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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

2-Gen Repro in rats NOAEL 200 ppm (11.3-17.6 mg/kg/day), OECD 416, OPP 83-4, JMAFF 59-NohSan-4200, Reliability = 1

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-4 (Reproduction and Fertility Effects)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MAFF Testing Guidelines for Toxicology Studies NohSan59, No. 4200
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Substance ID: DPX-JE874-221 Technical
Lot #: DPX-JE874-221
Purity: 97.4%
Species:
rat
Strain:
other: Crl:CD®BR
Details on species / strain selection:
The Crl:CD®BR rat has been selected on the bases of extensive experience with this strain and its suitability with respect to longevity, hardiness, sensitivity, and low incidence of spontaneous diseases.
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
acetone
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples (approximately 10 grams each) were collected from each concentration of diet prepared with the test substance on test days -1 and 62 of the P1 generation and days 65 and 121 of the F1 generation.
The measured concentrations of the test substance in the recovery samples that were prepared with each diet analysis were 105.6 to 111.5% of nominal at the low concentrations and 87.2 to 109.9% of nominal at the high concentrations. These data indicate that the method performed satisfactorily over the entire concentration range.
Measured concentrations of the test substance in samples of test day -1, were 19.7 to 19.9 ppm at the 20 ppm level (C.V. = 0.51% for top, middle, and bottom); from 194 to 214 ppm at the 200 ppm level (C.V. = 5.1%); and from 768 to 842 ppm at the 800 ppm level (C.V. = 5.4%). These data indicate that the test substance was distributed homogeneously in the diet. Test substance was not detected in control diet.
Concentrations of the test substance were from 92.4 to 101.1% of nominal for all storage conditions. These data indicated that test substance was stable in diets that were stored at room temperature for 7 or 14 days or refrigerated for 14 days.
Diet samples were prepared on test day 62, P1, test day 65, F1, and test day 121, F1. Measured concentrations of the test substance in these samples were from 97.0 to 107.0% of nominal, 97.5 to 109.9% of nominal, and 102.6 to 110.0% of nominal, respectively. The test substance was not detected in control diets for any of the submittals.
Duration of treatment / exposure:
For 2 generations (approximately 9 weeks of age (P1) to scheduled necropsy (F1))
Frequency of treatment:
Daily
Dose / conc.:
20 ppm
Dose / conc.:
200 ppm
Dose / conc.:
800 ppm
No. of animals per sex per dose:
30
Control animals:
yes, plain diet
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in the incidence of diarrhea in P1 males in the rats fed 800 ppm. Statistically significant increase in the incidence of alopecia for P1 females during gestation in the rats fed 800 ppm.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reductions in mean body weight, and overall mean body weight gain for P1 males in the rats fed 800 ppm. Statistically significant reduction in mean body weight for P1 females during gestation and on lactation days 0, 7, and 14 in the rats fed 800 ppm.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reductions in overall mean food consumption for P1 males, for P1 males during premating and gestation in the rats fed 800 ppm.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reductions in overall mean food efficiency for P1 males during premating in the rats fed 800 ppm.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Evidence for altered lipid metabolism; statistically significant decrease in mean triglyceride concentration for P1 males and females, and statistically significant increase in mean cholesterol concentration for P1 females in the rats fed 800 ppm.
Statistically significant increase in hepatic enzyme activities and serum bilirubin concentration indicating hepatocellular injury and cholestasis for P1 males in the rats fed 800 ppm.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in hepatic peroxisomal ß-oxidation rate for P1 males and females in the rats fed 800 ppm.
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no biologically or statistically significant dose-related differences in mating, fertility, or gestation indices, implantation efficiency, or gestation length in the P1 generation.
Key result
Dose descriptor:
NOAEL
Effect level:
200 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
food efficiency
clinical biochemistry
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in the incidence of alopecia for F1 females during the premating and gestation in the rats fed 800 ppm.
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
For F1 litters of 800 ppm females, 0-4 day viability was statistically significantly reduced, however, that reduction was considered not to be adverse since the value (98.8%) fell well within the range of control data.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significantly reduced mean pup weight throughout the 21-day lactation period for F1 litters in the rats fed 800 ppm.
Statistically significant reductions in mean body weight, and overall mean body weight gain for F1 males in the rats fed 800 ppm.
Statistically significant reduction in mean body weight for F1 females on lactation days 0, 7, and 14 in the rats fed 800 ppm.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reductions in overall mean food, consumption for F1 males during premating and gestation in the rats fed 800 ppm.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Evidence for altered lipid metabolism; statistically significant decrease in mean triglyceride concentration for F1 males and females, and statistically significant increase in mean cholesterol concentration for F1 males and females in the rats fed 800 ppm.
Statistically significant increase in hepatic enzyme activities and serum bilirubin concentration indicating hepatocellular injury and cholestasis for F1 males in the rats fed 800 ppm.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in mean relative liver weight for F1 females in the rats fed 800 ppm. Statistically significant decreases in mean absolute liver weight for F1 males in the rats fed 800 ppm.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant increase in hepatic peroxisomal ß-oxidation rate for F1 males and females in the rats fed 800 ppm.
There were no biologically or statistically significant dose-related differences in mating, fertility, or gestation indices, implantation efficiency, or gestation length in the F1 generation.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
200 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significantly reduced mean pup weight from postpartum day 4 through the end of lactation period for F2 litters in the rats fed 800 ppm.
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
200 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Key result
Reproductive effects observed:
no
Conclusions:
Rat NOAEL (Parental and offspring): 200 ppm
Executive summary:

A two-generation reproduction study was conducted with the test substance involving the production of one set of litters in each generation according to the guidelines OECD 416 and EPA 83-4. Throughout this study, rats (30/sex/concentration) were fed diets containing concentrations of 0, 20, 200, or 800 ppm. Following at least 70 days of diet administration, the animals were bred within their respective treatment groups, and allowed to deliver and rear their offspring until weaning (postpartum day 21). At weaning, 30 F1 rats/sex/group were randomly selected to produce the next generation. At least 105 days after weaning, the F1 rats were bred within their respective treatment groups to produce F2 litters. Barring F1 weanlings selected for propagation of the next generation, twenty F1 and F2 weanlings/ sex/concentration were designated for gross postmortem examination. The remaining unselected weanlings were sacrificed without pathological examination.


Prior to mating, clinical chemistry evaluations were performed on selected adult animals (10/sex/concentration) in both generations. After litter production, all parental rats were given a gross pathological examination. Testes (weighed), epididymides, prostate, seminal vesicles, coagulating gland, and pituitary were collected from each male. Ovaries, uterus, cervix, vagina, and pituitary were collected from each female. Livers of all adult animals were weighed and peroxisomal ß-oxidation assays were performed on liver samples of selected adult animals (5/sex/concentration) in both generations that had undergone clinical chemistry evaluations. The loss of liver samples resulted in ß-oxidation-evaluation of only 4 rats/group in the 200 ppm P1 male and F1 male and female groups. Tissues from rats in the control and 800 ppm groups of both generations were examined microscopically. In addition, gross lesions and target organs from adult rats in all dose groups were microscopically examined.


At the 800 ppm level, adverse effects considered to be related to the treatment include:



  • Statistically significant reductions in mean body weight, and overall mean body weight gain for P1 and F1 males.

  • Statistically significant reductions in overall mean food, consumption for P1 and F1 males, and overall mean food efficiency for P1 males during premating.

  • Statistically significant increase in the incidence of diarrhea in P1 males.

  • Statistically significant reductions in mean body weight, overall mean body weight gain, and overall mean food consumption for P1 and F1 females, and overall mean food efficiency for P1 females during the premating period.

  • Statistically significant reductions in mean body weight and overall mean food consumption for P1 and F1 females during gestation.

  • Statistically significant reduction in mean body weight for P1 and F1 females on lactation days 0, 7, and 14.

  • Statistically significant increase in the incidence of alopecia for F1 females during the premating period and for P1 and F1 females during gestation.

  • Statistically significantly reduced mean pup weight throughout the 21-day lactation period for F1 litters and from postpartum day 4 through the end of lactation period for F2 litters.

  • Statistically significant increase in hepatic peroxisomal ß-oxidation rate for P1 and F1 males and females.

  • Statistically significant increase in mean relative liver weight for P1 and F1 females.

  • Evidence for altered lipid metabolism; statistically significant decrease in mean triglyceride concentration for P1 and F1 males and females, and statistically significant increase in mean cholesterol concentration for P1 and F1 females and F1 males.

  • Statistically significant decreases in mean absolute liver weight for P1 and F1 males, and mean relative liver weight for P1 males.

  • Statistically significant increase in hepatic enzyme activities and serum bilirubin concentration indicating hepatocellular injury and cholestasis for P1 and F1 males.


No adverse compound-related effects were observed at dose levels of 200 ppm and below. Therefore, the no-observed-effect level (NOEL) for adult rats and their offspring was 200 ppm.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
A guideline 2-generation study was available in rats.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In the multigeneration reproduction study in rats with famoxadone, the NOAEL for adult rats and their offspring was 200 ppm (11.3-17.5 mg/kg bw/day).  This was based on body weight effects (decreased body weight, body weight gains, food consumption, and food efficiency), hepatotoxicity (increased liver enzymes, serum bilirubin, and peroxisome proliferation), and clinical signs (diarrhoea and alopecia) in one or more of the 800 ppm adult groups (male and female P1 and F1 generations), which was equivalent to mean daily intakes of 44.7 to 62.1 mg/kg bw/day.  The reproductive indices were unaffected by famoxadone exposure; there were decreased pup weights observed in both the F1 and F2 generations at 800 ppm.

Effects on developmental toxicity

Description of key information

Rat Developmental Maternal NOAEL 250 mg/kg/day, Fetal NOAEL 1000 mg/kg/day, OECD 414, OPP 83-3, JMAFF 59-NohSan-4200, Reliability = 1


Rabbit Developmental Maternal NOAEL 350 mg/kg/day, Fetal NOAEL 1000 mg/kg/day, OECD 414, OPP 83-3, JMAFF 59-NohSan-4200, Reliability = 1

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
other: MAFF Testing Guidelines for Toxicology Studies NohSan 59, No. 4200
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Substance name: DPX-JE874
Lot #: DPX-JE874-221
Purity: 97.4%
Species:
rat
Strain:
other: Crl:CD®BR
Route of administration:
oral: gavage
Vehicle:
other: water containing 0.5% Tween 80
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
on days 7-16 of gestation
Frequency of treatment:
Once daily
Duration of test:
10 days
Dose / conc.:
125 mg/kg bw/day
Dose / conc.:
250 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No compound-related effects on the incidence or type of clinical observations were seen at any dose level.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two rats died prior to scheduled sacrifice but neither death was related to administration of the compound. One rat in the control group sacrificed in extremis on Day 15G after clinical observations suggestive of gavage trauma were recorded. Postmortem observations confirmed that the animal had been misdosed. One rat in the 125 mg/kg/day group was found dead was Day 5G. The urinary bladder obstructed with a calculus, causing hydronephrosis. Since this animal died before dosing started, another animal was assigned to the 125 mg/kg/day group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight gains were significantly reduced at 500 and 1000 mg/kg/day over 7-9G. No other effects on maternal weights, weight gains, or adjusted weights were seen.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Maternal food consumption was significantly reduced at 500 and 1000 mg/kg/day over 7-9G. For the 1000 mg/kg/day group, a rebound in food consumption was observed as the mean food consumed over days 17-22G was significantly increased. No other effects on maternal food consumption were seen.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No compound-related effects were detected during the gross postmortem examinations.
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
No compound-related effects on fetal mortality were observed. The incidence of early, late, or total resorptions was comparable across dose groups. At the high dose level, there was on litter that consisted of two dead fetuses. However, at necropsy, the maternal uterus was observed to be twisted and distended with red fluid. This finding is not believed to be compound related.
Other effects:
no effects observed
Description (incidence and severity):
No compound-related effects on any reproductive parameter (pregnancy rate, incidence of dams with total resorptions, mean corpora lutea, mean number of implantations, mean number of live and dead fetuses per litter, and mean sex ratio) were detected.
Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Mean fetal weight was unaffected by exposure to the test substance
Other effects:
no effects observed
Description (incidence and severity):
No compound-related effect on the incidence of any fetal malformation was detected.
No compound-related effect on the incidence of any fetal variation was detected.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: highest dose tested
Key result
Developmental effects observed:
no
Conclusions:
Rat NOAEL: 250 mg/kg/day (maternal toxicity); 1000 mg/kg/day (developmental toxicity, highest dose tested)
Executive summary:

This study was conduted following OECD guideling 414 and US EPA 83-3. The test substance was administered by gavage to groups of 25 Crl:CD®BR female rats on days 7-16 of gestation at dose levels of 0, 125, 250, 500, or 1000 mg/kg/day. Maternal toxicity was evident at 500 and 1000 mg/kg/day as significant dose-related decreases in maternal body weight gain and food consumption. No evidence of maternal toxicity was detected at 250 or 125 mg/kg/day. Therefore, under the conditions of this study, the maternal NOAEL was 250 mg/kg/day. Developmental toxicity was not detected at any dose level. The NOAEL for developmental toxicity was 1000 mg/kg/day. The test substance is not considered to be uniquely toxic to the conceptus.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MAFF Testing Guidelines for Toxicology Studies NohSan 59, No. 4200
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Substance name: DPX-JE874
Lot #: DPX-JE874-221
Purity: 97.4%
Species:
rabbit
Strain:
New Zealand White
Remarks:
Hra:(NZW)SPF
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: HRP, Inc., Denver, Pennsylvania
- Weight at study initiation: 2722 to 4063 grams (on Day 4 of gestation)
- Fasting period before study: No
- Housing: Housed individually in suspended, wire-mesh, stainless steel cages.
- Diet: The rabbits were provided approximately 150 grams of Purina Certified Rabbit Chow #5325 per day.
- Water: Tap water, ad libitum
- Acclimation period: At least 4 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20±2°C
- Humidity: 50±10%
- Photoperiod: 12 hrs dark /12 hrs light
Route of administration:
oral: gavage
Vehicle:
other: 0.5% Tween 80/water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples (~3 mL each) of each test formulation were taken three times during the study. At the first sampling, four independent samples from each test formulation were collected. One sample of the vehicle and three of the four samples from each test formulation were analyzed immediately after submission. The fourth sample was held for five hours at room temperature, then analyzed for stability. At the second and third samplings, one sample of the vehicle and two samples from each test formulation were analyzed immediately following submission, to verify concentration.
The results of these analyses indicated that the dosing formulations were at expected concentrations, were homogeneous, and were stable for five hours at room temperature. DPX-JE874-221 was not detected in the control formulation.
Details on mating procedure:
Time-mated rabbits were used
Duration of treatment / exposure:
GD 7-19
Frequency of treatment:
Once daily
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
350 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
20 time-mated females per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels of 0, 100, 350, and 1000 mg/kg were selected based on the range finding (rabbits dosed at 2000 and 3000 mg/kg) and pilot developmental (dosed at 0 and 1000 mg/kg) studies conducted on rabbits. comparable to control group values. Under the conditions of this pilot study, maternal and fetal toxicity were not detected at levels up to 1000 mg/kg/day, the maximum achievable dose. Thus, the maximum tolerated dose, which is greater than 1000 mg/kg/day, was not determined in this study.
Maternal examinations:
Observations for morbidity and mortality were made daily. Females were weighed on gestation Days 4, 7-20, 24 and 29. Food was weighed daily on Days 4-29 and individual clinical signs were recorded each morning on Days 4-29 and each afternoon on Days 7-19 (the dosing period).
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes (all per litter)
- Soft tissue examinations: Yes (all per litter)
- Skeletal examinations: Yes (all per litter)
- Head examinations: No data
Statistics:
Sequential trend testing was applied to the data. Linear contrast of means from ANOVA for the parameters Maternal weight, Maternal weight changes and Maternal food consumption. Jonckheere test for Live fetuses, Dead fetuses, Resorptions, Nidations, Corpora lutea and Incidence of fetal alterations. Cochran-Armitage test for Incidence of pregnancy, Clinical observations, Maternal mortality, Incidence of abortion, Females with total resorptions and Early deliveries. Linear contrast of least square means from ANCOVA for the parameters Fetal weight (Covariates: litter size, sex ratio) and Sex ratio (Covariate: litter size).
If significant dose-response was detected, data from the top dose group was excluded and the test repeated until no significant trend was detected- For litter parameters, the proportion of affected fetuses per litter or the litter mean was the experimental unit for statistical evaluation. The level of significance selected was p≤0.05.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Over Days 7-19, the incidence of small stools and/or tan stools was significantly increased at 1000 mg/kg/day; six of 20 rabbits were affected. This condition persisted for three animals resulting in a statistically significant increase for Days 20-29. Three of 20 rabbits in this group also had either a small amount of stool or no stool over Days 7-19. These findings are due to the fact the dosing suspension for the high dose group was maximally concentrated and the relatively large volume of dosing suspension that was administered. Otherwise, no compound-related effects on the incidence of any clinical observation were observed.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No compound-related mortality occurred during this study. One rabbit in the 100 mg/kg/day group died prior to scheduled sacrifice as a result of injuries sustained during dosing.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Gross pathological findings:
no effects observed
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
The incidence of females that aborted was statistically significantly increased at 1000 mg/kg/day; four of 20 does aborted over days 19-23 of gestation. At 100 mg/kg/day, there were two does that aborted. Although abortion can typically be considered an adverse developmental outcome, there was also evidence of significant maternal stress in the affected animals.
Prior to actually aborting, all four animals at 1000 mg/kg/day exhibited severe decrements in body weight gain and food consumption. These animals also had tan stools. Additionally, postmortem findings for one of these four animals indicated trichobezoar. For one of the females at 100 mg/kg/day, no evidence of toxicity was seen before the abortion which occurred on day 18 of gestation. This particular abortion is believed to have occurred by chance and is not considered to be compound-related or dosing-related. The other female at 100 mg/kg/day did exhibit reductions in weight gain and food consumption, similar to those seen in the affected does from the 1000 mg/kg/day group, prior to aborting on day 21 of gestation. Postmortem evaluation revealed white fibrous stomach contents. This observation is likely indicative of trichobezoar. For this animal and for those animals that aborted at 1000 mg/kg/day, these observations are believed to be a result of the confounding stress associated with the method of compound/dosing suspension delivery.
Because of the lack of demonstrable toxicity in pilot work, the doses for the current study were set to span a range of levels up to the limit dose level of 1000 mg/kg. These relatively high dose levels necessitated working with the maximum achievable suspension concentration. Thus, the dosing suspensions were quite thick, especially for the 1000 mg/kg/day group, and are believed to have caused a mechanical impaction of the gastrointestinal tract of the affected animals. For one of the four affected females at 1000 mg/kg and for the one affected female at 100 mg/kg, this impaction was likely facilitated by the alleged trichobezoar. The clinical observations in the five affected animals are consistent with gastrointestinal tract impaction. The abortions are therefore considered secondary to the gastrointestinal tract impaction.
Additional support for this conclusion is provided by the following points. First, this finding is not observed in a dose-related fashion; no abortions occurred at 350 mg/kg/day. Second, there is no other manifestation of compound-related toxicity in any other non-aborting study animal when either maternal or fetal endpoints are considered. These factors support the conclusion that the abortions were a stress-related response to being gavaged with a large volume of a thick, maximally-concentrated dosing suspension.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: clinical signs and abortions
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on fetus
Remarks on result:
other: no effects at the highest dose tested
Key result
Developmental effects observed:
no
Conclusions:
Maternal NOEL (rabbit): 1000 mg/kg/day, NOAEL = 350 mg/kg/day
Developmental NOAEL (rabbit): 1000 mg/kg/day
Executive summary:

The purpose of this study was to evaluate the developmental toxicity of the test substance in rabbits according to the guidelines OECD 414 and EPA 83-3. The test substance was administered by gavage to groups of 20 Hra:(NZW)SPF time-mated female rabbits on days 7-19 of gestation at dose levels of 0, 100, 350, or 1000 mg/kg/day. There were no effects that were considered evidence of systemic toxicity of the test substance. There were, however, effects which were attributed to the physical properties of the dosing suspension.


The incidence of females that aborted was statistically significantly increased at 1000 mg/kg/day; four of 20 does aborted over days 19-23 of gestation. At 100 mg/kg/day, there were two does that aborted. Although abortion can typically be considered an adverse developmental outcome, there was also evidence of significant maternal stress in the affected animals.


Prior to actually aborting, all four animals at 1000 mg/kg/day exhibited severe decrements in body weight gain and food consumption. These animals also had tan stools. Additionally, postmortem findings for one of these four animals indicated trichobezoar. For one of the females at 100 mg/kg/day, no evidence of toxicity was seen before the abortion which occurred on day 18 of gestation. This particular abortion is believed to have occurred by chance and is not considered to be compound-related or dosing-related. The other female at 100 mg/kg/day did exhibit reductions in weight gain and food consumption, similar to those seen in the affected does from the 1000 mg/kg/day group, prior to aborting on day 21 of gestation. Postmortem evaluation revealed white fibrous stomach contents. This observation is likely indicative of trichobezoar. For this animal and for those animals that aborted at 1000 mg/kg/day, these observations are believed to be a result of the confounding stress associated with the method of compound/dosing suspension delivery.


Because of the lack of demonstrable toxicity in pilot work, the doses for the current study were set to span a range of levels up to the limit dose level of 1000 mg/kg. These relatively high dose levels necessitated working with the maximum achievable suspension concentration. Thus, the dosing suspensions were quite thick, especially for the 1000 mg/kg/day group, and are believed to have caused a mechanical impaction of the gastrointestinal tract of the affected animals. For one of the four affected females at 1000 mg/kg and for the one affected female at 100 mg/kg, this impaction was likely facilitated by the alleged trichobezoar. The clinical observations in the five affected animals are consistent with gastrointestinal tract impaction. The abortions are therefore considered secondary to the gastrointestinal tract impaction.


Additional support for this conclusion is provided by the following points. First, this finding is not observed in a dose-related fashion; no abortions occurred at 350 mg/kg/day. Second, there is no other manifestation of compound-related toxicity in any other non-aborting study animal when either maternal or fetal endpoints are considered. These factors support the conclusion that the abortions were a stress-related response to being gavaged with a large volume of a thick, maximally-concentrated dosing suspension.


Under the conditions of this study, systemic compound-related toxicity was not demonstrated at daily dose levels up to 1000 mg/kg/day. The maternal and developmental no-observed-effect level (NOEL) for systemic compound-related toxicity was 1000 mg/kg/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In the rat teratogenicity study, maternal effects were limited to reduced body weight and food consumption at 500 and 1000 mg/kg bw/day.  No compound-related changes were observed in any foetal endpoint.  As a result, the maternal NOAEL was 250 mg/kg bw/day, and the NOAEL for the conceptus was 1000 mg/kg bw/day.


In the rabbit teratogenicity study, an increase in small and/or tan stools and increased incidence of abortions were observed at the high dose of 1000 mg/kg bw/day.  No effects attributed to exposure to famoxadone were observed in any foetal endpoint.  Therefore, the maternal NOAEL was 350 mg/kg bw/day, and the foetal NOAEL was 1000 mg/kg bw/day.

Justification for classification or non-classification

Famoxadone is not a reproductive or developmental toxin and does not present a unique hazard to the conceptus.  Therefore, the test substance is not classified for reproductive toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information