Reproductive and Developmental Effects
Fluorinated and Fluoride Pesticides

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

-- Food and Agricultural Organization of the United Nations

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

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

In a 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 ppm.
• 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.

Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Cyhalothrin, 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.

Abstract (2002).
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 receptive females.
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 systems.
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

Dichlorofluoromethane (Freon 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. 434]
Ref: TOXNET profile from Hazardous Substances Data Base for DICHLOROFLUOROMETHANE

Reproductive Hazard. Dichlorofluoromethane may damage the developing fetus.
Produced by: New Jersey Department of Health and Senior Services.
Provided by: Canadian Centre for Occupational Health and Safety.

Ethalfluralin - 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.

Fipronil - Acaracide, Insecticide, Wood Preservative - CAS No.120068-37-3

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), respectively. 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).
In 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.
Ref: Reproductive adverse effects of fipronil in Wistar rats. Ohi M, Dalsenter PR, Andrade AJ, Nascimento AJ. Toxicol Lett. 2004 Jan 15;146(2):121-7.

Flazasulfuron - 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.

Flonicamid - 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.
Ref: 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
-- Chronic dietary. 2-Generation Reproduction rat. Parental LOAEL = 22 mg/kg/day based on increased kidney weights, kidney hyaline deposition, increased blood serum LH (F1 females).

Prenatal 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
-- Maternal. NOAEL 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)

Ref: August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule. Federal Register.

Fluazifop-P-butyl - Herbicide - CAS No. 79241-46-6

Chronic/Subcrhonic 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 system.
Ref: Material Safety Data Sheet for Fusilade DX (active indredient Fluazifop-P-Butyl). Syngenta. January 21, 2002.

"Fluazifop-P-butyl 79241-46-6 Withdrawn. Teratogenic and suspected reproductive effects in experimental animals. 1991."
Definition: "Withdrawn. A substance which the manufacturer has either withdrawn from the market, or for which he has withdrawn his application for registration, approval, or renewed approval and when it is clear that these measures were undertaken due to the health or environmental properties of the substance."

Ref: Euopean Commission. Appendix 5. Substances which may not be included as active ingredients in approved pesticide products, Chapter 15, Section 2, subsection one.

Flubendiamide - Insecticide - CAS No. 272451-65-7

Results 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 pups.
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"
•• This 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.
•• This 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 PA 15205

Fluometuron - 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) is applied.
Ref. 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.

Fluopicolide (click 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 group.
• 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.

Fluoroacetamine - Rodenticide, Insecticide - CAS No. 640-19-7
(also known as Fluoroacetamide or Compound 1081)

Ref: FLUOROACETAMIDE CASRN: 640-19-7. Hazardous Substances Data Bank.

Fluorochloridone - Herbicide - CAS No. 61213-25-0

"Fluorochloridone 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.

Fluorouracil - Former insect chemosterilant; now used as a chemotherapeutic drug- CAS No. 51-21-8

Developmental abnormalities 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.

Abstract: Biologically 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

Fluoxastrobin - Fungicide - CAS No. 193740-76-0

- Rats. Offspring systemic: decreased body weights, delayed preputial separation*, and incomplete ossification in the F1 and/or F2 males and females. Parental systemic: decreased premating body weight gain of the P-generation males and females and decreased premating absolute body weight of the F1 males and females.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

*Note: Preputial separation is an indicator of sexual maturation

Flusilazole - 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. (Page 30)
-- 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 21)
-- 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 21)
-- 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. (Pages 21-22)
-- 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 22)
-- 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 22)
-- 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)
Ref: 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.

-- Although 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 Directorate-General.

Gamma-cyhalothrin - Insecticide - CAS No. 76703-62-3

3-Generation 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).
Ref: April 8, 2004. Federal Register. Lambda-Cyhalothrin and Gamma-Cyhalothrin. Tolerances for Residues. FINAL RULE.

Hexaflurate - Herbicide, Wood Preservative - CAS No. 17029-22-0

Carcinogen, Suspected Developmental or Reproductive Toxin
Note: Hexaflurate is an inorganic Arsenic compound.
Ref: PAN Pesticides Database - Chemicals

Hydramethylnon - Insecticide - CAS No. 67485-29-4

- 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 degeneration...
- 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.

Indoxacarb - Insecticide - CAS No. 173584-44-6

-- 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 and mortality.
Offspring systemic/neurotoxicity 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.

Lactofen - Herbicide - CAS No. 77501-63-4

Reproduction 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 male fertility.

Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.

Mefluidide and its potassium and diethanolamine salts - Herbicide, Plant growth regulator - CAS Nos. 53780-34-0, 53780-36-2, 83601-83-6)  

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).
Ref: USEPA. Mefluidide - Toxicology section for the Reregistration Eligibility Decision Document (RED) (January 31, 2007)

Metaflumizone (BAS 320 I) - Insecticide - CAS No. 139968-49-3

-- Reproductive and developmental toxicity. ... 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 tolerance petition.

Novaluron - Insecticide - CAS No. 116714-46-6

Excerpt from Table 1.--Subchronic, Chronic, and Other Toxicity
-- 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.
Re: June 2, 2004. Novaluron; Pesticide Tolerance. Final Rule. Federal Register.

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, 2006.

Noviflumuron - 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
Ref: August 2005 - Summary of toxicological data. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

PFOS - PFOS - Insecticide, US EPA List 3 Inert

Due to length, click here for effects page

Pyridalyl - Insecticide - CAS No. 179101-81-6

Species Evaluation Test NOAEL Note
Rat Two-generation reproductive toxicity study

P Male: 2.80 mg/kg bw/day

P Female: 3.11 mg/kg bw/day

F1 Male: 3.40 mg/kg bw/day

F1 Female: 3.62 mg/kg bw/day

Delayed sexual maturation in females
Ref: Evaluation Report. PYRIDALYL. January 14, 2004. Japan Food Safety Commission. Pesticides Expert Committee.

Sodium fluoride - Wood preservative, EPA List 4B Inert - CAS No. 7681-49-4

Due to length, click her for effects page

Sulfluramid - 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 Ellen Connett..)

Tetraconazole -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. (page 5-6)
Ref: August 2005 - Evaluation of Tetraconazole in the product Domark 40ME Fungicide. Australian Pesticides and Veterinary Medicines Authority.

1,2,4-triazole - 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....
Ref: Human Health Aggregate Risk Assessment for Triazole-derivative Fungicide Compounds (1,2,4-Triazole, Triazole Alanine, Triazole Acetic Acid). US EPA, February 7, 2006.

Reproductive 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. Final Rule.

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. [drnathan/sitedex.htm]."

- Balanopreputial skin fold- see:

• 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)
Ref: August 2005 - Evaluation of Tetraconazole in the product Domark 40ME Fungicide. Australian Pesticides and Veterinary Medicines Authority.

Tolylfluanid - 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 (arthrogryposis [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.

Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.

Published by AVENUES A National Support Group for Arthrogryposis Multiplex Congenita -

"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.

Tributyltin fluoride (TBTF) - 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).
Ref: 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

• Excellent "Mitosis animation" available at (scroll down):

Triflumizole - 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. Final Rule.

-- 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 (3.5 mg/kg/day).
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.

Trifluralin - 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. .(page 11-12)
Ref: 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) 28, 1-77.

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