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Description of key information

In a GLP study conducted according to OECD Guideline 408 (available at the time), a 90-d NOAEL of 300 mg/kg bw/day was established for the related material trisodium EDDS based on a reduction in body weight gain and single cell death and fatty infiltration in the pancreas seen in rats at 700 mg/kg bw/day and above following repeated dietary administration (Dotti et al. 1995).
In a GLP study designed to assess toxicity and mineral balance, no adverse effects were observed when trisodium EDDS was given to male rats in the diet for 28 days at up to 400 mg/kg bw/day, considered the study NOAEL. A dose-related and statistically significant increase in the urinary excretion of zinc was observed at all tested doses (50 mg/kg bw/day and above; considered the study LOEL), which was compensated for by a decrease in faecal zinc excretion (measured only in the two highest dose groups) so that the overall total excretion of zinc was unaltered (Dotti, 1995).
In a GLP study, trisodium EDDS showed no evidence of toxicity when fed in the diet to male rats for 14 days at up to 1250 mg/kg bw/day, considered the study NOEL (Dotti and Wilson, 1996).
In a 14-day dietary study, trisodium EDDS exhibited toxicity at 2500 mg/kg bw/day and above in male and female rats, seen as loss of body weight, reduced food and water consumption, diarrhoea and hunched posture. The study NOAEL is therefore 500 mg/kg bw/day (Dotti, 1993).
No human data, and no dermal or inhalation repeated dose laboratory animal data were identified on EDDS acid or its trisodium salt.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

In a GLP study conducted according to OECD Guideline 408 (available at the time), trisodium EDDS was assessed for its ability to cause adverse effects in a 90-day dietary study in male and female Wistar rats. Groups of 10 animals of each sex were given either 0, 50, 300, 700 or 1000 mg/kg bw/day in a pelleted diet; further groups of 10 animals of each sex were given the control or high-dose diets for 90 days, followed by a 28-day recovery period. Animals were observed for clinical signs of toxicity throughout the study and blood samples were analysed at 4 and 13 weeks (or 17 weeks for the satellite groups). Ophthalmoscopic examinations took place at 4, 13 and 17 weeks. The duration of the estrus cycle was determined in females over the last month of the study. Sperm concentration, motility and morphology in males were also assessed. At study termination, animals were examined both macroscopically and microscopically, and absolute and relative organ weights determined. No treatment-related deaths or clinical signs of toxicity occurred and there were no treatment-related differences in ophthalmoscopic data, organ weights, urinary analysis, clinical chemistry or length of estrus cycle. At 1000 mg/kg bw/day, body weight gain was reduced (as was food consumption in this group) and there were some slight changes in haematological parameters for both sexes (which were no longer statistically significant at the end of the recovery period). At 700 mg/kg bw/day, there was a slight decrease in body weight gain in males during the last three weeks of treatment. In males at the top dose, an increase in the numbers of abnormal sperm (but no effects on motility or concentration), atypical residual bodies of minimal severity and incidence in the testes, and minimal changes occurred in some clinical biochemical parameters, all of which had mainly regressed by the end of the recovery period. In the pancreas, there was an increased incidence of single cell death and fatty infiltration at 700 mg/kg bw/day and above, the latter of which was still present in the top dose group at the end of the recovery period. At week 13 in the high-dose groups, there was a significant decrease in plasma zinc levels in male and female animals and plasma copper and magnesium levels in males compared to controls; these effects were considered to be treatment-related. In conclusion, in a 90-day dietary study a no-observed-adverse-effect level (NOAEL) of 300 mg/kg bw/day was established for trisodium EDDS based on a reduction in body weight gain and single cell death and fatty infiltration in the pancreas at 700 mg/kg bw/day and above (Dotti et al. 1995).

In a GLP study, trisodium EDDS was assessed for toxicity and its effect on mineral balance in a 28-day dietary study in Wistar rats. Groups of five male rats were fed a diet containing either 0, 50, 150, 300 or 400 mg/kg bw/day of the test substance for 28 days. The animals were examined daily for clinical signs of toxicity. Urine and faeces were collected over the last 3 days of the study for analysis of mineral content (calcium, sodium, potassium, magnesium, zinc, phosphorus, iron, manganese and copper) and blood was sampled before study termination. Ophthalmoscopic examination was performed pretest and on day 21. At necropsy organs and tissues were examined for gross abnormalities and a limited number of organs were subjected to microscopic examination. Mineral levels were determined in the liver, kidney, right femur and sternum. There were no treatment-related deaths or signs of clinical toxicity, and body and organ weights and food consumption were similar in treated and control animals. At necropsy, no macroscopic or microscopic abnormalities were evident and haematology, ophthalmoscopic examination and urinalysis showed no evidence of treatment-related changes. The NOAEL was therefore determined as 400 mg/kg bw/day. A dose-related and statistically significant increase in the zinc content of urine was evident at all doses (50 mg/kg bw/day and above; considered the study lowest-observed-effect level (LOEL)). However, this increase was compensated for by a decreased zinc output in faeces in the 300 and 400 mg/kg bw/day groups (faecal zinc was not determined in the other two treatment groups), resulting in no overall change in total zinc excretion. Levels of copper in animals given 300 or 400 mg/kg bw/day increased in the urine, and the urinary content of magnesium increased in the highest dose group alone. Changes in other mineral levels were inconsistent and not dose-related and were considered to be incidental. In conclusion, a 28-d LOEL and NOAEL of 50 and 400 mg/kg bw/day, respectively, were established for trisodium EDDS (Dotti, 1995).

In a GLP study, trisodium EDDS was assessed for its toxicity in a 14-day dietary study in male Wistar rats. Groups of 5 animals per dose were fed the test substance at 0, 750, 1000 or 1250 mg/kg bw/day in pelleted diet and observed for clinical signs of toxicity, food consumption, body weight gain and at study termination the internal organs were macroscopically examined for evidence of adverse effects. No animals died during the study and no differences were seen in body weight gain or food consumption between the groups. No clinical signs of toxicity were observed during the study and on necropsy no macroscopic findings were evident. In conclusion, trisodium EDDS showed no evidence of toxicity when fed to male rats at up to 1250 mg/kg bw/day, considered the no-observed-effect level (NOEL) in this study (Dotti and Wilson, 1996).

Trisodium EDDS was assessed for its toxicity in a 14-day dietary study in male and female rats. Groups of 5 animals of each sex were fed the test substance at 0, 50, 500, 2500 or 5000 mg/kg bw/day in the diet and observed for clinical signs of toxicity, food and water consumption, body weight gain and at study termination the internal organs were macroscopically examined for evidence of adverse effects. One male in the high-dose died during the study and all other animals at this dose level were killed in extremis on day 10 of the study. Ruffled fur, diarrhoea, emaciation and hunched posture were noted in both males and females treated at 2500 and 5000 mg/kg bw/day, and sedation was also observed in the highest dose group. Food and water consumption were reduced and body weight loss occurred at the two highest doses. No test substance-related changes were noted on macroscopic or microscopic examination. In conclusion, trisodium EDDS exhibited toxicity at 2500 mg/kg bw/day and above, seen as loss of body weight, reduced food and water consumption, diarrhoea and hunched posture, in rats of each sex in a 14-day dietary study. The study NOAEL is therefore 500 mg/kg bw/day (Dotti, 1993).

[Data on trisodium EDDS is considered relevant to use for understanding the potential repeated dose toxicity of EDDS acid, and is acceptable for using as read-across information.]

No human data, and no dermal or inhalation repeated dose laboratory animal data were identified on EDDS acid or its trisodium salt.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: pancreas

Justification for classification or non-classification

According to EU CLP and DSD regulations, EDDS acid (and its trisodium salt) would not be classified as a specific target organ toxicant under the conditions of the 90-day test as the observed critical effects (on the pancreas) were seen at doses significantly higher than 100 mg/kg bw/day.