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EC number: 239-701-3
CAS number: 15625-89-5
A final report is attached in the reference. In this, all results, including summary tables of all findings as well as historical data, can be found.
Two relevant tables has been included in this section, Table 1 describing Test Article Intake and Table 2 describing Summary Test Item-Related Microscopic Findings – Stomach
CONCENTRATION AND HOMOGENEITY ANALYSIS
No test item was detected in the control group diet.
The mean accuracies for the concentrations in the formulations of the 300, 900 and 2500 ppm group (Week 1, Week 6 and Week 12 formulations) were between 92% to 100% and therefore in agreement with the target concentrations for suspensions (80% and 120%).
The coefficient of variation for the formulations of the 300 and 2500 ppm group (Week 1, Week 6 and Week 12 formulations) and 900 ppm (week 1 formulation) were between 0.51 and 1.7% and therefore the formulations were considered homogeneous (i.e. coefficient of variation ≤ 10%).
Stability in rat diet (powder, SM R/M-Z; supplier SSNIFF®) over the concentration range 500 to 15000 ppm was confirmed for at least 3 weeks in the freezer (≤-15°C) and for at least 4 days at room temperature (Test Facility Study No. 20265399 (method development and validation study)). In addition, stability in rat diet (powder, SM R/M-Z; supplier SSNIFF®) at 300 ppm is confirmed for at least 3 weeks in the freezer (≤-15°C) and for at least 4 days at room temperature (Test Facility Study No. 20265399 (method development and validation study)).
TEST ARTICLE INTAKE
Table 1: Test Article Intake
Nominal Dietary Inclusion Level [ppm]
Mean over Means Intake [mg test item/kg body weight]
(mean range indicated within brackets)
Table 2: Summary Test Item-Related Microscopic Findings – Stomach
Dose level (ppm)
STOMACH (non-glandular) a
Hyperplasia squamous cell
Infiltration mixed cell, submucosal
a = Number of tissues examined from each group. Bold values indicate a test item-related effect.
A 90-day dietary rat toxicity study was conducted according to OECD/EC guidelines and in accordance with GLP principles. Wistar Han rats were administered with 2-ethyl-2-[[(1-oxoallyl)oxy]methyl]-1,3-propanediyl diacrylate (TMPTA) for 90 days by dietary administration at dose levels of 300, 900 and 2500 ppm. The animals of the control group received the standard rodent diet alone. The dose levels were selected based on the results of a 14-day dietary rat study (Test Facility Study No. 20265400), in which Wistar Han rats (5 males and 5 females per dose) were administered 1500, 3500, 5000, 10000 and 15000 ppm TMPTA in the diet. In the 14-day study, at 10000 and 15000 ppm, animals were prematurely euthanized based on excessive toxicity. In addition, at 5000 ppm, body weight and food consumption were clearly affected in both sexes. Also in males treated at 3500 ppm, a lower bodyweight gain and food consumption was observed. Histopathological examination of the stomach showed test item-related findings at 1500 and 3500 ppm consisted of squamous cell hyperplasia and hyperkeratosis in males and females, and ulcerations in the non-glandular stomach of females. Based on the severity of these stomach findings at 3500 ppm, it was expected that at this dose, the stomach findings would become more severe after 90 days of dosing. The stomach findings in animals treated at 1500 ppm were only minimal and the risk of severe toxicity resulting in mortalities was expected to be low. Based on these findings, and in order to select a dose level which could lead to some toxic effect without excessive lethality, 2500 ppm was selected as the high dose concentration and the mid-dose and low-dose levels were set at 900 and 300 ppm.
In the main study dietary analyses conducted in Weeks 1, 6 and 12 confirmed that the formulation of the test item in the diet was prepared accurately and homogenously.
No mortality occurred during the study. No test item-related effects were noted in males and females at 300 and 900 ppm.
At clinical chemistry assessment, a test item-related increase in alanine aminotransferase activity and calcium concentration was observed in males at 2500 ppm. At the low severity observed and in absence of a histopathological correlation, these findings were considered to be not adverse.
At necropsy, test item-related irregular surface was observed in the non-glandular stomach in all males and females at 2500 ppm.
Test item-related microscopic findings were present in the non-glandular stomach of all males and females at 2500 ppm. These findings consisted of squamous cell hyperplasia and hyperkeratosis (mild, diffuse). In addition, some females at 2500 ppm presented a few other microscopic findings in the non-glandular stomach including mucosal erosion (4/10, minimal, focal), submucosal edema (6/10, minimal, regionally extensive to diffuse) and submucosal mixed cell infiltrates (7/10, up to mild degree, regionally extensive to diffuse). The recorded alterations in the non-glandular stomach were local test item effects and likely resulting from the irritating properties of the test item.
No test item-related changes were noted in the following parameters investigated in this study: mortality, clinical appearance, body weight, food consumption, functional observations, ophthalmoscopy, hematology, coagulation and organ weights).
In conclusion, no systemic adverse effects were associated with the administration of 2-ethyl-2-[[(1-oxoallyl)oxy]methyl]-1,3-propanediyl diacrylate by dietary administration for at least 90 days in Wistar Han rats up to dose levels of 2500 ppm in males and females. Test item-related local effects were observed macroscopically and microscopically in the non-glandular stomach at 2500 ppm.
Based on these results, the systemic No Observed Adverse Effect Level was considered to be at least 2500 ppm (corresponding to an actual test article intake of 173 and 190 mg/kg body weight/day for males and females, respectively). Selecting higher dose levels for this 90-day dietary study was considered to be not justified, based on the toxicity (mortality at 5000 ppm) observed in the 14-day dietary rat study (Test Facility Study No. 20265400) and the local effects observed in glandular stomach.
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