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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan
- Age at study initiation: 8 weeks
- Weight at study initiation: 170 to 223 g
- Fasting period before study: None
- Housing: Animals were individually housed in suspended, stainless steel, wire-mesh cages
- Diet (e.g. ad libitum): Certified Rodent Chow #5002, PMI Feeds, Inc., St. Louis, Missouri; available ad libitum
- Water (e.g. ad libitum): Tap water; available ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature: 68 to 72°F (20 to 22.2°C)
- Humidity (%): 48 to 71%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
The test article was added to the vehicle to achieve the required concentrations, and mixed using a magnetic stir bar. The prepared test article solutions were transferred to amber glass containers by syringe and stored under refrigerated conditions.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test article was characterized using a combination of HPLC and 1H and 13C NMR
Details on mating procedure:
- Impregnation procedure: [purchased timed pregnant] Females were time mated upon delivery, and the day on which evidence of copulation was observed was designated gestational day 0
- Proof of pregnancy: Not reported
Duration of treatment / exposure:
From gestational day 6 to 19
Frequency of treatment:
Once/day
Duration of test:
day 6 of gestation until day 20 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
30 females/group
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice per day during the study period.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily from Days 6 through 20 of gestation, each animal was removed from the cage and given a detailed clinical exarnination. The detailed examination included, but was not limited to, observations ofthe generat appearaß.ce and condition, activity and behavior, excretory matter, respiration, body swface abnorrnalities (scabbing, hair lass), and oral, nasal, and ocular regions. Observations included location, size, and color when applicable.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights recorded on gestational days 0, 6, 9, 12, 15, 18, and 20. Body weight change was recorded for gestational days 0 to 6, 6 to 9, 9 to 12, 12 to 15, 15 to 18, 18 to 20, 6 to 20, and 0 to 20.

FOOD CONSUMPTION: Yes
- Food consumption reported as g food consumed/animal/day for gestational days 0 to 6, 6 to 9, 9 to 12, 12 to 15, 15 to 18, 18 to 20, 6 to 20, and 0 to 20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Uterus, any other organ showing gross lesions
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
- Other: Position of cervix, gross examination of placentae, location of viable and non-viable fetuses, and location of early and late resorptions
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: No
Statistics:
Differences between groups were assessed using Levene’s test, Dunnett’s test, Welch’s test with a Bonferroni correction, Fischer’s exact test with a Bonferroni correction, Chi-square test, Kruskal-Wallis test, Mann-Whitney U-test, and Pearson Chi-square test.
Indices:
None reported
Historical control data:
Yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Description (incidence and severity):
Discoloured feces was observed in 77 and 100% of the animals in the 400 and 1000 mg/kg groups, respectively. Although this observation was considered to be treatment-related, it was likely due to the presence of the test article in the feces, and its toxicological significance is unknown.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No animals died during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test article-related changes in body weight or body weight gain were noted in treated groups when compared with the vehicle control group. Body weights and body weight gain were comparable among all groups, including the vehicle centrot group, during the study.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test article-related changes in food consumption were noted during the study. Food consumption was comparable between the vehicle cantrot and treatment groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test article-related findings were noted at necropsy ofthe dams. One dam from the 1000 mg/kg/day group had a liver adhesion and a nodule an the right kidney. One dam from the 100 mg/kg/day group had granular material on the surface of the right kidney. All other animals were normal at necropsy. Since only single incidences of all findings were noted and no dose response was evident, these findings were considered to be spontaneaus in nature and unrelated to test article administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
not specified
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Remarks:
Maternal toxicity
Effect level:
1 000 mg/kg bw (total dose)
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed at any dose tested.

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One fetus in the 1000 mg/kg group had omphalocele, and another fetus in the 1000 mg/kg group (from a different litter) had an absent tail and anal atresia. These findings were considered to be spontaneous and not treatment-related.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Vertebral malformation was observed in 7.1% of fetuses in the 1000 mg/kg group, compared to 0% in the control group. Slight increases in the incidence of rudimentary ribs and misaligned sternebra were noted in the 100 and 1000 mg/kg groups compared to the control. The incidence of misaligned sternebra and vertebral malformations were considered to be within historical control ranges, and were therefore not considered biologically relevant or treatment-related. Although the incidence of rudimentary ribs was slightly above the historical control range, a dose-related pattern was not observed, and there was no significant difference in incidence compared to the control group. Thus, the incidence of rudimentary ribs was not considered to be biologically relevant or treatment-related.
Visceral malformations:
no effects observed
Description (incidence and severity):
No test article-related effects were noted. Sporadic findings were observed in all groups including the vehicle control, but the incidences were low and no dose relationship was evident.
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Remarks:
Developmental toxicity
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed at any dose tested.

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

As no adverse maternal or fetal effects were observed following the administration of 100, 400, or 1000 mg/kg/day to rats between gestational days 6 and 19, the results of this study indicate that test substance is not teratogenic to rats.

Applicant's summary and conclusion

Conclusions:
The NOEL for pre-natal developmental toxity by oral route in rats was determined to be 1000 mg/kg bw/day since no effects were observed at the highest dose texted.
Executive summary:

A pre-natal developmental toxicity test was performed with FB220 (CAS 16470-24-9) according to OPPTS Guideline 870.3700, equivalent to OECD Guideline 414 (GLP study). Dose levels of 0 (control), 100, 400 and 1000 mg/kg/day were administered via oral gavage daily from Days 6 through 19 of gestation at a volume of 10 mL/kg. The females were time mated upon delivery. The day an which evidence of copulation was observed was considered to be Day 0 of gestation. Observations of dams included clinical signs, gestational body weights and food consumption. Litters were delivered by cesarean section an Day 20 of gestation. Gravid uterine weights were recorded. Total number of irnplantations, early and late resorptions, live and dead fetuses, and sex and individual body weights of fetuses were recorded. External abnormalities of fetuses were recorded. Approximately one-half of the fetuses were examined for visceral abnonnalities, and the remaining fetuses were examined for skeletal abnormalities (hone and cartilage). No mortalities were observed during the study, and the only test article-related clinical observation noted was discolared feces. No changes in maternal body weight, body weight gain, or food consumption were noted in the treatment groups when compared with the vehicle control group. No test article-related necropsy findings were seen. Uterine parameters, including numbers of corpora lutea, irnplantations, live fetuses, and resorptions, gravid uterine weight, and adjusted body weight and body weight gain were comparable between vehicle controls and treatment groups. Pre- and postimplantation loss were similar among all groups, and no test article effects were noted. Fetal extemal, visceral, and skeletal evaluations did not reveal any test article-related effects. All findings were either comparable with the concurrent vehicle control and/or historical control incidences. The No Observed Effect Level (NOEL) for both maternal and developmental toxicity was 1000 mg/kg/day.