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Description of key information

The repeated dose toxicity of the test substance MBS was evaluated in a chronic feeding study with Sprague-Dawley rats (Monsanto Co. 1982). Male and Female rats were treated with 0, 5, 50 or 400 mg MBS /kg bw and day. A biological relevant decrease in body weight gain and increase in absolute and/ or relative kidney weights were noted in animals of the high dose group (400 mg/kg bw/d). Based on the findings of this study a NOAEL of 50 mg/kg bw and day is suggested.
The inhalation toxicity of MBS was examined in a subacute inhalation study (Monsanto Co. 1981). The study is limited concerning the recommended particle-size distribution given in current guidelines and thus an exposure of all relevant regions of the respiratory tract might not have been given. The biologically relevance of sporadic findings reported, especially systemic effects are questionable; whereas local effects noted in the inhalation study will be used as supporting evidence. Based on the fact that signs of nasal irritation observed at clinical examination were reversible, only short in duration and could not be correlated to histopathological effects, no toxicological significance was attached to this finding, and thus, no relevant local effects were observed up to 0.0102 mg/l.
The dermal toxicity of the test substance MBS was evaluated in a 21-day dermal toxicity study (Monsanto Co. 1981). No test substance-related death or systemic toxicity was indicated in any of the treated animals. No compound related macroscopic lesions nor dermal irritation were noted. A few rabbits in the test group exhibited very slight to slight erythema, edema and desquamation. Similar changes of the skin were noted in treated and untreated animals, like hyperkeratosis and infiltration of inflammatory cells in the dermis (Monsanto Co. 1981). Based on the findings of this study a NOAEL of 2000 mg/kg bw and day is suggested.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
50 mg/kg bw/day

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
2 000 mg/kg bw/day

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: oral

A chronic feeding study was performed to investigate the toxicity and carcinogenicity of the test substance MBS. Male and Female Sprague-Dawley rats (main experiment 50 per sex and concentration, satellite group 10 per sex and concentration) were feed with the test substance MBS for 113 weeks (satellite group 54 weeks). The animals were treated with 0, 5, 50 or 400 mg MBS /kg bw and day.

Clinical changes seen in this study was generally typical of that seen in the ageing CD rat. Treatment with the test substance MBS did not appear to affect the incidence or severity of the observed changes. An increase in the mortality rate was noted in males of the mid and high dose group between weeks 58 and 85. There was also strong evidence of a trend with dose (p<0.01). Significant excess mortality was seen in males of the mid and high dose group. The differences then declined and at termination there was no evidence of a treatment-related trend in mortality. In the latter part of the study the female medium and high dose group mortality rate was lower than that of the control group.

Males from the high dose groups gained less weight than controls from the very early part of the study so that at study termination there was a difference between the groups of about 22 %. A similar less pronounced trend was seen in the male medium dose group, a difference from control group of about 7 % being seen at termination. Males of the low dose group showed a reduction in body weight gain of ca. 2 %. This trend was also seen in treated females. At study termination high dose group females weighed about 28 % less than controls and medium dose group about 10 % less. There was also a small difference (about 5 %) between low dose females and controls, but this did not begin to develop until week 65. The reduced weight gain was associated with slight reductions in food consumption. High dose males ate slightly less than controls. This pattern was also evident in females of the mid and high dose groups. The differences were of the order of 5 %. Low and mid dose group males and low dose group females had similar food consumption patterns compared to the controls.

In haematology no biologically relevant changes in haematological parameters were noted. In clinical biochemistry considerable variation within groups was detected in some parameters, notably some plasma enzyme activities and bilirubin concentrations. The males and female high dose animals trend to have lower plasma LDH activities than control. The biological relevance of this decrease is unclear. In urine analysis male rats of the high dose group tended to have more urinary reducing substances than controls. The differences were, however, small and did not appear to be due to glycosuria. Microscopic examination of urinary deposits showed no trends to suggest an effect of treatment.

Slight changes were seen in the absolute and relative weights of certain organs at necropsy. The changes in the kidney and liver weights suggested a slight response to treatment. The necropsy at week 54 (interim kill) revealed a slight increase of absolute and relative liver weights (+ 7% and + 21 %) and absolute and relative kidney weights (+ 16 % and + 32 %) in males of the high dose group compared to control. Females of the high dose group showed a slight increase in relative liver and kidney weights (+ 15 %, + 22 %). At study termination the absolute kidney weights of males and females of the high dose group were slightly increased (+ 7 % and + 4 % vs. control); the relative liver and kidney weights of the high dose animals were significant increased (p<0.01) (males + 24 % and + 42 % and females + 32 % and + 52 %). A very slight increase in the absolute kidney weights were also noted in animals of the mid dose groups (interim kill females: kidney weights + 7%, terminal kill males and females kidney weights + 1 %). The relative weights of the liver showed also a very slight increase (raged from + 3 % in males from the interim kill to + 10 % in females from the terminal kill). The relative kidney weight was also increased and ranged from + 6% in males from the interim kill to + 12 % in females from the terminal kill.

The changes in the weights of other organs are considered to be a secondary effect of treatment, reflecting the interference with the normal growth pattern.

Gross pathology examinations revealed palpable subcutaneous masses identified in a proportion of the animals in all groups in the course of the study. The masses were of the type commonly seen in the CD rat and were most frequently seen in the axillae and mammary glands. The time to first mass was not affected by treatment. Males of the mid and high dose groups showed a statistically significant increase in palpable masses, whereas the corresponding female groups showed a reduced incidence. The microscopic pathology data did not indicate this to be a carcinogenic response (for more details of the carcinogenic potential see endpoint carcinogenicity)

Moreover, a variety of non-neoplastic conditions was found in both sexes. These did not; however appear to be influenced, in terms of incidence or severity, by treatment (Monsanto Co. 1982).

Based on the findings of the study, mainly of the decrease in body weight gain and the increase in absolute and/or relative liver weights a NOAEL of 50 mg/kg bw and day is suggested.

Repeated dose toxicity: inhalation

In a subacute inhalation study (Monsanto Co. 1981) male and female Sprague-Dawley rats were exposed to the dust of MBS six hours per day, 5 days per week during a 29-day experimental period. The mean nominal exposure concentrations were 0.068, 0.168, 0.53 mg/l (corresponding to mean analytical concentrations of 0.0044, 0.0098, 0.0102 mg/l). The equivalent aerodynamic diameter was 9.8 µm with a geometric standard deviation of 3.63. This distribution of MBS particle sizes was above the recommendations given in current inhalation guideline tests.

Immediately after some of the 6-hours exposure periods, the rats exhibited nasal irritation in relation to the concentration. By the following morning this symptom had generally disappeared (no more data). Several rats exhibited skin irritation in the form of alopecia which did not appear to be concentration related. No significant difference in food consumption was revealed. No body weight effects were observed in treated females, whereas males of the highest dose groups showed a slight decrease in body weight (ca. 8 %). Haematology and urinalysis were all within the normal rage of variation. In all treated males and females a significant increase in SGOT values and a significant decrease in blood glucose were noted when compared to control (II). The effects did not appear to be concentration related for either parameter. The slight depressions in blood glucose and the elevations in SGOT values were not associated with the presence of any tissue lesions, and thus were considered to be more accidental than biologically relevant. All other biochemical parameter appeared comparable to both controls. No test substance related gross pathologic lesions or organ weight variations were observed in any animals at necropsy, except for the males of the highest dose groups, which showed a decrease in absolute and relative lung weights, however the biologically relevance is questionable because the effects are mainly caused by the high variability in absolute lung weight of both control groups. Moreover, no microscopic lesions interpreted as compound related were observed in any tissues examined from rats of the highest dose group (Monsanto Co. 1981).

In summary, the study is limited concerning the recommended particle-size distribution given in current guidelines. To allow for exposure of all relevant regions of the respiratory tract, aerosols with mass median aerodynamic diameters (MMAD) ranging from 1 to 3 µm are recommended. The MMAD used was above the recommendations given (9.8 µm) and therefore, a limited systemic exposure seems reasonable. Thus, the findings of this study are questionable, especially for systemic effects. Whereas the local effects on the respiratory tract noted should be used as supporting evidence.

Repeated dose toxicity: dermal

The test substance MBS was evaluated in a 21-day dermal toxicity study. MBS was administered by dermal application to three groups of 10 male and 10 female rabbits, one-half with intact skin and one-half with abraded skin, five days per week for three consecutive weeks at dosage levels of 125, 500 and 2000 mg/kg bw and day. An identical control group was treated with saline. Criteria evaluated for treatment effect included mortality, pharmacotoxic signs, body weights, dermal irritation, haematological and clinical biochemical determinations, organ weights and macroscopic and selected microscopic evaluation of tissues. No major signs of local or systemic toxicity were noted in the treatment groups. Three rabbits died during the study, these deaths were not attributed to the test substance MBS. A control rabbit was sacrificed in extremis. A number of incidental and spontaneous pharmacotoxic signs were noted for a few rabbits in all groups. No statistically significant differences were seen in group mean body weights. A few rabbits in the test group exhibited very slight to slight erythema, edema and desquamation. The control group exhibited very slight desquamation and red raised areas on the shaven backs. A slight decrease in hematocrit, hemoglobin and total erythrocytes was noted in females of the highest dose group. Although the means of these values for the females receiving 2000 mg/kg bw/d were statistically significant lower (p<0.05) than the mean of the control females the actual differences were slight. In the absence of any changes for males receiving 2000 mg/kg bw/d it was considered that this decrease in hematologic parameters for females receiving 2000 mg/kg bw/d was not related to the test substance. Simular changes of the skin were noted in treated and untreated animals. The main lesion on the skin from the application site of control and experimental animals were hyperkeratosis and infiltration of inflammatory cells in the dermis (Monsanto Co. 1981).

Based on the findings of this study a NOAEL of 2000 mg/kg bw and day is suggested.

In conclusion:

Oral

The repeated dose toxicity of the test substance MBS was evaluated in a chronic feeding study with Sprague-Dawley rats (Monsanto Co. 1982). Male and Female rats (main experiment 50 per sex and concentration, satellite group 10 per sex and concentration) were feed with the test substance MBS for 113 weeks (satellite group 54 weeks). The animals were treated with 0, 5, 50 or 400 mg MBS /kg bw and day. Clinical changes seen in this study was generally typical of that seen in the ageing CD rat. Treatment with the test substance MBS did not appear to affect the incidence or severity of the observed changes. An increase of the mortality rate was noted in males of the mid and high dose group between week 58 and 85. However, this increase declined and at termination there was no evidence of a treatment-related trend in mortality in males. In treated females (mid and high dose group) a lower mortality rate was noted in the latter part of the study. A biological relevant decrease in body weight gain and increase in absolute and/ or relative kidney weights were noted in animals of the high dose group (400 mg/kg bw/d). In haematology no biologically relevant changes in haematological parameters were noted. In clinical biochemistry considerable variation within groups was detected, however the biological relevance of these findings is unclear. In urine analysis male rats of the high dose group tended to have more urinary reducing substances than controls. The differences were, however, small and did not appear to be due to glycosuria. Gross pathology revealed palpable subcutaneous masses identified in a proportion of the animals in all groups in the course of the study. The time to first mass was not affected by treatment. Males of the mid and high dose groups showed a statistically significant increase in palpable masses, whereas the corresponding female groups showed a reduced incidence. The microscopic pathology data did not indicate this to be a carcinogenic response. A variety of non-neoplastic conditions was found in both sexes. These did not; however appear to be influenced, in terms of incidence or severity, by treatment (Monsanto Co. 1982).

Based on the findings of this study a NOAEL of 50 mg/kg bw and day is suggested.

Inhalation

The inhalation toxicity of MBS was examined in a subacute inhalation study (Monsanto Co. 1981). The study is limited concerning the recommended particle-size distribution given in current guidelines and thus an exposure of all relevant regions of the respiratory tract might not have been given. The biologically relevance of sporadic findings reported, especially systemic effects are questionable. In light of these limitations the data from the oral chronic toxicity study (NOAEL: 50 mg/kg bw and day, Monsanto 1982) will be used for calculation of the systemic DNEL; whereas local effects noted in the inhalation study will be used as supporting evidence. Based on the fact that signs of nasal irritation observed at clinical examination were reversible, only short in duration and could not be correlated to histopathological effects, no toxicological significance was attached to this finding, and thus, no relevant local effects were observed up to 0.0102 mg/l.

Dermal

The dermal toxicity of the test substance MBS was evaluated in a 21-day dermal toxicity study (Monsanto Co. 1981). No test substance-related death or systemic toxicity was indicated in any of the treated animals. No effects on body weight or dermal irritation were noted. Some incidental changes in haematology were observed. No compound related macroscopic lesions or statistically significant organ weight changes were found in this study. A few rabbits in the test group exhibited very slight to slight erythema, edema and desquamation. Similar changes of the skin were noted in treated and untreated animals, like hyperkeratosis and infiltration of inflammatory cells in the dermis (Monsanto Co. 1981).

Based on the findings of this study a NOAEL of 2000 mg/kg bw and day is suggested.

Justification for classification or non-classification

No classification is required according to the classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).