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Description of key information

In the sub-chronic studies performed in rats, the main target organ was the blood (with anaemia effects). The NOAEL obtained in the two studies is very similar. The GLP study reported in 1987 is more reliable as all the parameters required in Directive 2001/59/EC, Annex V, Method B.26 were evaluated and reported while in the non GLP study published in 1995 all these parameters were not reported (or incompletely reported). The thyroid effects described by McCauley et al.(1995) at levels above 100 mg/kg bw are of uncertain clinical significance and were not observed in the rat and dog GLP studies. An increased level of thyroid colloid depletion compared to control can be regarded the result of a physiological adaptation and not an adverse effect per se. 
In the 90-day study performed in the dog, there were no significant toxic effects up to the highest dose level tested. Considering that dogs have lower levels of methaemoglobin reductase than humans and thus are more susceptible to methaemoglobin, the higher NOAEL level in this studies for dogs adds to the confidence of the reliability of the 100 mg/kg NOAEL obtained in rats. The overall lowest sub-chronic NOAEL is 100 mg/kg bw/day, based on effects on erythrocytes; and a No Observed Effect Level (NOEL) of 38 mg/kg in males and 55 mg/kg in females when considering the physiological colloid depletion observed at the dose of 128 mg/kg in males and 209 mg/kg in females in the McCauley study.
Effects on haematology and the thyroid were also observed in a three week study in rats (NOAEL 35 mg/kg bw males and 40 mg/kg bw females) and no effects were seen in mice (NOAEL 350 mg/kg bw males and 365 mg/kg bw females) (NTP 2005).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Additional information

Concerns for subchronic and chronic chlorate exposures are related to its competitive inhibition of iodide transport through thyroid follicular cells, required for thyroid hormone synthesis. This results to an initial decrease in the T3 and T4 serum levels followed by a compensatory increase of TSH. This in turn results to an increase in thyroid cell proliferation with subsequent restored thyroid hormone production, and thus maintaining homeostasis. Thyroid effects were already visible after intake from 5 mg/kg/day in animal (rat) studies. These effects indicate a physiological compensatory mechanism to maintain homeostasis upon the presence of chlorate. For further details see Annex I on the MoA of the CSR for a position paper by Ledirac and Pontal 2008.

 

Sub-chronic and chronic studies do not show a high level of toxicity. A 90-day studies in rats resulted in a NOAEL of 100 mg/kg bw/day and a90-day study in the dog resulted in a NOAEL of 360 mg/kg bw/day, the highest dose tested.

Available studies differ in their reported effects on thyroid. One study did not show any effect after 90-days up to 1000 mg/kg/day, whereas in NTP studies hypertrophy was observed from around 40 mg/kg/day. Another 90-day study in rats indicated possible effects of thyroid colloid depletion, and concluded to a NOAEL in rats of 38 (males) and 55 mg/kg bw/day (females). A two generation reproduction study on rats indicated a parental NOEL of 10 mg/kg bw/day for males and 70 mg/kg bw/day for females, based on slight to moderate follicular hyperplasia and signs of slight to moderate hyperactivity of the thyroid gland. The NOAEL for parental toxicity is 70 mg/kg bw/day for the females, based on signs of hyperactivity of the thyroid glands (grade 4) at the next highest dose level.


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

Justification for classification or non-classification

Concerns for subchronic and chronic chlorate exposures are related to its competitive inhibition of iodide transport through thyroid follicular cells, required for thyroid hormone synthesis. This results to an initial decrease in the T3 and T4 serum levels followed by a compensatory increase of TSH. This in turn results to an increase in thyroid cell proliferation with subsequent restored thyroid hormone production, and thus maintaining homeostasis. Thyroid effects were already visible after intake from 5 mg/kg/day in animal (rat) studies. These effects indicate a physiological compensatory mechanism to maintain homeostasis upon the presence of chlorate. This is an adaptive reponse to chlorate exposure. Furthermore a response to which rats are more sensitive than humans.

Therefore sodium chlorate is not classified for target organ specific toxicity.