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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:
04 March 2016 to 21 April 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
On one occasion too much test item was used for the Group 2 formulation. In the range finding study, temporary deviations from the daily mean relative humidity occurred. The study integrity was not adversely affected by the deviations.
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
On one occasion too much test item was used for the Group 2 formulation. In the range finding study, temporary deviations from the daily mean relative humidity occurred. The study integrity was not adversely affected by the deviations.
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
Identification: Bismuth Trinitrate
Chemical name (IUPAC), synonym or trade name: Bismuth(3+) trinitrate, Bismuth trinitrate, Bismuth(III) nitrate pentahydrate
CAS Number: 10361-44-1

Specific details on test material used for the study:
Appearance: White crystalline powder
Batch: 2011001922
Test item storage: At room temperature
Stable under storage conditions until 30 April 2017 (retest date)
Purity/composition correction factor: No correction factor required
Test item handling: No specific handling conditions required
Stability at higher temperatures: Yes

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI(Han)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Approximately 10-14 weeks.
- Weight at study initiation: 174 to 254 g
- Fasting period before study: not specified
- Housing: Females were individually housed in Macrolon plastic cages (MIII type, height 18 cm).Sterilized sawdust as bedding material (Lignocel S 8-15, JRS-J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment/nesting material (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom) were supplied.
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap-water.
- Acclimation period: At least 5 days prior to treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): a relative humidity of 40 to 70%
- Air changes (per hr): at least 10 air changes/hour
- Photoperiod (hrs dark / hrs light): a 12-hour light/12-hour dark cycle.

IN-LIFE DATES: From: 04 March 2016 To 21 April 2016

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at WIL Research Europe B.V.
- Concentration in vehicle: 20 mg/mL, 60 mg/mL, 200 mg/mL
- Amount of vehicle (if gavage): 5mL/kg
- Lot/batch no.: Not specified
- Purity: Not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical conditions:
Instrument: Agilent 7500CE (Agilent Technologies, Tokyo, Japan)
Cone: Nickel
Nebulizer Type: MicroMist, Material quartz
Spray chamber: Material quartz, Temperature 15°C
Torch: 2.5 mm i.d.
Detection of Bi:
Reaction gas: none
Integration time: 0.1 seconds per replicate
Replicates per analysis: 5
Quantitation on m/z: 209

Test Samples:
A small response at the retention time of the test item was observed in the chromatograms of the Group 1 formulation prepared for use during treatment. It was not considered to derive from the formulation since a similar response was obtained in the analytical blanks.
The concentrations analysed in the formulations of Group 2 and Group 3 were in agreement with target concentrations (i.e. mean accuracies between 90% and 110%).
For the formulation of Group 4 prepared for use during treatment, the mean accuracy was slightly below the target concentration (i.e. 88% of target). Since the deviation was small and the result was similar to the mean recovery of the QC samples at concentration level 200 mg/g, the results were accepted and to have no effect on the integrity of the study.
Homogeneity
The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%).
Details on mating procedure:
Untreated females were mated at the Supplier, and were at Day 0 or 1 post-coitum on arrival at the Test Facility (Day 0 post-coitum was the day of successful mating; confirmed by vaginal plug).
Duration of treatment / exposure:
From Days 6 to 20 post-coitum, inclusive.
Frequency of treatment:
Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.
Duration of test:
20 days after mating
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
22 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on results of the dose range finding study.
- Rationale for animal assignment: One day after receipt, by computer-generated random algorithm according to body weight, with all animals within ± 20% of the mean per subgroup. Females which were mated on the same day are classified in the same subgroup.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality / viability at least twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily from Day 2 post-coitum onwards up to the day prior to necropsy. The time of onset, grade and duration of any observed signs were recorded. Signs were graded for severity and the maximum grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored.

BODY WEIGHT: Yes
- Time schedule for examinations: Days 2, 6, 9, 12, 15, 18 and 21 post-coitum.

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum.

WATER CONSUMPTION: Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day:
Females surviving to planned necropsy: Day 21 post-coitum.
Females with early delivery (nos. 10, 11, 30, 31, 74): Within 24 hours of early delivery.
Spontaneous deaths (no. 77): As soon as possible after death and always within 24 hours.
- Organs examined: All animals surviving to the end of the observation period and all animals showing premature delivery were sacrificed using an oxygen/carbon dioxide procedure and subsequently subjected to an external, thoracic and abdominal examination, with special attention being paid to the reproductive organs. All macroscopic abnormalities were recorded, collected and fixed in 10% buffered formalin (neutral phosphate buffered 4% formaldehyde solution, Klinipath, Duiven, The Netherlands).
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes (not for animals found dead)
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes, externally visible macroscopic fetal abnormalities.
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]
- The weight of each fetus (not for animals found dead).
- The sex of each fetus from the ano-genital distance (during necropsy) and also from gonadal inspections (during further fetal examination).

External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).

External:
Each viable fetus was examined in detail, weighed and sexed. All live fetuses were euthanized by administration of approximately 0.05 mL (=10mg) of sodium pentobarbital (Euthasol® 20%; AST Farma B.V., Oudewater) into the oral cavity using a small flexible plastic or metal feeding tube.
For late resorptions a gross external examination was performed, after which they were discarded.

Visceral (Internal):
Approximately one-half of the fetuses (live and dead) in each litter (all groups) were examined for visceral anomalies by dissection in the fresh (non-fixed) state. The thoracic and abdominal cavities were opened and dissected using a technique described by Stuckhardt and Poppe. This examination included the heart and major vessels. Fetal kidneys were examined and graded for renal papillae development as described by Woo and Hoar. The sex of all fetuses was confirmed by internal examination.
The heads were removed from approximately one-half of the fetuses in each litter and placed in Bouin's solution (Klinipath, Duiven, The Netherlands) for soft-tissue examination of all groups using the Wilson sectioning technique. After examination, the tissues without variation or malformations were discarded.
Any remaining tissues (from the fetuses used for fresh visceral examination) were discarded. The carcasses were processed and stained with Alizarin Red S (as described below), but not examined in first instance.

Skeletal:
From the other one-half of the fetuses (live and dead) in each litter (all groups), the sex was confirmed by internal examination. All fetuses were eviscerated, fixed in 96% aqueous ethanol, macerated in potassium hydroxide (Merck, Darmstadt, Germany) and stained with Alizarin Red S (Klinipath, Duiven, The Netherlands) by a method similar to that described by Dawson. Skeletal examination was done for one-half of the fetuses (i.e. the fetuses with heads).
The specimens were archived in glycerin (BRENNTAG Nederland B.V., Dordrecht, The Netherlands) with bronopol (Alfa Aesar, Karlsruhe, Germany) as preservative.
A few bones were not available for skeletal examination because they were accidentally damaged or lost during processing. The missing bones were listed in the raw data; evaluation by the fetal pathologist and study director determined there was no influence on the outcome of the individual or overall skeletal examinations, or on the integrity of the study as a whole.
Statistics:
The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control group.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test (Ref. 8) was applied to frequency data.
- The Mann Whitney test (Ref. 9) was used to compare mean litter proportions (percent of litter) of the number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and post-implantation loss, and sex distribution.
- Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test (Ref. 10) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test (Ref. 11) was used to compare the compound-treated groups to the control group. All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations might be rounded off before printing. Therefore, two groups might display the same printed means for a given parameter, yet display different test statistics values. No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and post-implantation loss.
Indices:
For each litter the following calculations were performed:
Pre-implantation loss (%) = (number of corpora lutea - number of implantation sites)/ number of corpora lutea x 100
Post-implantation loss (%) = (number of implantation sites - number of live fetuses)/ number of implantation sites x 100
The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a mean litter proportion on a total group basis, where:
Viable fetuses affected/litter (%) = number of viable fetuses affected/liter/number of viable fetuses/litter x 100
Historical control data:
Historical Control Data were used from Rat: Crl:WI(Han).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Incidental findings that were noted included scales and scabs, rales and alopecia. As these signs were observed for single females only, they were not considered to be toxicologically relevant.
Dermal irritation (if dermal study):
not specified
Description (incidence and severity):
Not a dermal study.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female (no. 77) at 1000 mg/kg died directly after dosing on Day 18 post-coitum. No clinical signs were observed. At necropsy, discolouration of the lungs, heart and thymus was noted and the thoracic cavity contained fluid. Based on these findings, this death was considered to be caused by gavage procedure and not related to treatment with the test item. This female was pregnant and had 9 dead fetuses and 1 early resorption. No remarkable morphological findings were noted for these fetuses.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Mean body weights, body weight gain and body weight gain corrected for gravid uterus weight of treated females remained in the same range as controls over the treatment period. Body weight gain was statistically significantly lower at 1000 mg/kg on Day 9 post-coitum, compared to controls. As this decrease was very slight, and not consistent over time, this was not considered to be treatment related.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Mean food consumption (before and after correction for body weight) was similar between treated and control females.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.
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):
Macroscopic examination at necropsy revealed no treatment-related findings.
A nodule on the liver of one female at 100 mg/kg and a diaphragmatic hernia of the liver of one female at 300 mg/kg were considered to be incidental and not treatment related. Alopecia was noted for one female at 1000 mg/kg, confirming the clinical sign observed during the in life phase.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
No maternal toxicity was observed in the 100, 300 and 1000 mg/kg groups.

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No females aborted.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
There were no toxicologically relevant effects on the number of corpora lutea, implantation sites, pre- and post-implantation loss by treatment up to 1000 mg/kg.
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
Group 1 (0 mg/kg): 7 early resorptions and 0 late resorptions.
Group 2 (100 mg/kg): 9 early resporptions and 1 late resorption.
Group 3 (300 mg/kg): 10 early resorptions and 0 late resorptions.
Group 4 (1000 mg/kg): 12 early resorptions and 1 late resorption.
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
Group 1 (0 mg/kg): 7 early resorptions and 0 late resorptions.
Group 2 (100 mg/kg): 9 early resporptions and 1 late resorption.
Group 3 (300 mg/kg): 10 early resorptions and 0 late resorptions.
Group 4 (1000 mg/kg): 12 early resorptions and 1 late resorption.
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no dead fetuses.
Changes in pregnancy duration:
effects observed, non-treatment-related
Description (incidence and severity):
Females with early delivery (nos. 10, 11, 30, 31, 74): Five females (nos. 10, 11 (Group 1), 30, 31 (Group 2) and 74 (Group 4)) delivered on Day 21 post-coitum. As these findings concerned different groups and no dose-response relationship was observed, it was not considered to be treatment related.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
Six females (nos. 32, 44 (Group 2), 63, 65 (Group 3), 69 and 87 (Group 4)) were not pregnant. Moreover, one control female (no. 19) was pregnant, but had only one early resorption. As these findings concerned different groups and no dose-response relationship was observed, it was not considered to be treatment related.
Other effects:
not specified
Details on maternal toxic effects:
No maternal toxicity was observed in the 100, 300 and 1000 mg/kg groups. No developmental toxicity was observed in the 100, 300 and 1000 mg/kg groups.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: No maternal toxicity was observed up to the highest dose tested. No developmental toxicity was observed up to the highest dose tested.

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no effects on fetal body weight (per sex and combined for both sexes) noted by treatment up to 1000 mg/kg.
Mean fetal body weights (sexes combined) were 5.0 g, 5.1 g, 5.1 g and 5.1 g for the control, 100, 300 and 1000 mg/kg groups
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): There were no effects on fetal body weight (per sex and combined for both sexes) noted by treatment up to 1000 mg/kg.
Mean fetal body weights (sexes combined) were 5.0 g, 5.1 g, 5.1 g and 5.1 g for the control, 100, 300 and 1000 mg/kg groups
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
One control female (no. 19) was pregnant, but had only one early resorption. All other pregnant females had live fetuses.
Changes in sex ratio:
effects observed, non-treatment-related
Description (incidence and severity):
No toxicologically relevant changes in male:female ratios were noted by treatment up to 1000 mg/kg
Mean sex ratios (males:females) were 41:59, 53:47, 55:45 and 54:46 for the control, 100, 300 and 1000 mg/kg groups, respectively. The statistically significant changes in sex ratio in all treated groups compared to control were considered to have arisen as a result of slightly high number of female fetuses in the control group. As the ratios of the treatment groups were within normal limits and in absence of a dose response relationship, this was not considered to be treatment related.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There were no treatment related effects on litter size for any group. Mean litter sizes were 10.1, 10.5, 10.3 and 10.4 fetuses/litter for the control, 100, 300 and 1000 mg/kg groups, respectively.
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
One control female (no. 19) was pregnant, but had only one early resorption. All other pregnant females had live fetuses.
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment related effects on external morphology following treatment up to 1000 mg/kg.
There were only two external malformations observed in this study. Group 4 fetus A085-01 had a cleft palate and Group 2 fetus A025-03 had a small lower jaw. Both these malformations were confirmed at skeletal examination and since they occurred singly, they were considered chance findings.
External variations were not seen in any group.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment related effects on skeletal morphology following treatment up to 1000 mg/kg.
Four malformed fetuses were revealed at skeletal examination. Group 4 fetus A085-01 (the one with cleft palate externally) also appeared to have fused nasal bones. In Group 2, fetus A031-01 and A037-01 both had bent limb bones and the latter one also had a vertebral anomaly. The last affected fetus was control fetus A017-12 which had bent limb bones as well. The group distribution and low incidence of the above mentioned malformations do not suggest any treatment relationship.
Skeletal variations occurred at an incidence of 90.1%, 89.3%, 86.0% and 80.7% per litter in Groups 1, 2, 3 and 4, respectively. All the ones noted were not considered to be treatment related as they occurred in the absence of a dose-dependent relationship, infrequently and/or at frequencies that were within the range of available historical control data.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment related effects on visceral morphology following treatment up to 1000 mg/kg.
Visceral malformations were not observed. The variations that were noted in this study occurred at low incidences and in the absence of a dose-related incidence trend and were therefore not considered to be treatment related.
Details on embryotoxic / teratogenic effects:
No developmental toxicity was observed in the 100, 300 and 1000 mg/kg groups.

Effect levels (fetuses)

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 developmental toxicity was observed up to the highest dose tested.

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Figures and tables are attached below under 'Attached background material'.

Applicant's summary and conclusion

Conclusions:
Mated female Wistar Han rats were assigned to four dose groups, each containing twenty-two animals. The test item was administered once daily by gavage from Day 6 to 20 post-coitum at doses of 100, 300 and 1000 mg/kg (Groups 2, 3 and 4 respectively). The rats of the control group (Group 1) received the vehicle, propylene glycol, alone.

Accuracy and homogeneity of formulations were demonstrated by analyses.

Maternal findings
No maternal toxicity was observed in the 100, 300 and 1000 mg/kg groups.

Developmental findings
No developmental toxicity was observed in the 100, 300 and 1000 mg/kg groups.

In conclusion, based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for Bismuth trinitrate was established as being at least 1000 mg/kg
Executive summary:

Study outline

Eighty-eight mated female Wistar Han rats were assigned to four dose groups. The test item was administered once daily by oral gavage from Days 6 to 20 post-coitum at doses of 100, 300 and 1000 mg/kg (Groups 2, 3 and 4 respectively). The rats of the control group received the vehicle, propylene glycol, alone. Females were checked daily for the presence of clinical signs. Food consumption and body weight were determined at periodic intervals. Formulations prepared on one day during treatment were analyzed for accuracy and homogeneity.

All animals surviving to Day 21 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and corrected body weights (changes) were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. All live fetuses were euthanized. One half of the fetuses were decapitated and the heads were fixed in Bouin’s fixative; these fetuses were dissected and examined for visceral anomalies. The other one-half of the fetuses were processed and stained with Alizarin Red S for skeletal examinations.

 

RESULTS

Accuracy and homogeneity of formulations were demonstrated by analyses.

 

Maternal findings

No maternal toxicity was observedin the 100, 300 and 1000 mg/kg groups.

 

Developmental findings

No developmental toxicity was observedin the 100, 300 and 1000 mg/kg groups.

 

CONCLUSION

Based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for Bismuth trinitrate was established as being at least 1000 mg/kg.