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EC number: 233-791-8 | CAS number: 10361-44-1
In conclusion, although no systemic toxicity is seen after treatment up to 1000 mg/kg for 90-days, based on mortality and the local test item-related morphologic alterations in the stomach of males and females, a NOAEL of 300 mg/kg was established.
Figures and tables are attached below under 'Attached Background Material'.
Repeated dose 90-day oral toxicity study with Bismuth Trinitrate by daily gavage in the rat.
The study was based on the following guidelines:
· EC No 440/2008, B.26 Repeated Dose (90 days) Toxicity (oral), 2008.
· OECD 408, Repeated Dose 90-day Oral Toxicity Study in Rodents, 1998.
· OPPTS 870.3100, EPA 712-C-98-199, 90-Day Oral Toxicity in Rodents, 1998.
· Japanese Chemical Substances Control Law 1973, Notification of Mar. 31 2011 by MHLW (0331 No.7), METI (H23.03.29 SeiKyoku No. 5) and MOE (No. 110331009).
Rationale for dose levels:
Based on the results of a 14-day range finding study, the dose levels for this 90-day oral gavage study were selected to be 0, 100, 300 and 1000 mg/kg.
The test item, formulated in propylene glycol, was administered daily for at least 90 days by oral gavage to SPF-bred Wistar rats. One control group and three treated groups were tested, each consisting of 10 males and 10 females.
Chemical analyses of formulations were conducted in Weeks 1, 6 and 13 to assess accuracy, homogeneity and stability over 5 hours at room temperature under normal laboratory light conditions and over 8 days in the refrigerator protected from light.
The following parameters were evaluated: clinical signs daily; functional observation tests in Week 12-13; body weight and food consumption weekly; ophthalmoscopy at pretest and in Week 13; estrous cycle determination during the last 2 weeks; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues.
Formulation analyses confirmed that formulations of test item in propylene glycol were prepared accurately and homogenously, and were stable over at least 5 hours at room temperature under normal laboratory light conditions and over 8 days in a refrigerator.
Test item-related mortality occurred in this study. Unscheduled deaths were observed at 1000 mg/kg (males 35, 40 and females 72, 76). These animals showed macroscopic changes in the gastro-intestinal tract (black-brown/red foci on the glandular stomach, irregular surface of the glandular stomach, black content in the cecum, GI-tract distended with gas) and thymus and/or spleen (reduced size). This correlated microscopically with ulcerations/erosions, necrosis and hemorrhage(s) in the glandular stomach and lymphoid depletion/atrophy in thymus and/or spleen. Additional microscopic findings were lymphoid depletion in the mesenteric lymph nodes and mandibular lymph node in a single female and increased adipocytes in the bone marrow, which was most likely secondary to the moribund condition of the animals. Particularly the ulcerations/erosions in the stomach are considered to be largely responsible for the cause of death/moribundity of the early sacrifices. The animals showed salivation at most of the days during treatment period. The following symptoms were
noted in the days or up to two weeks prior to death: hunched posture, labored or deep respiration, rales, gasping, squeaking, scabs in the neck, piloerection, lean or pale appearance, swelling of the abdomen, hypothermia.
Two unscheduled deaths treated at 100 mg/kg (male 13) and 1000 mg/kg (female 79) showed macroscopic and/or microscopic findings suggestive for a dosing error (male 13: fluid in the thoracic cavity, granulocytic inflammatory infiltrates with foreign material in the tissue adjacent to the aorta; female 79: granulocytic infiltration, epithelial erosion and hemorrhages in the esophagus). Animal no.13 showed labored respiration on Days 42 and 43. And animal no.79 showed salivation during the treatment period and hunched posture, labored respiration, rales, swelling of the abdomen and lean appearance, a few days prior to death.
The surviving animals showed at 1000 mg/kg rales during the treatment period. Towards the end of the treatment period additional symptoms were noted such as hunched posture, piloerection and labored or deep respiration. Salivation was also noted in these animals (and at 300 mg/kg), however this symptomwas not considered toxicologically relevant, taking into account the nature and minor severity of the effect and its time of occurrence (i.e. after dosing).Functional observation tests revealed no adverse changes. The lower motor activity of females at 1000 mg/kg, and a trend towards lower motor activity for males at 1000 mg/kg were considered not to represent an adverse effect on neurobehaviour. These results were not supported by clinical observations or other functional observation tests, were slight in nature (within the normal range for rats of this age and strain), and had no supportive morphological correlates in examined neuronal tissues.
The females at 1000 mg/kg showed slightly lower body weight gain compared to control animals, which was not supported by an effect in food consumption
Macroscopic and microscopic examination revealed test item-related black content in the stomach and/or cecum in surviving males and females at 300 and 1000 mg/kg. A single female at 1000 mg/kg showed a reduced size of thymus and spleen. No microscopic correlate was found for the black content of stomach and/or cecum, the microscopic correlate for reduced thymus was lymphoid depletion. The single female of the scheduled sacrifices with marked lymphoid depletion did not show lymphoid depletion/atrophy in any of the other lymphoid organs and no other characteristics that could explain the marked lymphoid depletion in the thymus were found in the other organs. Therefore, the thymus depletion in this particular female rat was likely an incidental finding rather than a test item-related finding.
Microscopic examination revealed slight hemorrhage(s) in the glandular stomach in a single male at 1000 mg/kg (minimal hemorrhage was considered to be background), which was considered not to be adverse based on the absence of any other findings in the stomach.
Slight effects in haematology and clinical biochemistry were observed (i.e. changes in red blood cell count, reticulocyte count, mean corpuscular volume, haematocrit level and changes in levels of cholesterol, total protein, albumin, total bilirubin and creatinine). These changes were slight and with no clear related morphological changes and therefore considered to be not toxicologically significant.
There were no indications of possible reproductive toxicity based on the parameters determined in this study. All females showed a normal (regular) estrous cycle of 4 days during the period in which estrous cycle length was determined (Day 79 up to and including Day 97), and histopathological examination of the male and female reproductive organs (including spermatogenesis staging) did not show treatment-related lesions.
Repeated oral toxicity:
No published data or studies for determination the effects of repeated oral doses of bismuth trinitrate are available.
Annex XI of the REACH Regulation specifies rules for adaptation of the standard testing requirements. Point 1.5 of Annex XI permits read-across from substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.
In an available publication, treatment with bismuth had no significant effects on clinical signs, body weights, food consumption, haematology, clinical chemistry, urinalysis, organ weights, necropsy, or histopathological findings in a 28-day repeated oral dose toxicity study. As a result of the findings, the NOAEL of bismuth was determined to be 1000 mg/kg for males and females.
A read-across concept is applicable from bismuth to bismuth trinitrate considering that they both contain bismuth, the moiety of toxicological concern, and that the substances have similar physicochemical properties.
In addition to fulfil the data requirements for a substance imported or manufactured in quantities 100 to 1000 t/y according to the Annex IX of the regulation (EC) 1907/2006, a 90-day oral toxicity study in rats according to OECD guideline 408 is proposed using read-across substance, bismuth subnitrate.
Repeated dermal toxicity:
A dermal repeated dose toxicity study for bismuth trinitrate is considered to be scientifically unjustified considering that dermal absorption of bismuth is considered to be negligible.
Repeated inhalation toxicity:
No reliable or relevant studies or data are available for bismuth trinitrate. One publication about intratracheal administration of bismuth to rats for 13 weeks is available, however, the exposure route is not reliable for risk assessment. The results showed that dose-dependent, but not specific adverse effects, were attributable to bismuth administration in the rat.
The above oral repeated dose toxicity study has been ranked reliability 2 according to the Klimisch et al system. This ranking was deemed appropriate because sufficient dose ranges and numbers are detailed; hence it is appropriate for use based on reliability and animal welfare grounds. By read across, the above results triggered no classification under the Dangerous Substance Directive (67/548/EEC) and the CLP Regulation (EC No 1272/2008).
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