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EC number: 810-509-7 | CAS number: 14708-87-3
OECD408 Repeat dose toxicity oral study in rats with additional reproductive toxicology endpoints. The study was conducted by daily oral gavage administration of bismuth subnitrate at dose levels of 0, 40, 200 and 1000 mg/kg/day over a period of 90 days. In addition to the standard reproductive endpoints included in the study design such as weights and pathological assessment of organs and tissues of the reproductive tract, oestrus cyclicity was evaluated together with analysis of circulating testosterone levels and analysis of sperm morphology. Stages of the oestrous cycle were evaluated via vaginal smears taken daily for 21 days, on all test and control group females, during the final three weeks of the study. The sperm analysis was assessed on the left testis and epididymis removed from all males at necropsy. For the epididymis, the distal region was incised and a sample of the luminal fluid was collected and transferred to a buffer solution for analysis of sperm motility. The tunica albuginea was removed from the testis and also the cauda epididymis was separated from the epididymis and the tissue stored frozen until later thawed and homogenized. Samples of the homogenate were examined to determine the number of homogenization resistant spermatids present. Morphological assessment was performed on a sample of a minimum of 200 sperm to determine the number with apparent structural anomalies. Assessment of homogenization resistant spermatids and morphological evaluation were only performed for control and 1000 mg/kg bw/day males. As there were no treatment-related findings, these evaluations were not extended to males from other dose groups.
Tables 1 to 17 are attached below under 'Attached background information'.
The study was designed to investigate the systemic toxicity of the test item and is compatible with the following regulatory guidelines:
i) The OECD Guidelines for Testing of Chemicals No. 408 "Subchronic Oral Toxicity - Rodent: 90 Day Study” (Adopted 21 September 1998).
This study was also designed to be compatible with Commission Regulation (EC) No 440/2008 of 30 May 2008, laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).
Additional reproductive toxicity endpoints were evaluated in this study including estrous cycling, sperm analysis and testosterone analysis.
The test item was administered by gavage to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dose levels of 40, 200 and 1000 mg/kg bw/day. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP).
Clinical signs, functional observations, body weight change, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Plasma concentrations of testosterone were evaluated for all males on Day 90 of dosing. Ophthalmoscopic examination was also performed on control group and high dose animals. In addition, sperm concentrations and motility were analyzed for males at necropsy followed by an evaluation of morphology and homogenization resistant spermatid counts in control and high dose males. Estrous cycling was also evaluated for females toward the end of the treatment period.
All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues from high dose and control animals was performed.
There were no unscheduled deaths during the study.
Throughout the treatment period, there were no clinical signs deemed to be indicative of test item toxicity.
Behavioral assessment scores across the test-item treated animals of either sex remained similar to the respective controls.
Functional Performance Tests
There were no treatment-related changes in functional performance at any dose level.
Sensory Reactivity Assessments
Sensory reactivity scores were comparable across all dose groups including controls.
There was no adverse effect of treatment with Bismuth Subnitrate at any dose level on body weight development in animal of either sex.
There was no adverse effect of treatment with Bismuth Subnitrate at any dose level on food consumption or food conversion efficiency in animal of both sexes.
Visual inspection of water bottles did not reveal any intergroup differences.
Ophthalmoscopic examination of males and females from control and 1000 mg/kg bw/day dose group during Week 12 of the study did not reveal any treatment-related differences.
There was no effect of treatment with the test item on estrous cycling activity assessed over the last three weeks of dosing in females.
Hematology evaluations did not reveal any toxicologically significant effects in animals of either sex resulting from treatment with the test item.
Blood chemistry evaluations did not indicate any effects of toxicological relevance in animals of both sexes resulting from test item administration.
Testosterone Hormone Assessment
There was no effect of treatment with the test item at any dose level on plasma levels of testosterone.
Changes noted in the colour of the caecal contents in a number of animals of either sex given 200 (one female) or 1000 mg/kg bw/day were not associated with any microscopic observations and as such this findings was considered to be no toxicological relevance. Any other macroscopic findings observed at necropsy were considered unlikely to be related to treatment with the test item.
There were no intergroup differences considered to be of toxicological relevance.
Analyses of sperm concentration, motility, morphology and homogenization resistant spermatids did not identify any treatment-related differences.
No findings were observed at histopathology which could be related to treatment with Bismuth Subnitrate within the confines of this study.
The oral (gavage) administration of Bismuth Subnitrate, to male and female Wistar Han™:RccHan™:WIST strain rats at dose levels up to 1000 mg/kg bw/day was well tolerated.
There was no adverse effect of treatment on body weight development and dietary intake in animals of either sex. Hematology, blood chemistry, testosterone hormone assessment, estrous cycle assessment in females, sperm analysis in males and microscopic examination of the selected tissues did not identify any findings of toxicological relevance. A dose level of 1000 mg/kg bw/day is therefore considered to be the ‘No Observed Adverse Effect Level’ (NOAEL).
Treatment with bismuth subnitrate over 90 consecutive days to rats did not show any effects on the reproductive organs of males or females (weights and pathology). Also there were no effects of treatment at any dose level on plasma concentrations of testosterone in males or estrous cycling activity in females as assessed over the last three weeks of dosing.
At necropsy, sperm analysis did not indicate any appreciable differences in group mean sperm concentration and motility at any dose level. An evaluation of homogenization resistant spermatids and morphology in males from the control and 1000 mg/kg bw/day dose groups also did not reveal any treatment-related differences.
OECD414 Prenatal developmental toxicity study in rats by oral gavage administration between Days 5 to 19 of gestation. Bismuth subnitrate was administered at dose levels of 0 (control), 100, 300 or 1000 mg/kg/day. The study was designed to investigate the effects of the test item on embryonic and foetal development following repeated administration by oral gavage to the pregnant female during gestation including the period of organogenesis.
Tables 1 to 11 are attached below under 'Attached background information'.
The study was performed according to the study plan and was designed to investigate the effects of the test item on embryonic and fetal development following repeated administration by gavage to the pregnant female during gestation including the period of organogenesis.
The study was designed to comply with the following guidelines: OECD Guidelines for Testing of Chemicals, No 414, ‘Prenatal Developmental Toxicity Study’ (adopted 22 January 2001).
The test item was administered by gavage to three groups each of twenty-four time mated Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, between Days 5 and 19 of gestation inclusive at dose levels 100, 300, and 1000 mg/kg bw/day. A further group of twenty-four time mated females was exposed to the vehicle only (Arachis oil BP) to serve as a control.
Clinical signs, body weight change, food and water consumptions were monitored during the study.
All females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, fetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.
Throughout the study, there were no clinical observations for any of the animals.
There was no effect of treatment with the test item at any dose level on body weight development.
There was no effect of treatment with the test item at any dose level on food consumption.
Post Mortem Studies
There were no macroscopic findings for any of the females on the study.
Litter Data and Litter Placental and Fetal Weights
No treatment-related effects were detected in the uterine parameters examined, in fetal viability or in fetal growth and development.
No treatment-related effects were detected on external development or in the type and incidence of skeletal or visceral findings.
The oral administration of Bismuth Subnitrate, to pregnant rats by gavage during gestation at dose levels of 100, 300 or 1000 mg/kg bw/day was well tolerated. The ‘No Observed Effect Level’ (NOEL) for maternal toxicity was considered to be 1000 mg/kg bw/day.
No treatment-related changes were detected in the offspring parameters measured. The ‘No Observed Effect Level’ (NOEL) for developmental toxicity, was therefore, considered to be 1000 mg/kg bw/day.
The test item was administered by gavage to three groups each of twenty-four time-mated female rats, between Days 5 and 19 of gestation inclusive at dose levels 100, 300, and 1000 mg/kg bw/day. A further group of twenty-four time-mated females was exposed to the vehicle only as a control. All females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, foetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.
The dose levels up to 1000 mg/kg/day bismuth subnitrate by oral administration were well tolerated in both the 90-day toxicity study in rats (with additional reproductive endpoints) and also in pregnant female rats in the developmental toxicity study. There were no treatment-related changes in any of the reproductive endpoints assessed in the 90-day study nor on pregnant females following exposure during the gestation period. Similarly, there were no treatment related effects on the development of offspring from those treated dams. Hence the high dose level of 1000 mg/kg/day in both studies was determined to be the No Observed Adverse Effect Level (NOAEL) for both reproductive toxicity in adult rats, maternal toxicity and developmental effects. Consequently, it is concluded that no classification for reproductive or developmental toxicity is required for the target substance.
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