Acetic acid, 2-oxo-, reaction products with ethylenediamine, iron chloride (FeCl3) and phenol, potassium salts

Endpoint summary

Description of key information

In a 90 -day oral (gavage) key repeated dose toxicity study with FeEDDHMA in rats (Schoenmakers, 1996; see also read across document in section 13), the NOEL was established at 20 mg/kg bw/day in male rats and at 100 mg/kg bw/day in female rats. In this study, treatment with the test item resulted in slight haematological changes and a slightly increased relative liver weight in male rats treated at 100 mg/kg bw/day. The slight increase in relative kidney weight was, however, not corroborated by histopathological renal effects, and was not seen in female rats at this level. Histopathological kidney effects were observed in both male and female rats at the next higher level of 500 mg/kg bw. In addition, two oral 28-day studies were available. The NOAEL in one of these oral 4 -week studies (Banks, 1988) was 200 mg/kg bw; in the second oral 4 -week study (Korn, 1990) 200 mg/kg bw was a LOAEL, however, the only change observed at that level consisted of slight fatty degenerations of renal tubular epithelial cells; no increase in relative kidney weight was observed at that level.

The subchronic toxicity of FeNaEDDHA by the oral route was investigated in rats (Novartis Crop Protection AG, 1998). The test item FeNaEDDHA was administered to 10 Sprague-Dawley derived rats/sex/dose level by oral gavage at 5, 50 or 200 mg/kg bw/day for 90 days. A concurrent control group was treated with the vehicle only. Additional 10 animals/sex of the high dose and control group were kept on control diet for a 4 -week recovery period before sacrifice. Treatment with the test item resulted in lower food intake and impared body weight development at 200 mg/kg bw/day. Reversible effects on red blood cell (normochromic anaemia) and white blood cell parameters, and higher values of platelets and prothrombin activity were noted at 50 and/or 200 mg/kg bw/day. In addition, changes of blood chemistry and urine parameters concerning the liver and kidneys were noted. The body weight relative heart weight was increased in males at 200 mg/kg bw/day. Under the conditions of this study, the NOAEL for FeNaEDDHA when administered by daily oral gavage for three months was 10 mg/kg bw/day (estimated from the LOAEL).

In a repeated dose dermal toxicity study (CIBA-GEIGY Limited, 1996b), FeNaEDDHA was administered to the skin of 5 Sprague-Dawley derived rats/sex/dose level at 10, 100 or 1000 mg/kg bw/day for 28 days (5 days/week). A concurrent control group was treated with the vehicle only. Dermal treatment with the test item resulted in no mortality, no relevant clinical signs, no changes in food consumption, no effects on haematology and clinical chemistry parameters and no gross findings. A transient slight body weight loss was noted in females at 1000 mg/kg bw/day during the first week of treatment. There was an increase in adrenal weight in males at 1000 mg/kg bw/day. Microscopically, the skin application sites of females at 1000 mg/kg bw/day revealed epidermal hyperkeratosis associated with an increased severity of acanthosis. In 2/5 males at 1000 mg/kg bw/day centrilobular hypertrophy of hepatocytes was noted. Based on the slight effects on the liver and skin and due to the increased adrenal weight noted at 1000 mg/kg bw/day, the NOEL was established at 100 mg/kg bw/day.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Additional information

For FeEDDHMA, the NOEL in male rats was 20 mg/kg bw; the NOEL in female rats was 100 mg/kg bw. In view of the absence of histopathological kidney effects in males treated with 100 mg/kg bw, and in view of the slight haematological changes, the NOAEL in male rats was considered to be close to 100 mg/kg bw and was conservatively set at 50 mg/kg bw. The results of this study are supported by two oral 28-day studies and the results of a one-generation test.

For FeNaEDDHA, a more realistic NOAEL was estimated from the LOAEL of 50 mg/kg bw/day applying an assessment factor of 5. This method is applicable and scientifically justified for this test, as only slight adverse effects were observed at 50 mg/kg bw/day (haematology parameters - anaemia). To take the relatively large concentration gap between 5 (clear NOEL) and 50 mg/kg bw/day into account, 5 mg/kg bw/day was not taken as NOAEL, but extrapolated form the LOAEL. The guidance on information requirements and CSA, R.8 (ECHA, 2008 -2010) recommends a factor between 3 and 10 for extrapolation from LOAEL to NOAEL. An assessment factor of 5 seems to be approprate and conservative enough for the current study as only slight effects were observed at the LOAEL of 50 mg/kg bw/day. Consequently a NOAEL of 10 mg/kg bw/day is calculated for this study.

No data on repeated inhalation exposure are required. Exposure by the inhalation route is considered to be negligible as the particle size distribution showed a limited percentage for particles below 100 µm and a very low percentage (or even zero) less than 10 µm. In addition, the substance showed only very low toxicity after acute inhalation exposure with a 4 -h LC50 value greater than 1240 or 4200 mg/m³ (technically highest attainable concentrations) in the rat.

In a key subacute 28-day dermal toxicity study with the structurally related substance EDDHA-Fe (CIBA-GEIGY Limited, 1996b), the NOEL was established at 100 mg/kg bw/day based on slight effects on the liver and skin and due to increased adrenal weight noted at the high dose level of 1000 mg/kg bw/day.

     

Justification for classification or non-classification

Based on the results of the key repeated dose toxicity studies with special regard to specific target organ toxicity after repeated 90 -day exposure and considering the NOAEL of 10 mg/kg bw/day established for the oral route for FeNa-EDDHA, and 50 mg/kg bw for FeEDDHMA, these substances are not not subject to classification and labelling according to Regulation No 1272/2008 (CLP) since the slight and reversible changes parameters noted at the next higher dose level were limited.