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EC number: 403-030-6 | CAS number: 137398-54-0
Oral administration of the test item, AS 100 (Di-isopropyl xanthogen polysulphide), to rats for a period of up to ninety consecutive days, at dose levels of 10, 50 and 250 mg/kg bw/day, resulted in treatment-related changes in animals from the high (250 mg/kg
bw/day) and intermediate (50 mg/kg bw/day) dose groups.
There were no clinical signs to indicate toxicity, however, oral administration of the formulated test item to animals at 250 and 50 mg/kg bw/day and on occasion in 10 mg/kg bw/day animals, induced episodes of transient increased salivation around the time of dosing. Excessive salivation is frequently reported following oral administration of slightly irritant/unpalatable test item formulations and is therefore seldom associated directly with systemic toxicity. A relationship with the irritative properties of the test item may also have contributed to the one interim death (250 mg/kg bw/day female on Day 69) in this study.
Further demonstration of the irritative properties of the test item in high dose group animals involved histopathological evidence of gastric acanthosis and ulceration and duodenal mucosal hyperplasia. It is reasonable to assume a relationship between the intestinal congestion (seen microscopically) and the impaired bodyweight, food efficiency and conspicuous increase in water consumption identified in these animals. Animals tested at 50 mg/kg bw/day also showed slightly low weight gains in comparison with controls. However, in the absence of other overt toxicological findings, the significance of lower bodyweight, in these animals, was thought to be minimal.
Examination of high dose group haematological data revealed a reduction in erythrocyte count, together with associated changes in mean corpuscular haemoglobin and mean cell volume, strongly indicating an induced anaemia; a condition further indicated by a
meaningful increase in reticulocyte numbers. Additionally, high dose group animals showed elevated levels of neutrophils (females only) and an increased platelet count (both sexes). It is conceivable, given the function of these latter parameters, that the increased production may have been stimulated by the intestinal lesions that were identified microscopically. Animals at 50 mg/kg bw/day also exhibited a slight disruption in erythrocytes and mean cell volume; however, reticulocyte numbers appear not to have been greatly affected; indicating the anaemia in these animals to be of lesser relevance. Nevertheless, histopathological examination identified an affect on haemopoiesis, indicated by increased levels of haemosiderin in the spleen in animals treated at 250 mg/kg bw/day and to a lesser extent in those treated at 50 mg/kg bw/day. Haemosiderin results from deposition of iron containing pigment during the destruction of erythrocytes and the presence of this finding was also thought to be the origin for the elevated spleen weights in both sexes at 250 and 50 mg/kg bw/day. Biochemical examinations in high dose males revealed elevated levels of alanine aminotransferase
(an enzyme commonly associated with hepatic function) and increased plasma bilirubin levels (also observed in high dose females and in 50 mg/kg bw/day males). As bilirubin is a breakdown product of haemoglobin it is reasonable to associate the heightened
levels with the accelerated breakdown of erythrocytes (anaemia) that was identified in high and possibly intermediate dose groups animals. Microscopic liver changes in high dose animals involved hepatocellular hypertrophy, increased cytoplasmic glycogen and
minimal single cell necrosis (the latter in males only). Minimal centrilobular hepatocelluar hypertrophy and glycogen increase were also detected in a few 50 mg/kg bw/day males. Hepatocellular hypertrophy is commonly observed in the rodent liver following the
administration of xenobiotics and in the absence of associated inflammatory or degenerative changes a condition generally considered to be an adaptive response to treatment.
The remaining noteworthy treatment-related findings attested to an affect on kidney function that was characterised by blood biochemical changes in high group dose animals (primarily in males) involving statistically significant fluctuations in a number of
electrolyte levels. In addition, an increase in kidney weight was also evident in either sex at 250 and 50 mg/kg bw/day. Histopathologically, tubular hypertrophy was detected in both sexes at 250 mg/kg bw/day. These findings confirm impaired renal function with the cellular changes considered to be adaptive in nature possibly resultant of the presence of high concentrations of the test item. The irritative characteristics of the test item were further indicated by detection of minimal epithelial diffuse hyperplasia in the urinary bladder.
This study was designed to investigate the systemic toxicity of the test item and is compatible with the recommendations of 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).
The test item was administered continuously 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, 50 and 250 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. Haematology and blood chemistry were evaluated for all animals at the end of the study. Ophthalmoscopic examination was also
performed on control group and high dose animals prior to start of treatment and during Week 12 of the study.
All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues from all test and control animals was performed.
One 250 mg/kg bw/day female (No. 71) was found dead on the morning of Day 69. In the absence of any supporting evidence of toxicity this death was considered a result of a mal-dose and not test item toxicity.
There were no further unscheduled deaths which occurred during the study.
Increased salivation developed in 50 and 250 mg/kg bw/day animals within the first two weeks of treatment and persisted through to study termination. Occasional instances of excessive post dose salivation were also observed in a small number of 10 mg/kg bw/day animals. Associated with the excessive salivation were instances of soiled fur that was seen sporadically in test animals.
There were no treatment-related changes in the behavioural assessments observed.
Functional Performance Tests.
Functional performance assessments did not indicate any evidence of neurotoxicological changes.
Sensory Reactivity Assessments.
Sensory reactivity assessments did not indicate any adverse effects of treatment.
Impaired body weights were evident in either sex at 250 mg/kg bw/day throughout the study. A similar trend albeit of lesser significance was also apparent in either sex at 50 mg/kg bw/day. Body weight development in males and females receiving 10 mg/kg bw/day remained unaffected by treatment.
Food Consumption and Food Efficiency.
Dietary intake in test animals was comparable to that of the controls throughout the study. However, reduced food efficiency was evident in 250 mg/kg bw/day males and females. Food efficiency in animals from the remaining treatment groups remained similar to that of the controls throughout the treatment period.
Gravimetric measurement of water consumption revealed both sexes treated at 250 mg/kg bw/day to have consumed considerably more water than the corresponding controls. Water intake in animals from the remaining treatment groups remained similar to that of the controls throughout the treatment period.
No ocular changes were detected in any of the control or high dose animals prior to start of treatment or prior to termination.
Males and females treated with 250 mg/kg bw/day showed a reduction in circulating erythrocytes together with associated changes in mean corpuscular haemoglobin and mean cell volume together with increases in platelet and reticulocyte counts. In addition, 250 mg/kg bw/day females also showed an increase in leucocyte count in comparison with controls. Both sexes at 50 mg/kg bw/day showed slightly lower numbers of erythrocytes and an increase in mean cell volume in comparison with controls. There were no convincing treatment-related changes in animals treated at 10 mg/kg bw/day.
Elevated levels of alanine aminotransferase were detected in 250 mg/kg bw/day males accompanied in both sexes by increased plasma bilirubin levels, the latter was also observed in males at 50 mg/kg bw/day. In addition, elevated levels of sodium and chloride and a reduction in inorganic phosphate were detected in 250 mg/kg bw/day males and an increase in potassium and a reduction in creatinine were seen in females at 250 mg/kg bw/day when compared to controls. 250 mg/kg bw/day males and males at 50 mg/kg bw/day showed a noteworthy increase in calcium levels in comparison with controls. There were no other convincing treatment-related changes detected.
Males and females treated with 50 and 250 mg/kg bw/day showed treatment-related statistically significant increases in the weights of the liver, kidney and spleen in comparison with controls.
Macroscopic changes detected in animals at the end of the treatment period were confined to reddened lungs in one female at 10 mg/kg bw/day, white fibrous adhesions between the lungs and heart in one female at 50 mg/kg bw/day with similar changes together with reddened lungs in three females at 250 mg/kg bw/day.
Examination of the one unscheduled death (No.71) revealed fluid filled reddened lungs.
Examination of animals that survived treatment revealed:
Liver - Hepatocellular hypertrophy in animals at 250 mg/kg bw/day accompanied by increased glycogen content in the cytoplasm of the hepatocytes, and minimal single cell necrosis of the hepatocytes amongst males only. A small number of males treated at 50 mg/kg bw/day also showed minimal centrilobular hepatocelluar hypertrophy and glycogen increase in the cytoplasm of the hepatocytes.
Kidneys - Tubular hypertrophy was seen in 250 mg/kg bw/day males and in a few females from this treatment group. In addition, minimal diffuse hyperplasia of the transitional epithelium of the urinary bladder was observed in a few males and females at 250 mg/kg bw/day.
Stomach - Acanthosis of the forestomach was seen in males and a few females at 250 mg/kg bw/day accompanied in one of the females by ulceration in the forestomach. These changes were accompanied in a number of each sex at 250 mg/kg bw/day by
diffuse mucosal hyperplasia in the duodenum.
Spleen - Increased hemopoiesis and hemosiderin deposits in the spleen, and increased cellularity of the femur bone marrow were seen in animals at 50 and 250 mg/kg bw/day.
Oral administration of AS 100 (Di-isopropyl xanthogen polysulphide) to rats for a period of up to ninety days at dose levels of 10, 50 and 250 mg/kg bw/day resulted in the presence of treatment related changes in both sexes of animals from all dose groups precluding identification of a No Observed Effect Level.
The treatment-related findings detected at 50 mg/kg bw/day in the absence of degenerative histopathological changes was considered to be a No Observed Adverse Effect Level (NOAEL).
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