Registration Dossier

Diss Factsheets

Administrative data

Description of key information

In a 90-day oral (gavage) key repeated dose toxicity study in rats (Novartis Crop Protection AG, 1998), the NOAEL was established at 10 mg/kg bw/day based on a transient normochromic anaemia present at higher dose levels (estimated from LOAEL). Changes in clinical laboratory parameters noted at higher dose levels and indicative of effects on kidneys and/or liver were without microscopic correlate under the conditions of this study. A supporting and preceding dose range finding subacute oral (gavage) toxicity study (CIBA-GEIGY Limited, 1996a) in rats provided further indication that the haematopoietic system and, at higher dose levels, the kidney represented target organs following repeated oral exposure. In a key subacute 28-day dermal toxicity study (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. No data on repeated inhalation exposure are required. Exposure by the inhalation route is considered to be negligible.     

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Additional information

Oral route

The subchronic toxicity 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).

Estimation of NOAEL:

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 and used for DNEL and PNEC(oral) derivation.

In a dose range-finding subacute oral toxicity study (CIBA-GEIGY Limited, 1996a), FeNaEDDHA was administered to 5 Sprague-Dawley derived rats/sex/dose level by oral gavage at 50, 200 or 1000 mg/kg bw/day for 28 days. A concurrent control group was treated with the vehicle only. Treatment with the test item resulted in impaired body weight development at 200 and 1000 mg/kg bw/day and correspondent lower food intake. An anaemia without erythropoietic response was noted at 200 and 1000 mg/kg bw/day. At the same dose levels, the kidney was revealed as target organ by microscopical examination, by blood chemistry data evaluation and by organ weight evaluation. In addition, body weight relative organ weight changes were noted in the heart, adrenals and spleen. However, the relevance of these findings was considered as equivocal. This study was used as scientific basis for dose level selection for the above-mentioned 90 -day repeated dose oral toxicity study in the rat.

Dermal route

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.

Inhalation route

In accordance with column 2 of REACH Annex IX, the test repeated dose toxicity after inhalation (required in section 8.6) does not need to be conducted as repeated dose toxicity studies for oral and dermal application are available. Inhalation exposure is regarded negligible as the particle size distribution for particles below 100 µm were found to be 2.7 % and no particles were found less than 10 µm. In addition, the substance showed only very low toxicity after acute inhalation exposure with an LD50 of greater than 4200 mg/m³ in the rat.


Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: hematopoiesis

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on the results of the key repeated dose toxicity studies with special regard to specific target organ toxicity after repeated exposure and considering the NOAEL of 10 mg/kg bw/day established for the oral route, the substance is not subject to classification and labelling according to Regulation (EC) No 1272/2008, as amended for the ninth time in Regulation (EC) No 2016/1179 since the slight and reversible changes in haematology parameters noted at higher dose levels were of minimal toxicological relevance.