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EC number: 939-191-9 | CAS number: -
OECD 422: NOAEL= 15 mg/kg bw/day
Dose Formulation Analyses
- No test item was detected in the Group 1 (control group) formulation.
- The concentrations analyzed in the formulations of Groups 2, 3 and 4 were in agreement with the target concentrations (i.e. mean accuracies between 85% and 115%).
- The formulations of Group 2 and Group 4 prepared were homogeneous (i.e. coefficient of variation ≤ 10%).
A Combined 28-Day Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening test was performed in Wistar Han rats in accordance with OECD 422 and GLP principles. Additional groups with a 15 day recovery period were included for the control and high dose levels to study the reversibility of possible effects. The recovery animals (used to study the potential reversibility of possible toxic effects) were not mated and consequently were not used for the assessment of reproduction/ developmentaltoxicity. The substance was administered orally (by gavage) at dose levels of 0, 5, 15 and 50 mg/kg bw/day (referred to as group 1, 2, 3 and 4, respectively) in propylene glycol. These dose levels were based on the results of a previously performed 14 day dose range finder. Chemical analyses of formulations were conducted once during the study to assess accuracy and homogeneity. 10 animals/ dose/ sex were used for the main groups and 5 animals/ dose/ sex for the recovery groups. The following parameters and end points were evaluated in this study: mortality/ moribundity, clinical signs, functional observations (for 5 selected animals/sex/group and all Recovery group animals at the end of treatment), body weight and food consumption, oestrous cycle determination, clinical pathology (for 5 selected animals/sex/group and all Recovery group animals at the end of treatment and end of recovery), measurement of thyroxine (T4) and thyroid stimulating hormone (TSH), gross necropsy findings, organ weights and histopathologic examinations.
Formulation analyses confirmed that formulations of test item in propylene glycol were prepared accurately and homogenously. At 50 mg/kg bw/day, a total of 3 Main group females were found dead. No relevant signs were noted prior to the spontaneous death for these animals, and no clear cause of death could be established histopathologically. Although it is conceivable that these deaths could be related to the blood sampling procedure/anaesthesia, given that in total 3 high dose Main females were found dead in this study, a possible treatment-related effect could not be ruled out. Significantly higher serum levels of total T4 were recorded in non-lactating females at 50 mg/kg bw/day (2.4 x of control) at end of treatment. This increase occurred in the absence of any corroborating changes in serum level of TSH or findings at the organ level for the thyroid gland (organ weight, morphology). However, given its magnitude (2.4 x of control) the observed increase in total T4 was considered to represent a potentially adverse, compound-related effect. Also in males, a treatment-related increase inserum levels of total T4 was observed following treatment at 15 and 50 mg/kg bw/day. The observed changes in total T4 levels were not accompanied by either clear changes in TSH or findings for the thyroid gland (organ weight, morphology). Given the relatively slight magnitude of change (i.e. 1.3 x and 1.2 x of control, respectively) and the fact that group mean values for males at 15 and 50 mg/kg bw/day remained within the historical control range, it was regarded as non-adverse. At the end of the recovery period, serum levels of T4 and TSH in males and non-lactating females at 50 mg/kg bw/day were within the normal range of biological variation.
At 50 mg/kg bw/day, lower body weight and body weight gain accompanied by lower food consumption (before and after correction for body weight) was recorded for females from Week 1 of the post-coitum period onwards. Over Days 17 to 20 of the post-coitum period, these females showed a slight weight loss (on average approximately 6%) along with a more pronounced decrease in food intake. These effects on body weight and food intake were considered to have occurred secondary to the hampered fetal development (none of the females at this dose delivered offspring). At 15 mg/kg bw/day, body weight and body weight gain of females was lower from the second week of the post-coitum period onwards, which was accompanied by a lower food consumption during the last week of lactation. These findings were not regarded to be adverse, given that they were reversible and of a generally mild degree, and were considered to be related to the lower litter size at this dose. Females at 15 and 50 mg/kg also displayed piloerection starting during the mating phase, which had resolved prior to or during the first week of the recovery period. Other parental changes that were considered to be treatment-related but non-adverse consisted of black or bluish discoloration of body parts/faeces, extramedullary haematopoiesis in the spleen with associated haematological changes, higher liver weight and clinical biochemistry changes, as described in more detail below. A non-adverse black or bluish discoloration of faeces, skin and/or eyes, and all examined organs was noted in all animals at 15 and 50 mg/kg bw/day, and remained present at the end of the recovery phase at 50 mg/kg bw/day. At 5 mg/kg bw/day, discoloration was confined to bluish discolouration of the liver in a few females. This discolouration most likely represented the test item/test item metabolite as the test item had a black appearance. These findings were considered as non-adverse based on the mild character and absence of any other test-item related change indicative of tissue/organ damage. A non-adverse slightly increased incidence and severity of extramedullary haematopoiesis was recorded in the spleen of males at 50 mg/kg bw/day. Severity was low (up to slight) and showed complete recovery. This finding was supported by changes in red blood cell parameters consisting of marginally lower red blood cell counts, and higher reticulocyte counts, red blood cell distribution width, mean corpuscular haemoglobin, and mean corpuscular haemoglobin concentration at the end of treatment. Recovery females at 50 mg/kg bw/day showed higher reticulocyte counts and red blood cell distribution width at the end of treatment, but red blood cell counts were unaffected and there were no morphological correlates. Except for higher reticulocyte counts, all these haematological. changes were of a minor degree. At the end of recovery, most of these parameters showed full recovery, except for mean corpuscular volume and mean corpuscular haemoglobin which were (still) higher in males at 50 mg/kg bw/day. Overall, given the generally slight severity of these findings these were not considered to represent an adverse effect on red blood cell turn over. Non-adverse changes in clinical biochemistry at the end of treatment at 50 mg/kg bw/day consisted of lower total protein in males and Recovery females, and higher sodium in Main and Recovery females. At the end of the recovery phase, total protein remained lower for Recovery group females. None of these changes had histopathological correlates, and given that these changes were generally slight they were not considered adverse.
A non-adverse higher liver weight (relative to body weight) was noted in 15 and 50 mg/kg bw/day. Main males at the end of treatment (approximately 8 or 14% higher than controls, respectively). In absence of correlating microscopic or clinical pathology findings, and based on reversibility of this finding after the 15-day recovery period, this higher liver weight was not considered to be adverse. In conclusion, NOAEL of 5 mg/kg bw/day is derived based on mortality (Charles River Laboratories 2018).
14 day dose-range finder
The objective of this dose range finder was to select dose levels for a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of in Wistar Han rats by oral gavage. The oral route was selected as it is a possible route of human exposure during manufacture, handling or use of the test item. The substance was administered as a suspension in propylene glycol at dose levels of 1000, 200, 50 and 100 mg/kg bw/day (group 2, 3, 4 and 5) subsequently to 4 males and 4 females. A vehicle control group (group 1 was taken along). Chemical analyses of formulations for Groups 1, 2 and 3 were conducted once during the study to confirm accuracy and homogeneity. No chemical analyses was performed for the last added two Groups 4 and 5. The following parameters and end points were evaluated in this study: clinical signs, bodyweights, food consumption, clinical pathology (haematology, coagulation and clinical chemistry), gross necropsy findings and organ weights. Administration of the substance was not tolerated at dose levels of 100, 200 and 1000 mg/kg bw/day. Within 3 to 5 days (1000 and 200 mg/kg bw/day) and 9 to 11 days (100 mg/kg bw/day) all animals were either found dead or euthanizedin extremis(in the 200 mg/kg bw/day group only). This high toxicity was not expected based on the available data from an acute toxicity study indicating an LD50 > 10000 mg/kg bw/day. General observations prior to their deaths included piloerection (both sexes) and hunched posture (females only), body weight loss and reduced food consumption (absolute and relative to body weight). Severity increased with higher dose, and females seemed to be more sensitive to treatment than males. At necropsy, two females at 1000 mg/kg bw/day had several to many, purple foci on their thymus. In addition, all animals were noted with bluish discoloration of their bodies, including internal tissues/organs, which most likely was related to the black colour of the test item. In these groups, organ weights of liver, kidneys, adrenals and spleen could only be determined for the animals at 200 mg/kg/day that were euthanizedinextremis. Incidental changes included increased weights of liver and kidneys (one male and one female), increased weight of adrenals (one male). No data on clinical laboratory parameters are available from all these animals that died preterm. Only limited toxicity was seen at 50 mg/kg bw/day. In-life findings included piloerection (both sexes) and hunched posture (females only). At end of treatment (Day 15), blood levels of cholesterol were markedly decreased (both sexes). In addition, higher levels of bile acids were recorded in one male and all females. There were no test item-related mortalities, bodyweight and food consumption remained within the normal range, and no clear changes in haematology parameters (incl. clotting) and organ weights were noted. In conclusion, based on the results of this dose range finder, doses of 5, 15 and 50 mg/kg bw/ day were selected for the combined 28-day repeated dose toxicity study with the reproduction/ developmental toxicity screening test (Charles River Laboratories 2018).
Based on the available data, the substance has to be classified as STOT-RE2 (H373: May cause damage to organs through prolonged or repeated exposure) in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.
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