternal toxicity was observed
at 1 mg/kg/day and above, based on reduced body weight gains during
the dosing period, followed by a rebound in body weight gains
post-dosing. Developmental toxicity was observed at the highest
dose tested, 4 mg/kg/day. Effects included fetolethality, skeletal
variations (unossified skull bones,
sternebrae, talus, pubis and extra full rib) and decreased
fetal body weights. A maternal NOAEL was not established and the
maternal LOAEL was 1 mg/kg/day, based on reduced body weight gains.
The developmental NOAEL was 2 mg/kg/day... 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.
US EPA. New Pesticide Factsheet. Lithium
Perfluorooctane sulfonate (LPOS). August 1990. EPA-730-F-99-009.
Lithium Perfluorooctane sulfonate (LPOS) was administered by gavage
at 3, 6, or 12 mg/kg to mated Crl:CDĄBR VAF/PlusĄ female rats
once daily on days 6 through 15 of gestation. Body weights and
clinical observations were on days 0, 6, 9, 12, 16, 20 of gestation.
Food consumption was also measured. Cesarean sections were done
on surviving animals on day 20 of gestation, and the fetuses were
removed for examination. The dams were necropsied following sacrifice.
Clear maternal toxicity was observed in both the 6 and 12 mg/kg
groups. Five out of 25 females in the 12 mg/kg group did not survive
to scheduled sacrifice. Both the 6 and 12 mg/kg groups had test
material-related changes including lower mean body weights, body
weight gains, and food consumption. Treatment
at 12 mg/kg resulted in embryolethality as evidenced by lower
uterine weights, fewer live fetuses per litter, reduced fetal
bodyweights and lower percent of live fetuses than the control
treated. There was also significant
increased incidences of cleft palate (79%), and
edema (36%). Variations at this dose included reduced ossification
of bone and unossified bone. The no-observable-effect level
(NOEL) for LPOS for teratogenicity in rats is 6 mg/kg, whereas
the NOEL for maternal toxicity in rats is 3 mg/kg.
1994 Mar;14(1):162; Developmental toxicity study with lithium
perfluorooctane sulfonate in rats;
SM, Costello AC, Osimitz TG
Lithium perfluorooctane sulfonate (LPOS) was administered by gavage
at 1, 2, or 4 mg/kg to mated New Zealand White female rabbits
once daily on Days 7 through 19 of gestation. Body weights and
clinical observations were made on Days 0, 7, 10, 13, 16, 20,
24, and 29 of gestation. Cesarean sections were done on surviving
animals on Day 29 of gestation, and the fetuses were removed for
examination. The does were necropsied following sacrifice. Treatment
at the 4-mg/kg level resulted in abortions; premature deliveries;
and lower mean body weights, lower body weight gains, and lower
gravid uterine weights than those of the control groups. Cesarean
sections revealed a treatment-related increase in postimplantation
losses at the 4-mg/kg level. Mean fetal body weight (mean = 10.01
g, n = 11) at the 4-mg/kg level was lower than that of controls
(mean = 39.93 g, n = 16) and represents developmental toxicity.
Fetal morphological examinations disclosed no evidence of teratogenicity
of LPOS in rabbits at any level. There were increased incidences
of unossified skeletal structures at the
2- and 4-mg/kg levels. These variations along with the lower fetal
body weights suggest retarded development at the 4-mg/kg level.
The no-observable-effect level of LPOS for developmental toxicity
in rabbits is considered to be 2 mg/kg.
Ref: Henwood SM et al. (1994). Developmental
toxicity study with lithium perfluorooctane sulfonate in
Teratology 1994 May;49(5):398.
(BAS 320 I) -
Insecticide - CAS
In a developmental (teratology) toxicity
study in the Himalayan rabbit,
the results indicated that the NOAEL for maternal toxicity was
100 mg/kg b.w./day, based on several clinical symptoms of toxicity
(including ataxia and poor general state) occurring in 4 of 25
does at 300 mg/kg b.w./day, for which 2 of these 4 does had abortions
prior to being sacrificed early, with a third doe at 300 mg/kg
b.w./day being sacrificed moribund. Similarly, the NOAEL for fetal
(prenatal)/ developmental toxicity was 100 mg/kg b.w./day, based
on slightly decreased mean fetal body weights as well as an increased
rate for a certain skeletal variation, namely incomplete ossification
Ref: October 27,
2004. Federal Register. Pesticide
- Herbicide - CAS No. 27314-13-2
For females (13-50
years) population subgroup, the acute No Observed Adverse Effects
Level (NOAEL) of 10 mg/kg/day was established based on increased
incidence in skeletal variations
observed in the developmental toxicity study in rabbits at the
Lowest Observed Adverse Effect Level (LOAEL) of 30 mg/kg/day...
The FQPA safety factor to account for the enhanced sensitivity
of infants and children be reduced to 3X based on increased incidence
in skeletal variations observed in
the developmental toxicity study in rabbits. This determination
is based on the following: the toxicity database is adequate;
the development toxicity studies in the rat and rabbit are acceptable
as an multi-generation study; a developmental neurotoxic study
is not required because there is no indication of increased susceptibility
in young rats to norflurazon exposure; and there are currently
no residential uses for norflurazon. The FQPA safety factor is
applicable to only females 13-50 population subgroup for acute
dietary risk assessment.
Ref: US EPA May 31, 2002. Tolerance Reassessment
Progress and Risk Management Decision.
A developmental toxicity
study was conducted in New Zealand White rabbits, which received
either 0, 10, 30, or 60 mg/kg/day norflurazon technical by oral
gavage on gestation days 7 through 19 inclusive... The developmental
toxicity NOEL was determined to be 30 mg/kg/day, and the developmental
toxicity LEL was determined to be 60 mg/kg/day, based on
statistically significant increases in the fetal incidence of
incompletely ossified frontal bones, 16
caudal vertebrae, unossified first metacarpal, unossified middle
phalanx of the fifth digit of the forelimb, and unossified proximal
epiphysis of the tibia at the 60 mg/kg/day dose level.
Ref: US EPA Reregistration Eligibility Decision:
-- A nine-month oral
toxicity study (MRID 00091056) was conducted using the F generation
of rats from a two-year carcinogenicity study (MRID 00082019).
In this study, rats were given technical norflurazon in the diet
at dose levels of 0, 125, 250, or 500 ppm (0, 6.25, 12.5, and
25 mg/kg/day) for 39 weeks. There were no significant effects
of norflurazon on survival, body weight, body weight gain, food
consumption, food efficiency, hematology, or clinical chemistry
in male or female rats at any dose level tested. At 500 ppm,
liver weight was increased by 14% and 23% in male and female
rats respectively, at 39 weeks. Kidney weight was not significantly
affected, but the incidence of hyaline pigment deposition (many
tubules) in male rats and hyaline pigment deposition (few tubules)
in female rats was increased, as was the incidence of
medullary congestion in high dose female rats... (guideline:
non-guideline study; classified as core supplementary; MRID 00091056).
-- Developmental and Reproductive Toxicity In a developmental
toxicity (teratology) study, rats of the Sprague-Dawley strain
received either 0, 100, 200, or 400 mg/kg/day norflurazon technical
by oral gavage on gestation days 6 through 15 inclusive. The maternal
toxicity NOEL was determined to be < 100 mg/kg/day, and the maternal
toxicity LEL was determined to be < 100 mg/kg/day, based on reductions
in body weight gain for the period
of dosing and for the dosing plus post-dosing period. The developmental
toxicity NOEL was determined to be > 400 mg/kg/day, and the developmental
toxicity LEL was determined to be > 400 mg/kg/day. Developmental
toxicity was suggested at the 400 mg/kg/day dose level in the
form of an increase in bipartite thoracic
vertebrae (10th-13th) and an increase in rudimentary 14th ribs.
However, these increases were not statistically significant and
are believed to be secondary to maternal effects at the high dose
(guideline 83-3; MRID 00063621).
-- A developmental toxicity study was conducted in New Zealand
White rabbits, which received either 0, 10, 30, or 60 mg/kg/day
norflurazon technical by oral gavage on gestation days 7 through
19 inclusive. The maternal toxicity NOEL was determined to be
30 mg/kg/day, and the maternal toxicity LEL was determined to
be 60 mg/kg/day, based on decreased body weight gain
and clinical toxicity (abortion) at this dose level. The
developmental toxicity NOEL was determined to be 30 mg/kg/day,
and the developmental toxicity LEL was determined to be 60 mg/kg/day,
based on statistically significant increases
in the fetal incidence of incompletely ossified frontal bones,
16 caudal vertebrae, unossified first metacarpal, unossified middle
phalanx of the fifth digit of the forelimb, and unossified proximal
epiphysis of the tibia at the 60 mg/kg/day dose level.
A 12% decrease in mean fetal weight
was also observed at the 60 mg/kg/day dose level (guideline 83-3;
MRID 00131151 and 00131152).
-- The studies examining developmental and reproductive toxicity
of norflurazon were considered by the Health Effects Division
RfD/Peer Review Committee in a meeting held March 16, 1995. Overall,
the committee concluded that treatment with norflurazon was associated
with reproductive toxicity in the form of
increased pup death, increased stillborn pups, and increased pup
deaths between days 5-14 of lactation at a dose of 1500
ppm. Developmental toxicity was not evident in treated rats, but
developmental toxicity in rabbits was evident at a dose of 60
mg/kg/day in the form of decreased mean fetal weight, slight
delays in ossification of the skull and limbs, and an increase
in the incidence of 13th ribs. These developmental effects
occurred at a dose that was maternally toxic.
-- Toxic Endpoints of Concern Identified for Use in Risk Assessment.
The Health Effects Division's (HED) Less than Lifetime Committee
selected the following toxicology endpoints for use in risk assessment
for norflurazon (Toxicology Endpoint Selection Document, 4/21/95):
The endpoint selected for the acute dietary risk assessment is
a NOEL of 30 mg/kg/day. This is the developmental NOEL based on
increased skeletal variations observed
at the dose of 60 mg/kg/day in a rabbit developmental toxicity
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION
NORFLURAZON. LIST A. CASE 0229.
-Insecticide - CAS No. 121451-02-3
-- “XDE-007: 90-Day Dietary Toxicity
Study with 28-Day Recovery in Beagle Dogs,” (Stebbins,
K.E., Thomas, J., Baker, P.C.; Toxicology & Environmental
Research and Consulting, The Dow Chemical Company, Midland, MI;
Laboratory Project Study ID #: 011194; 5/9/03). XDE-007 (98.4%
pure) was fed in diet to Beagle dogs (4/sex/dose) for 90 days
at 0, 0.003, 0.3 or 3.0% (equivalent to 0, 0.913, 115 and 1040
mg/kg/day - Males and 0, 1.06, 113 and 1150 mg/kg/day - females).
Recovery groups (4/sex/dose) were fed XDE-007 in diet at 0 or
3% for 90 days, then were maintained on control diet for 28 days.
... There was an increased incidence in
bone marrow hyperplasia (erythroid cell) at > 0.3% XDE-007
in the main dose group that persisted after recovery.
-- “XDE-007: One-Year Dietary Toxicity
Study in Beagle Dogs,” (Stebbins, K.E., Day, S.J.,
Thomas, J.; Toxicology & Environmental Research and Consulting,
The Dow Chemical Company, Midland, MI; Laboratory Project Study
ID #: 142640; 3/5/04). XDE-007 (97.9% pure) was fed in diet to
Beagle dogs (4/sex/dose) for 1 year at 0, 0.003, 0.03 or 0.225%
(equivalent to 0, 0.74, 9.3 and 69 mg/kg/day - Males and 0, 0.94,
8.7 and 70 mg/kg/day - females)... There
was an increased incidence in bone marrow erythroid hyperplasia
(erythroid cell) at > 0.3% XDE-007 (males, 0, 0, 4, 4 --each
dose level) and at 0.225% (females: 0, 0, 0, 1 --each dose level).
August 2005 - Summary of toxicological data. California EPA, Department
of Pesticide Regulation, Medical Toxicology Branch.
- Herbicide - CAS No. 42874-03-3
toxicity was most severe in the 2-generation reproduction
study in rats,in which pelvic mineralization
occurred.Other studies had indications of renal toxicity:increases
in organ weight and occasional histopathological observations.
-- In a developmental toxicity study (MRID 41806501),oxyfluorfen
(71.4%), was administered by gavage
to pregnant Crl:CD BR rats from gestation days 6-15.There were
27 rats/group.Doses were 0,18,183,or 848 mg/kg/day (adjusted for
analytical results).... There were 12 litters
in the mid-dose group with skeletal malformations which included
bent scapula,fused sternebrae,and bent bones in hindlimbs and
forelimbs compared to 0 litters in the control group with skeletal
malformations. The NOAEL for maternal toxicity is 18 mg/kg/day;the
maternal LOAEL is 183 mg/kg/day based on clinical signs (red vaginal
discharge,soft feces,scant feces). The NOAEL for developmental
toxicity is 18 mg/kg/day.The LOAEL for developmental toxicity
is 183 mg/kg/day based on increased early resorptions,decreased
fetal weight,and increased incidence of
fetal visceral and skeletal variations and malformations.
-- Goal Herbicide (71.4%a.i.) was
administered to groups of 25 male and 25 female Crl:CD ®BR rats
in the diet at concentrations of 0,100,400,or 1600 ppm of active
ingredient for two generations (MRID 42014901).One litter was
produced in each generation.Premating doses for the adult F0 males
were 0,7.8,30.9,and 120.0 mg/kg/day and for the F0 females were
0,8.5,32.8,and 131.2 mg/kg/day,respectively.Premating doses for
the adult F1 males were 0, 8.9,36.4,and 146.3 mg/kg/day and for
the F1 females were 0,8.9,35.7,and 151.3 mg/kg/day, respectively.F1
pups chosen to produce the F2 litters were weaned onto the same
diets as their parents. Animals were given test or control diet
for 10 (F0) or 14 (F1)weeks then mated within the same dose group.
One high-dose F1 male was sacrificed moribund during week 9 of
treatment;treatment- related chronic pyelonephritis secondary
to pelvic mineralization was described
at necropsy;this death was attributed to treatment.No treatment-related
clinical signs of toxicity were observed in parental animals of
either generation.Several intercurrent deaths of F0 females and
F1 males and females were considered incidental to treatment.
tudy which would not meet current guideline requirements.The study
was,however,adequate to determine a NOAEL value.
... 90-Day Oral Toxicity -Mouse In a 3-month dietary toxicity
study (MRID 00117602),Goal (72.5%
) was administered to Charles River CD-1 mice (15/sex/group)at
dietary concentrations of 0,200,800,or 3200 ppm for 13 weeks.Doses
were equivalent to 0,32.0,134.5,or 490.5 mg/kg/day in males and
0,44.4, 166.6,or 520.9 mg/kg/day in females... Bone
marrow hyperplasia was present in low-dose males and mid-and high-dose
males and females.Vacuolation of the adrenal cortex was
present in high-dose females.Thymic atrophy occurred in high-dose
males and females.
Ref: August 8,2001. OXYFLUORFEN. Toxicology
Chapter for RED. Submission No.S549936. P.C.Code:111601. Tox.Chem.No.188AAA.
to Terrestrial Organisms. The results of the risk assessment
do not suggest concern for acute risks to birds or mammals. Sub-chronic
and chronic risks to terrestrial birds and mammals present a serious
concern. These toxic effects may be manifested as reproductive,
developmental, and hemolytic consequences. The chronic LOC was
exceeded for birds in all crop scenarios and for mammals in scenarios
with the highest application rate (2 lbs ai/application). In the
bobwhite quail reproduction study, reduced chick weights were
observed, which would reduce fitness if experienced in the wild.
In the 2-generation rat reproduction study, toxic effects in adults
were mortality, decreased body weight, and liver and kidney histopathology,
and toxic effects observed in the pups were decreased body weight
and a decreased number of live pups/litter. In
three of the four developmental toxicity studies, increases
in spontaneous abortions, fetal resorptions, and fetal
bone deformities as well as decreases
in litter size were observed. Any of these effects would
have an effect on the fitness of individuals, and may have an
effect on the overall fitness of wild mammal populations exposed
Ref: December 11, 2001. Environmental Fate
and Effects Division’s Preliminary Risk Assessment for the Reregistration
Eligibility Document for Oxyfluorfen
- Herbicide - CAS No. 137641-05-5
-- In a developmental
study, picolinafen was given to rabbits by oral gavage at 0, 5,
20 or 50 mg/kg bw/day on days 6-28 of gestation... The number
of resorptions was slightly increased at 50 mg/kg bw/day and an
increased incidence of fused sternal centra
was observed in foetuses at 50 mg/kg bw/day. The NOEL for maternal
toxicity in this study was 5 mg/kg bw/day and the NOEL for embryotoxicity
and foetotoxicity was 20 mg/kg bw/day.
-- -- Picolinafen was given to pregnant rats by oral gavage at
0, 100, 500 or 1000 mg/kg bw/day on days 6 to 19 of gestation...
The incidence of bipartite ossification
in the thoracic vertebrae in foetuses at 1000 mg/kg bw/day
was increased, but no other alterations were observed. Since a
NOEL for maternal toxicity was not established in this study,
a follow-up study using 0, 5, 25 or 50 mg/kg bw/day was conducted.
No treatment-related effects were observed on dams or on foetal
development... In a developmental study, picolinafen was given
to rabbits by oral gavage at 0, 5, 20 or 50 mg/kg bw/day on days
6-28 of gestation. Soft or liquid faeces were observed at 50 mg/kg
bw/day and body weight gain and food consumption were reduced
at 20 and 50 mg/kg bw/day... The number of resorptions was slightly
increased at 50 mg/kg bw/day and an increased incidence of
fused sternal centra was observed in foetuses at 50 mg/kg
bw/day. The NOEL for maternal toxicity in this study was 5 mg/kg
bw/day and the NOEL for embryotoxicity and foetotoxicity was 20
Ref: Public Release Summary on Evaluation
of the new active PICOLINAFEN in the products SNIPER HERBICIDE
& PARAGON HERBICIDE. Australia. National Registration Authority
for Agricultural and Veterinary Chemicals November 2000.
were generally characterized by increased incidence/severity of
hemosiderin deposition in the spleen and/or Kupffer cells of the
liver and extramedullary hematopoiesis in the spleen and/or liver.
Under normal physiological conditions a certain amount of hemosiderin
deposition is routinely observed in the spleen due to normal breakdown
of effete red blood cells; however, for all species tested, increased
incidence/severity were noted for both sexes at the higher dose
levels. The increased incidence/severity of extramedullary hematopoiesis
was most likely a compensatory response to the increased hemolysis
of red blood cells noted for all species tested. Other histopathological
findings associated with regenerative hemolytic anemia included
increased erythropoietic activity in the bone marrow and
liver at higher doses. This was noted in rats following 28-day
dietary administration at 1000 ppm and was indicated by a change
in the myeloid:erythroid ratio from 2:1 in the controls to 1:1
in rats at 1000 ppm. For males, this shift to a more immature,
stronger population of red cells at 1000 ppm was considered to
account for the slight but significant decrease in erythrocyte
osmotic fragility. For females, this correlated with an increased
incidence of erythropoiesis in the bone
marrow (femur/joint and sternum).
February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02.
Alternative Strategies and Regulatory Affairs Division, Pest Management
- Fungicide - CAS
toxicity. Target / critical effect - Reproduction: No effects
on reproductive performance; reduced body
weights of offspring at the end of the lactation period
at parentally toxic doses (750 ppm). Lowest relevant reproductive
NOAEL / NOEL: 2-gen, rat: >750 ppm (78.2 mg/kg bw/d), this being
the highest dose tested; 200 ppm (parent rats) Target
/ critical effect - Developmental toxicity: Ossification
delay and increased incidence of skeletal variants
at maternally toxic doses. Lowest relevant developmental NOAEL
/ NOEL: rat: 30 mg/kg bw/day rabbit: 25 mg/kg bw/day
toxicological studies. o-phthalic
acid (Metabolite 15, grain): Survey of published literature
(November 2000) Acute oral LD50, rat: 7500-8400 mg/kg bw In-vitro
genotoxicity (Ames test & cytogenetic assay in CHO cells): negative.
Dominant lethal test: questionable positive test result involving
reduced male fertility and abnormal sperm morphology. Non-carcinogenic
in rats and mice according to NTP carcinogenicity programme. Reduced
foetal body weight and retarded ossification
in rats at maternal toxic doses
2003 - Review report for the active substance picoxystrobin. Picoxystrobin
SANCO/10196/2003-Final. 3 June 2003. Finalised in the [European
Commission] Standing Committee on the Food Chain and Animal Health
at its meeting on 4 July 2003 in view of the inclusion of picoxystrobin
in Annex I of Directive 91/414/EEC/.
This report identified o-phthalic
acid (Metabolite 15, grain)
as a "Toxicologically significant compound"
bifluoride - Wood preservative -
CAS No. 7789-29-9
may cause mottling of teeth and bone damage
(osteosclerosis) and fluorosis. Symptoms of fluorisis include
brittle bones,weight loss, anemia, calcified ligaments, general
ill health and joint stiffness.
POTASSIUM BIFLUORIDE. Material Data Safety Sheet.
Ingestion: May cause
osseous fluorosis (increased radiographic
density of the bones). May cause kidney damage, asthma
and symptoms resembling rheumatism. Target Organ Effects: Chronic
ingestion may cause kidney damage.
Material Safety Data Sheet for Potassium Hydrogendifluoride [synonym].
LA-CO INDUSTRIES, Inc./Markal Co. Product Name: SILVER BRAZING
FLUX PASTE Revision #: 1.5 Date Prepared: March 1, 1995. Date
Revised: August 6, 2002.
fluorosilicate - Insecticide, Wood Preservative
- CAS No. 16871-90-2
Source: English/French versions: Internet documents, 1999. Spanish
version: Instituto Nacional de Seguridad e Higiene en el Trabajo,
Ediciones y Publicaciones, c/Torrelaguna 73, 28027 Madrid, Spain,
1991. 2p. Illus.
Abstract: International Chemical Safety Card. Exposure routes:
inhalation and ingestion. Short term exposure effects: irritation
of the skin, eyes and respiratory tract; effects on the calcium
metabolism, resulting in cardiac
disorders and impaired function. Long-term
exposure effects: effects on the bone, resulting in fluorosis.
Threshold limit value: 2.5mg/m3 (TWA) as fluorine (ACGIH
Ref: Toxline at Toxnet.
Herbicide - CAS
-- Chronic toxicity:
Doses of 125 mg/kg/day administered in the diet to dogs over a
1-year period produced decreased body weight gain, anemia, increased
liver weight, and thyroid hyperplasia (abnormal growth) .
Rats fed dietary doses of about 180 mg/kg/day over 90 days showed
effects similar to those noted in dogs, as well as spleen weight
increases . In another study, doses of 480 mg/kg/day in rats
over 18 months produced increased incidence of tooth disorders,
chronic nephritis (kidney damage), and testicular atrophy .
In two 18-month studies in mice, testicular atrophy, chronic nephritis,
and increased tooth and bone disorders
were seen at doses of 180 mg/kg/day and 360 mg/kg/day, respectively
-- Teratogenic effects: No teratological effects were seen in
offspring of rabbits given doses of up to 600 mg/kg/day. In one
study of rats, delayed skeletal development
and lack of ossification was seen in offspring of pregnant
rats given doses of 500 mg/kg/day, while in another, 100 mg/kg/day
produced incomplete ossification of the
pubic bone . The available evidence suggests that primisulfuron-methyl
is not teratogenic except at very high doses.
-- Organ toxicity: Target organs identified in animal studies
include the liver, kidneys, spleen, and
testes, as well as the skeleton.
Ref: E X T O X N E T Extension Toxicology
Network Pesticide Information Profiles. Revised June 1996.
-- Acute toxicity.
For acute dietary risk assessment, the Agency used a NOEL of 100
mg/kg/day, based on delayed or absent ossification
effects in fetuses at the LEL of 500 mg/kg/day, from the oral
developmental study in rats. This risk assessment will evaluate
acute dietary risk to the population subgroup of concern, females
13+ years of age... Acute risk. The finding of developmental effects
in the rat study absent ossification
required that an acute dietary risk assessment be performed for
females 13+ years of age. The calculated MOE of 71,000 demonstrated
that acute pre-natal developmental risks were below EPA's level
Ref: Federal Register: December 17, 1997.Primisulfuron-methyl;
Pesticide Tolerances for Emergency Exemptions. Final Rule.
- Herbicide - CAS No. 94125-34-5
-- Reproductive toxicity.
Developmental toxicity: Skeletal variations
(rat) and resorptions (rabbit) at maternal toxic doses.
Lowest relevant developmental NOAEL / NOEL: NOAEL = 10 mg/kg b.w./day
Ref: July 2, 2002 - Review
report for the active substance prosulfuron. European Commission
Health & Consumer Protection Directorate-General.