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EC number: 701-354-5 | CAS number: -
There is a new OECD442 repeat dose study with reproduction and developmental screening available. It is to the current OECD guideline and full GP compliant.
Results dose range finder study:
Treatment related clinical signs were observed in the females treated at 500 as well as at 1000 mg/kg bw/day. Slightly reduced food consumption was only observed after treatment at 1000 mg/kg bw/day. On the other hand, it could not be ruled out from the results obtained in this dose range finder that the macroscopic observation of a small liver and enlarged spleen in a single female at 500 mg/kg bw/day were treatment related. Therefore it was decided to extend the dose range finder with an additional group to be treated at 750 mg/kg bw/day, but for a considerable longer time period of 25 days instead of ten days for the first two groups. The results of the additional group at 750 mg/kg bw/day indicated that the reduced food consumption observed at 1000 mg/kg bw/day should be regarded as a clearly treatment-related effect and that the changes in organ sizes in 1/3 female treated at 500 mg/kg bw/day were likely a fortuitous finding and not treatment-related.
Dose formulation analysis:
The concentrations analyzed in the formulations of the groups exposed to the test item were in agreement with the target concentrations (i.e. mean accuracies between 107.8% and 110.6%). The formulations of the low and the high dose groups were homogeneous (i.e. coefficient of variation ≤ 1.0%). No test item was detected in the control group formulation (<LLOQ). Formulations at the entire range were stable when stored at room temperature under normal laboratory light conditions for at least 8 days (i.e. relative difference ≤ 3.6%). In addition, the test item was stable in water over a storage period of at least 79 days at a temperature ≤ -70°C.
A combined 28 day repeated dose study with screening for reproductive and developmental effects was performed according to OECD/EC guidelines and GLP principles. Sodium Cocopropylenediamine Propionate was administered by daily oral gavage to male and female rats at dose levels of 50, 150 and 500 mg/kg bw/day. Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 29 days). Females that delivered offspring were treated for 2 weeks prior to mating, during mating, during post-coitum, and at least 13-15 days of lactation (for 60-70 days). Females that failed to deliver pups were treated for 40-42 days. In females at 150 mg/kg bw/day and in both females and males at 500 mg/kg bw/day, test item-related microscopic findings were observed in the mesenteric lymph node. These findings consisted of foamy macrophage foci at 150 mg/kg bw/day in females and at 500 mg/kg bw/day in males and females which were considered non-adverse, and of multifocal necrosis in a single female at 500 mg/kg bw/day which was considered adverse.
At 500 mg/kg bw/day, an increased neutrophils-to-lymphocytes ratio was observed in both male and female rats, i.e. an approximate twice as high ratio in males as well as in females at 500 mg/kg bw/day when compared to controls. Since an increased neutrophils-to-lymphocytes ratio is considered a marker for (systemic) inflammation, a relation of the changes in these ratios to the findings in the mesenteric lymph nodes could not be ruled out, but could not be established in the current study. In males at 500 mg/kg bw/day, decreased weight of the prostate glands was found (0.79x control weight). Since no histopathological findings were noted and no effects on the reproductive capabilities of these males were apparent, the change in prostate weights was considered to be non-adverse.
No treatment-related changes were noted in any of the remaining parameters investigated in this study (i.e. functional observations, body weight, food consumption, coagulation and clinical biochemistry parameters and macroscopic findings in both sexes and T4 thyroid hormone levels in males).
Based on the adverse effects on mesenteric lymph nodes (seen in 1/10 females) at 500 mg/ kg bw/ day, a No Observed Adverse Effect Level (NOAEL) for Sodium cocopropylenediamine propionate of 150 mg/kg bw/ day was established.
In the OECD 422 study on β-Alanine, N-(2-carboxyethyl)-N-[3-[(2-carboxyethyl)amino]propyl]-, N-C12-18-alkyl derivs., trisodium salt adverse effects were seen at 500 mg/kg bodyweight, of multi focal necrosis in the mesenteric lymph nodes in one female. This was accompanied by an increased neutrophils-to-lymphocytes ratio in both males and females at this top dose level, which is considered a marker for (systemic) inflammation. The NOAEL for these effects was 150mg/kg bodyweight. The mode of action would appear to be an inflammatory response to the test substance in the mesenteric lymph nodes. In most cases this resulted in foamy macrophages in the mesenteric lymph node but a more severe focal necrosis was seen in only one female at the 500mg/kg bodyweight top dose.
The adverse effects seen in the OECD 422 study on β-Alanine, N-(2-carboxyethyl)-N-[3-[(2-carboxyethyl)amino]propyl]-, N-C12-18-alkyl derivs., trisodium on the mesenteric lymph node in one female in the 500mg/kg bodyweight top dose, is not considered to be a severe systemic toxic effect. The classification of Specific Target Organ Toxicity for a study of 28 day duration is 300mg/kg for category 2 with the cut off for category 1 of 30 mg/kg bodyweight. There were no adverse effects at 150 mg/kg bodyweight so clearly classification as STOT category 1 is not appropriate. The adverse effect seen at 500 mg/kg was of low severity only affecting one female, so this with the clear no effect level of 150mg/kg bodyweight does not justify a category 2 STOT classification. Therefore β-Alanine, N-(2-carboxyethyl)-N-[3-[(2-carboxyethyl)amino]propyl]-, N-C12-18-alkyl derivs., trisodium salt does not require a classification of Specific Target Organ Toxicity.
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