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EC number: 800-430-6 | CAS number: 1419212-76-2
In a 90-day study in rats (oral gavage) no adverse effects were observed at the highest dose tested (Charles River 2016). In a study according to OECD 422 with a close analogue of the substance bronchopneumonia was observed in all dose groups (100, 300 and 1000 mg/kg bw). No NOAEL could be derived from this study.
For further detail on summary data, see APPENDIX as attached
Wk 8 onwards
Wk 4 onwards
Body weight (gain)
bile acids↓ (39%
Within historical control
Rel Kidneys (-4%)
-Uterus with fluid
-Hepatocellular Hypertrophy-Thyroid Hypertrophy
-Kidney Hyaline droplets
NTRE= no treatment related effects
↑/↓= significantly increased/decreased at 1% or 5% level (Dunnet test)
% compared to controls
1Analysis of Dose Preparations
1 Accuracy of preparation
The concentrations analysed in the formulations of Group 2, Group 3 and Group 4 were in agreement with target concentrations (i.e. mean accuracies between 85% and 115%).
A small response at the retention time of the test item was observed in the chromatograms of the Group 1 formulation prepared for use in Week 13. It was considered not to derive from carry over since no response was obtained in the analytical blanks. This finding was very slight in week 13 (max.1% of the Group 2 response) and in all other formulations of Group 1, no test item was detected.
The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation = 10%).
Analysis of Group 4 formulations after storage at room temperature under normal laboratory light conditions for at least 6 hours yielded a relative difference of = 10%. Analysis of Group 2 formulations yielded a relative difference of > 10%. As no loss of test item was observed and because a relative difference of + 41% seems not explainable by the physicochemical properties of the test item or vehicle, results were first accepted.
To confirm this result, analysis of Group 2 formulation was performed after in life phase. Analysis of Group 2 formulation after storage at room temperature under normal laboratory light conditions for at least 6 hours yielded a relative difference of = 10%.
Based on this, the formulations were found to be stable during storage at room temperature under normal laboratory light conditions for at least 6 hours.
A female treated at 1000 mg/kg (no. 72) was found dead on Day 88. During the in-life phase this animal showed salivation and alopecia. No effect was noted in body weight.
Macroscopic examination revealed watery-cloudy contents of the thoracic cavity and a beginning autolysis.
No further mortality occurred during the study period.
No toxicological relevant clinical signs during daily observations or abnormalities during weekly arena observations were noted during the observation period.
Salivation noted after dosing for all animals (with a dose increasing trend in incidences) was not considered toxicologically relevant, taking into account the nature and minor severity of the effect and its time of occurrence (i.e. after dosing). This sign was considered to be a physiological response to the test item rather than a sign of systemic toxicity.
Any other clinical signs noted during the treatment period occurred within the range of background findings to be expected for rats of this age and strain which are housed and atreated under the conditions in this study and did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment.
Hearing ability, pupillary reflex and static righting reflex were normal in all examined animals. Grip strength and motor activity was similar between control and high dose animals.
All groups showed a similar motor activity habituation profile with a decreasing trend inactivity over the duration of the test period.
No toxicologically relevant changes were observed in body weights and body weight gain over the study period.
No toxicologically relevant changes in food consumption before or after correction for body weight were recorded.
No ophthalmology findings were noted that were considered to be related to treatment.The recorded ophthalmology findings were within the range of background findings encountered in rats of this age and strain.
3.Clinical Laboratory Investigations
Haematological parameters of treated rats were considered not to have been affected by treatment.
Any statistically significant changes in haematology parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend.
No toxicologically relevant changes were noted in clinical biochemistry parameters.
Slightly lower total bilirubin and bile acids in males at 1000 mg/kg and slightly lower inorganic phosphate in females at 300 and 1000 mg/kg were only seen in one sex and were well within the expected range for these kind of rats. Therefore these changes were not considered toxicologically relevant.
Any other statistically significant changes in clinical biochemistry parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend.
There were no test item-related gross observations.
All recorded macroscopic findings were within the range of background gross observations encountered in rats of this age and strain.
There were no test item-related alterations in organ weights.
Only absolute kidney weights of females at 1000 mg/kg were statistically decreased compared to the concurrent controls (-8 %). This was in line with the small decrease in body weight (-4%), which was considered not toxicologically relevant.
Test item-related microscopic findings were noted in the liver of males at 1000 mg/kg and thyroid gland of females at 1000 mg/kg.
Summary Test Item-Related Microscopic Findings
Dose level (mg/kg/day):
a = Number of organs examined from each group.
Hepatocellular hypertrophy was present in 4/10 males at 1000 mg/kg (minimal) and absent in all other groups.
Summary Test Item-Related Microscopic Findings
THYROID GLAND a
b = Including Female 72, 88 testing days, no findings in the thyroid gland.
An increased incidence and/or severity of follicular cell hypertrophy in thyroid gland, was present in 6/10 females at 1000 mg/kg (up to slight), compared to minimal degrees in 2/10 at 0 mg/kg, 0/10 at 100 mg/kg and 1/10 at 300 mg/kg.
The remainder of the recorded microscopic findings were within the range of background pathology encountered in rats of this age and strain. There was no test item-related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations. (This includes the observed hyaline droplets of the male kidneys in groups 1 and 4).
The test item, formulated in propylene glycol, was administered daily for at least 90 days by oral gavage to SPF-bred Wistar rats. One control group and three treated groups were tested,
each consisting of 10 males and 10 females.
Chemical analyses of formulations were conducted during pre-treatment and in Weeks 3 and 13 to assess accuracy, homogeneity and stability over 6 hours at room temperature under normal laboratory light conditions and over 8 days in the refrigerator protected from light. Additional analysis was done after the in-life phase to confirm the stability at low dose levels.
The following parameters were evaluated: clinical signs daily; functional observation tests in Weeks 13; body weight and food consumption weekly; ophthalmoscopy at pretest and in Week 13; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues.
Formulation analyses confirmed that formulations of test item in propylene glycol were prepared accurately and homogenously, and were stable over at least 6 hours at room temperature. No toxicologically significant changes were noted in clinical appearance, functional observations, body weight, food consumption, ophthalmoscopy, clinical laboratory investigations, macroscopic examination or organ weights in the animals surviving up to the scheduled day of necropsy.
Microscopic examination revealed minimal hepatocellular hypertrophy in the liver of males at 1000 mg/kg. In the absence of any other indicator of hepatocellular toxicity this finding was not considered adverse. Furthermore an increase in incidence and/or severity (up to slight degree) of follicular cell hypertrophy was recorded in the thyroid gland of females at 1000 mg/kg. This was regarded to be non-adverse at the incidences and severities recorded.
From the results presented in this report a No Observed Adverse Effect Level (NOAEL) for Reaction products of tall oil fatty acids with diethylenetriamine and maleic anhydride of at least 1000 mg/kg was established.
90 -day toxicity study
Rats (10/sex) were exposed to the substance by oral gavage at 0, 100, 300 and 1000 mg/kg bw during 90 days. One female at 1000 mg/kg bw died on day 88. No treatment effects on clinical signs, bodyweight (gain), food consumption, ophtalmoscopy, functional observations, haematology, clinical biochemistry, organ weights, macroscopy and histopathology were found. The NOAEL is therefore 1000 mg/kg bw.
Based on the outcome of the 90 -day study with the substance, the substance does not need to be classified according to Regulation (EC) No 1272/2008 (CLP)
The chemical pneumonitis as seen in the OECD 422 test with the analogue is considered a secondary effect after oral exposure. No evidence for an aspiration hazard for humans is available and the kinematic viscosity of the substance is >> 20,5 mm2/s measured at 40oC, therefore no classification for aspiration hazards is needed.
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