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Description of key information

Ziram exerts effects on liver and red blood cell parameters

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1.6 mg/kg bw/day
Study duration:
chronic
Species:
dog

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
0.3 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Additional information

Repeated dose studies with ziram have been conducted in dogs, rabbits and rats.

In rats ziram decreased body weight gain, food intake and food efficiency. Dogs presented a subdued behaviour and/or unsteady gait, with slight alterations in body weight and food efficiency, increase in liver weight, they vomited and had diarrhoea.

In the rat, T4 serum level after four weeks showed a dose related reduction, T3 and TSH were not significantly affected. Moreover, minor, but consistent, changes in biochemical parameters were observed (total protein, albumin, Ca2+, RBC, urea nitrogen, creatinine and MCHC).

In the rat, the target organs were liver and kidneys, as shown by the presence of degenerative alterations. Dogs showed an increased liver weight.

 

In the subchronic experiment (90 day study), the non-glandular stomach was the target organ with minimal epithelial hyperplasia in rats. No effects indicative of neurotoxicity were apparent when FOB tests were performed in the rat.

In dogs, the target organs were liver and spleen, with at the start increased pigmentation of Kupffer cells and/or macrophages with Perls’ positive material, possibly reflecting increased iron metabolism and turnover. A slight lowering of red cell indices, acute inflammatory cell infiltration in the lungs, decreases in heart weight, likely related to convulsions were also observed.

 

The principal effects caused by ziram is haemolysis indicated by a decrease in red blood cells and haemoglobin and by an increase in the mean corpuscular volume and mean corpuscular haemoglobin concentration is accompanied by subsequent effects on spleen, kidneys and liver. Among these effects areincreased pigmentation of Kupffer cells, haemosiderosis and extramedullary haematopoiesis.

 

In a 21-day percutaneous test, ziram affected the liver in rabbits. This effect occurred at 300 mg/kg bw/d. No dermal reactions were observed.

 

In a 28-day inhalation study findings were observed in the larynx, lungs and tracheal bifurcation in the mid- and high-dose group. This is thought to be a species-specific local effect. Haemolysis was the most sensitive adverse effect at a LOAEC of 1 mg/m³. There was a partial to complete recovery in the following the 28 day recovery period.

 

Classification for repeated-dose toxicity:

DSD: Xn, R48 -22

CLP: STOT RE2, H373, liver and haematology effects

Derivation of relevant NOAEL: 

The dog appears to be the most sensitive species for ziram toxicity. A one-year study with ziram (Smith et al., 1993) revealed effects on body and prostate weight as well as histopathological findings in liver and spleen. The long-term LOAEL and NOAEL are equivalent to 6.6 and 1.6 mg/kg bw/day, respectively.

 

Likewise, the most sensitive short-term NOAEL was also found in a dog study. The critical effects in a 90-day feeding study in dogs with ziram (McLean et al., 1992) were focal necrosis and Kupffer cell pigmentation in the liver. The short-term LOAEL and NOAEL are equivalent to 12.2 and 4.1 mg/kg bw/day, respectively.


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

Repeated dose toxicity: inhalation - systemic effects (target organ) cardiovascular / hematological: other

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: other; digestive: liver

Justification for classification or non-classification

Ziram should be classified for repeated -dose toxicity:

DSD: Xn, R48 -22

CLP: STOT RE2, H373, liver and haematology effects