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Administrative data

acute toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
Justification for type of information:
on 3,5-DIIODO-L-THYROSINE, EMEA/MRL/320/97-FINAL June 1998, the substance is a precursor molecule in the synthesis of the thyroid hormones in the thyroid gland. In veterinary medicine the claimed indication for 3,5-Diiodo-L-thyrosine, in combination with levothyroxine, is activation of metabolism and digestion. It is used in the treatment of insufficient milk excretion, loss of weight, chronic indigestion and convalescence in cattle and pigs. 3,5-Diiodo-Lthyrosine is administered orally as a single treatment divided into two daily doses. It is given as a powder mixed with the diet, water or sugar-water. The intended dosage level per day is 0.20 to 0.58 mg/kg bw in cattle and 0.58 to 1.44 mg/kg bw in pigs (144 mg 3,5-Diiodo-L-thyrosine per animal and 84 mg iodine per animal). The treatment can be repeated once if needed in cattle and for 5 consecutive
days in pigs. In humans, 3,5-Diiodo-L-thyrosine has been used in the treatment of hyperthyroidism.
2. 3,5-Diiodo-L-thyrosine, consisting of one thyrosine molecule and two iodine atoms. The hormonally active iodothyronines (3,3´,5,5´-tetraiodo-L-thyronine also known as T4 and 3,3´,5-triiodo-L-thyronine also known as T3) are synthesised by coupling of iodothyrosines, 3-monoiodo-L-tyrosin and 3,5-Diiodo-L-thyrosine in the thyroid gland. The hormones formed are held in peptide linkage within the specific thyroprotein, thyroglobulin. Proteolysis of thyroglobulin liberates T4, T3 and small amounts of 3-monoiodo-L-tyrosin and 3,5-Diiodo-L-thyrosine into circulation. The major part of iodothyrosines (3-monoiodo-L-tyrosin and 3,5-Diiodo-L-thyrosine) liberated from thyroglobulin are rapidly deiodinated within the cell by the enzyme deiodinase. The physiological plasma concentration of 3,5- Diiodo-L-thyrosine in humans varies between 0.01-0.23 µg/l. 3,5-Diiodo-L-thyrosine has no physiological activity itself. The pharmacological effect of 3,5-Diiodo-L-thyrosine is based on the content of iodine (58.62%). Large amounts of ingested iodine or 3,5-Diiodo-L-thyrosine give rise to the Wolff-Chaikoff effect, an intrathyroidal regulatory mechanism, which inhibits the hormone secretion from the thyroid gland.
3. After oral administration of 3,5-Diiodo-L-thyrosine, the substance will be rapidly absorbed and
deiodinated by deiodinase in humans. The serum half-life in humans is 1 to 3 hours and after 6 to 8 hours 80 to 90% has been deiodinated. In the body iodide is largely confined to the extracellular fluid. There are two main pathways for the removal of iodide from the extracellular fluid. Small quantities are lost in expired air and through the skin, but the major clearance of iodine occurs via the thyroid and the kidneys. The thyroid contains the largest pool of body iodine, under normal circumstances approximately 8000 µg in humans. In the kidneys normally about 500 µg of iodine is cleared into the urine daily.
4. While no studies on acute toxicity, repeated-dose toxicity, tolerance in the target species and
reproduction toxicity, were provided, the Committee considered that these data were not necessary, as 3,5-Diiodo-L-thyrosine is a precursor of thyroxine, an endogenous compound.
5. While no data on mutagenicity and on carcinogenicity were provided the Committee considered that these data were not necessary as 3,5-Diiodo-L-thyrosine belongs to a group of substances which are recognised not to be mutagenic or carcinogenic and which have no chemical analogy with known carcinogens.
6. Thyroid agents have a long history of safe use in human medicine. In humans, 3,5-Diiodo-L-thyrosine has been administered by the oral route in mixed preparations in the treatment of thyrotoxic crisis.
Daily doses of minimum 40 mg and maximum 100 mg 3,5-Diiodo-L-thyrosine have been used.
Another indication of 3,5-Diiodo-L-thyrosine is preoperative treatment of hyperthyroidism. Adverse
effects of 3,5-Diiodo-L-thyrosine after administration of milligram doses are, besides of a possible
iodine-induced hypothyroidism and struma, also iodide acne and nasal catarrh.
7. No residue data were provided. However, it is noted that 3,5-Diiodo-L-thyrosine is a precursor of an endogenous substance.

Conclusions and recommendation
Having considered the criteria laid down by the Committee for the inclusion of substances in Annex II of Council Regulation (EEC) No 2377/90 and in particular that:
• 3,5-Diiodo-L-thyrosine is only used in a small number of individual animals and for non-regular
• the animals are unlikely to be sent for slaughter during or immediately after treatment,
• 3,5-Diiodo-L-thyrosine is rapidly absorbed and metabolised,
• 3,5-Diiodo-L-thyrosine is a precursor of an endogenous substance;
the Committee concludes that there is no need to establish an MRL for 3,5-Diiodo-L-thyrosine and
recommends its inclusion in Annex II of Council Regulation (EEC) No 2377/90

Data source

Materials and methods

Test type:
other: Case reported after a massive intentional L-thyroxine ingestion

Test material

Test material form:
Details on test material:
L-Thyroxine (T4) is commonly prescribed medication for hypothyroidism in humans and animals.
Specific details on test material used for the study:
L-Thyroxine (T4) is commonly prescribed medication for hypothyroidism in humans and animals.

Results and discussion

Applicant's summary and conclusion