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Description of key information

90 d NOAEL = 10 mg/kg bw/d (rat, oral: gavage; 0, 10, 100, 200 mg/kg bw/day): death of one male treated with 200 mg/kg bw/day, clinical signs of toxicity, reduced body weight development and food consumption, changes in the hematology parameters measured and microscopic changes in the mesenteric lymph nodes

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
90 day GLP/Guideline study , GLP, reliable without restriction

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

For the assessment of repeated dose toxicity of BADGE-IPD, a subacute (28 day) and a subchronic (90 day) study is available.

Subacute study

In the 28 day oral gavage study, males given 300 mg/kg/day had treatment-related decreases in body weight and body weight gains that were 11.1 and 22.7% less than controls, respectively by test day (TD) 28. Males and females given 100 or 300 mg/kg/day had treatment-related alterations in hematology parameters including: decreased hemoglobin (100 and 300 mg/kg/day), decreased hematocrit (300 mg/kg/day), increased white blood cell counts (300 mg/kg/day), increased reticulocytes (100 and 300 mg/kg/day), and a very slight increase in polychromasia of red blood cells (males given 100 mg/kg/day, and both sexes given 300 mg/kg/day).

Males and females given 100 or 300 mg/kg/day had treatment-related alterations in serum chemistry analytes including: increased alanine aminotransferase (300 mg/kg/day) and aspartate aminotransferase (300 mg/kg/day) activities and decreases in total protein (100 and 300 mg/kg/day), albumin (300 mg/kg/day), cholesterol (100 and 300 mg/kg/day), blood urea nitrogen (100 and 300 mg/kg/day), and bile acids (300 mg/kg/day). Females given 300 mg/kg/day had a treatment-related increase in urine volume with decreased specific gravity. At necropsy, males and females given 300 mg/kg/day had treatment-related decreases in final (fasting) body weights and multiple organ weights, which were secondary to body weight decrements. Organs affected included: liver (relative and absolute weights in males), spleen (relative weight in males), heart (relative and absolute weights in males and females), brain (absolute weight in males and females), and thymus (relative and absolute weights in males and females) weights. Female rats given 300 mg/kg/day had treatment-related increased spleen and adrenal weights (relative and absolute weights). Males and females given 100 or 300 mg/kg/day had treatment-related gross-pathological alterations including: increase in the size of the cecum and cecal lymph nodes, the absence of formed fecal pellets within the rectum, and decreased body fat reserves (females only) which were more prevalent in the high-dose group. Males and females given 100 or 300 mg/kg/day had treatment-related histological changes of the liver and lymph nodes (cecal and mesenteric), which were more prevalent in the high-dose group. In the liver, males and females given 300 mg/kg/day had multifocal individual hepatocyte necrosis (very slight to moderate) with accompanying inflammation. Background levels of multifocal aggregates of histiocytes were increased in severity from very slight to slight in both sexes. Females given 100 or 300 mg/kg/day had very slight periportal hepatocyte vacuolization, consistent with fatty change. In the mesenteric and cecal lymph nodes, males and females given 100 or 300 mg/kg/day had treatment-related very slight to moderate sinus histiocytosis. Males and females given 300 mg/kg/day had treatment-related very slight to moderate epithelial hyperplasia of the cecum and colon (males only), as well as a very slight to slight, diffuse infiltration of mixed leukocytes within the lamina propria of the cecum, colon, and rectum. Males and females given 300 mg/kg/day also had treatment-related histological alterations secondary to body weight changes, including: atrophy of adipose tissue and decreases in the amounts of secretory material in the prostate. Females given 300 mg/kg/day had treatment-related histopathological changes secondary to stress, including: hypertrophy of the adrenal zona fasciculata cells, and acinar cell hypertrophy of the submandibular salivary glands. Under the conditions of this study, the no-observed-effect level (NOEL) was 30 mg/kg/day BADGE IPD (#33) in male and female F344/DuCrl rats.

Subchronic study

In a subchronic toxicity study according to OECD Guideline 407 BADGE-IPD was administered by gavage to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for up to ninety consecutive days, at dose levels of 10, 100 and 200 mg/kg bw/day. A control group of ten males and ten females was dosed with vehicle alone (Propylene Glycol). Two recovery groups, each of ten males and ten females, were treated with the high dose (200 mg/kg bw/day) or the vehicle alone for up to ninety consecutive days and then maintained without treatment for a further twenty-eight days.

One male treated with 200 mg/kg bw/day was found dead on Day 48. There were no further unscheduled deaths. Increased salivation and noisy respiration was evident in animals of either sex treated with 200 mg/kg bw/day and to a lesser extent in animals of either sex treated with 100 mg/kg bw/day throughout the treatment period. Isolated incidences of a stained snout, labored respiration, decreased respiratory rate, hunched posture and fur loss were also evident in females treated with 200 mg/kg bw/day, a stained snout and sneezing was also evident in some males treated with 200 mg/kg bw/day and a decreased respiratory rate and hunched posture was also evident in some males treated with 100 mg/kg bw/day. During the treatment-free period, one male and one female that were previously given 200 mg/kg bw/day showed episodes of noisy respiration. No such effects were detected in males treated with 10 mg/kg bw/day however one female from this treatment group had increased salivation on Day 81 only. There were no toxicologically significant changes in functional performance and no treatment-related changes in sensory reactivity.

Males treated with 200 and 100 mg/kg bw/day showed a reduction in body weight gain during the first week of treatment. Periods of recovery were evident thereafter, however, generally body weight gain in these males was slightly below controls. Consequently overall body weight gain was lower than controls in these males. Significant improvement in body weight gain was evident in males previously treated with 200 mg/kg bw/day during the twenty-eight day treatment-free period. Females treated with 200 mg/kg bw/day showed a slight reduction in body weight gain during the first week of treatment, however, recovery was evident thereafter. No such effects were detected in females treated with 100 mg/kg bw/day or in animals of both sexes treated with 10 mg/kg bw/day.

Animals of both sex treated with 200 mg/kg bw/day and males treated with 100 mg/kg bw/day showed a reduction in overall food consumption. Incidences of reduced food conversion efficiency were also evident in males treated with 200 and 100 mg/kg bw/day during the treatment period. Improvement in food consumption was evident during the twenty-eight day treatment-free period. No such effects were detected in females treated with 100 mg/kg bw/day or in animals of both sexes treated with 10 mg/kg bw/day.

Visual inspection of water bottles did not reveal any inter-group differences in water consumption.

Ophthalmoscopic examination of animals of both sexes from the non-recovery control and 200 mg/kg bw/day dose groups during Week 12 of the treatment period did not indicate any treatment-related differences.

Animals of both sexes treated with 200 and 100 mg/kg bw/day showed an increase in neutrophils. Males treated with 200 mg/kg bw/day also showed an increase in total leukocyte count. The effect on neutrophils was also present in females previously treated with 200 mg/kg bw/day at the end of the twenty-eight day treatment -free period. No such effects were detected in both sexes treated with 10 mg/kg bw/day.

There were no toxicologically significant effects detected in the blood chemical parameters examined.

No toxicologically significant macroscopic abnormalities were detected in surviving animals. The male treated with 200 mg/kg bw/day that was found dead on Day 48 had a dark liver and lungs.

No toxicologically significant effects were detected in the organ weights measured.

The following treatment-related microscopic abnormalities were detected:

Mesenteric Lymph Nodes: Histiocytosis with granulomas was evident in animals of both sexes from all treatment groups, varying from minimal to moderate in severity and following a dose-dependent response. At 100 and 200 mg/kg bw/day the more severe grades of histiocytosis were often accompanied by minimal abscesses. Following the twenty-eight day recovery period, histiocytosis with granulomas and abscesses were evident in both sexes previously treated with 200 mg/kg bw/day. When compared with the main study, the incidence of abscesses was lower, whereas histiocytosis persisted at much the same incidence and severity.

Histiocytosis in the mesenteric lymph nodes is known to occur in response to the oral administration of some test items and is likely to represent accumulation of material, indicating delayed clearance of an exogenous or endogenous material.

The following microscopic abnormalities were evident, however, these were considered to reflect individual variation rather than an effect of treatment.

Adrenals: A slightly increased incidence of cortical vacuolation was evident in males treated with 200 mg/kg bw/day when compared with controls. The change was minimal in all cases, and was not apparent in females. As cortical vacuolation is a background finding with a variable incidence, this intergroup difference is considered to be by chance and to represent normal variation rather than an effect of treatment.

The oral (gavage) administration of BADGE-IPD for up to ninety consecutive days, to Wistar rats of both sexes at dose levels of 10, 100 or 200 mg/kg bw/day resulted in adverse treatment-related effects in animals of both sexes treated with 200 and 100 mg/kg bw/day. These findings included the death of one male treated with 200 mg/kg bw/day, clinical signs of toxicity, reduced body weight development and food consumption, changes in the hematology parameters measured and microscopic changes in the mesenteric lymph nodes. These changes were considered to represent an adverse effect of treatment at these levels. The effects evident in both sexes at 10 mg/kg bw/day were confined to minimal histiocytosis with granulomas in the mesenteric lymph nodes. Based on the level of severity of these changes evident in both sexes treated with 10 mg/kg bw/day, the 'No Observed Adverse Effect Level (NOAEL) was considered to be 10 mg/kg bw/day. 

Sinus histiocytosis is described as a normal finding in mesenteric lymph nodes; the macrophages may contain endogenous pigment (hemosiderin, lipofuscin) or exogenous material reflecting antigen uptake from the gastrointestinal tract. This is a common effect related to accumulation and delayed clearance of the test item. These changes are consistent with an inert compound. Thus, the effects are not regarded as significant toxic effect, but rather a port-of-entry effect. Additionally, inflammatory cells can be found in lymph nodes draining sites of the administration of an irritating test compound (Elmore, 2007).

Overall, the observed histopathological changes in the mesenteric lymph nodes (histiocytosis and granulomas) were interpreted to be localized, point of contact effects associated with the potential irritancy or delayed clearance of the test material and thus, do not warrant classification for specific organ toxicity after repeated exposure.

Reference:

Elmore, SA (2007). Histopathology of the Lymph Nodes.Toxicol Pathol. 2006; 34(5): 425–454.

Justification for classification or non-classification

The observed histopathological changes in the mesenteric lymph nodes (histiocytosis and granulomas) were interpreted to be localized, point of contact effects associated with the potential irritancy or delayed clearance of the test material and thus, do not warrant classification for specific organ toxicity after repeated exposure.