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toxicity to reproduction: other studies
Type of information:
other: not relevant, evaluation of mechanims
Adequacy of study:
supporting study

Data source

Reference Type:
other: company data, publication planed
Toxicological, endocrine and reproductive properties of Dioctyltin compounds

Materials and methods

Test material

Constituent 1
Reference substance name:

Results and discussion

Any other information on results incl. tables

Glucocorticoids, immune system and Zinc

In OECD 414 studies on DOTI in Mice and Rabbit were reported an increase in malformation. These reported maleformation occurs in maternal dose. There are similar findings in immunsuppressive substance above the intended effect dosis.Østensen [Østensen et al., Arthritis Research & Therapy 2006, 8:209] reviewed different anti-inflammatory and immunosuppressive drugs regarding reproduction. There was a dose related increase of adverse effects to reproduction in mice and rabbit in maternal doses.

For clarification it have to remarked, there is in assessment of chemicals no intended effect in animal or human, so the intended effect form drugs is always an adverse effect of chemicals.

It is well known, that administration of immune suppressive drugs cause a decrease in plasma zinc concentration [Ellul-Micallef et al., Postgraduate Medical Journal 52 (1976) 148-150,Flynn et al., The Lancet, 298,7735 (1971) 1169–1172,Peretz et al., Journal of Trace Elements and Electrolytes in Health and Disease, 3 (1989) 103-108,Fontaine et al, Int J Tissue React. 11,5 (1989) 253-259,Yunice et al., Am J Med Sci. 282,2 (1981) 68-74,DiSilvestro et al., Life Sci. 35,21 (1984) 2113-2118].

Etzel [Etzel et al., Biochem Biophys Res Commun.89, (1979) 1120-1126] and Quaife [Quaife et al, Dev Biol. 118,2 (1986) 549-555] pointed out, that Glucocorticoids are involved in the regulation of plasma zinc. After administration of dexamethasone the zinc concentration in rat serum decreased significantly within 14 hrs [Etzel et al., Biochem Biophys Res Commun.89, (1979) 1120-1126].

An increase of glucocorticoid level causes an increase in synthesis of this zinc-binding protein and produces a tissue-specific redistribution of zinc with a transient depression of zinc in the plasma and concomitant uptake of zinc by the liver, bone marrow, and thymus. Schroeder [Schroeder et al., Proc.Nati. Acad. Sci.87 (1990) 3137-3141] pointed out that IL-6 in the presence of glucocorticoid, is a major physiological determinant ofmetallothionein (MT)gene expression and zinc metabolism in hepatocytes. Further, IL-6-induced changes provide cytoprotection in a manner consistent with dependence upon increased cellular MT and/or zinc. It is assumed, that the increase of cellular MT and/or zinc may be servefor membrane stabilization.

As discussed before, glucocorticoids and Dioctyltin alter the Zn status by inducing the systhesis of MT [Klaassen et al., J Am Col Toxicol 8 (1989) 1315-1321], a protein binding Zn. MT appers to be an important storage of Zn. Metals (e.g. Zn in plasma) bind readily to the newly synthesized MT. Given the magnitude of induction of the protein, this beanding leads to a significant redistribution of Zn. This results in a further decrease of the plasma Zn concentratin, because extrahepatitic Zn is notunder homeostatic control [Hurley et al., Proc Soc Exp Biol Med 170 (1982) 48-52].

There is a strong evidence, that an inadequate zinc status cause teratogenic effects in animal and human,.

The embryo requires Zn for development and groth, and relies on the maternal plasma as its proximate source of Zn. Therefore, a decrease in the concentration of Zn in plasma may lead to a decrease in Zn to the embryo. [Daston, Developmental toxicology 2 (1994): 189-212].This condition of embryonic Zn deficiency is likley to be developmentally adverse, because even a short dietary Zn deficiency can lead to abnormal development in [Keen et al., In: Zinc and human biology (1989) 183-220,Hurley et al., Teratology 4 (1971) 199-204,Voljnk et al., J Nutr 107 (1977) 862-872,Shah et al., Br J Nutr 85,2 (2001) 101-102,Hickory et al., J Nutr 109,5 (1979) 883-891,Shah et al., Nutrition Reviews 64,1 (2006) 15-30,Krapels, BJOG 111,7 (2004) 661-668,Nriagu, Zinc Deficiency in Human Health]. Because of the large number of chemical and physical insults that induce metallothionein, these transitory embryonic Zn defiencies may be a relative common of maternal inticucation, thus a secondary effect.

This chain of events – hepatic metallothionein induction, sytemic redistribution of Zn, decrease of plasma Zn, embryonic Zn deficienciy – is developmentally adverse and has been evaluated for several chemicals [Daston, Developmental toxicology 2 (1994): 189-212,Amemiya et al., Teratology 34 (1986) 321-334,Amemiya et al., Teratology 39 (1989) 387-393,Keen et al., J Nutr 119 (1989) 607-611,Daston et al., Toxicol Appl Pharmacol 110 (1991) 450-463,Daston et al.m, Teratology 43 (1991) 469]. The typical induction at maternally toxic dosages was 120 to 150 µg metallothionein / g liver, compared to a baseline llevel of 5 to 10 µg/g. This was accomoanied by an increase in liver Zn concentration, particularly in cytosolic fraction of the liver where metallothionein resides, and a decrease in plasma Zn concentration. Daston confirms this by measurement of65Zn distribution [Daston, Developmental toxicology 2 (1994): 189-212].

Stress and developmental / reproduction toxicity

Developmental effects could causes by stess, produced by a variety of nonpharmacologic regimes. These have included physical restraint, loud noise, light, overcrowding and food oder water deprivation. Although the spectrum of effects varies by strain and stress paradigm, in mice these treatmens have produce decrease fetal weight, decreased embryonic viability, cleft palate, exencephaly, and supernumerary ribs. Supernumerary ribs, a a relativey common abnormality in mice and rats. Thus, there is evidence that maternal stress can produce development toxicity.

Endogenous response to stress is an increase in the concentration of circulating corticosteroids and an increased secretion of catechonlamines. In the human body, the most abundant catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine, all of which are produced from phenylalanine and tyrosine. Catecholamines cause general physiological changes that prepare the body for physical activity . Some typical effects are increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system. Both corticosteroids as well as catecholmines induce metallothionein[Klaassen et al., J Am Col Toxicol 8 (1989) 1315-1321]. Different toxicant can also increase the corticosteroid levels and catechlamine levelsm, causing adverse effects. Physical restraint in pregnant mice and rats or dietary restriction caused an inrecrease in plasma costicosterone followed by sytemic redistribution of Zn, decrease of plasma Zn, embryonic Zn deficienciy[Daston, Developmental toxicology 2 (1994): 189-212].

Applicant's summary and conclusion

DOT interacts with NR3C1, and causes immunosuppressive effects resulting in an zinc decrease / deficit in plasma.
The embryo requires Zn for development and groth, and relies on the maternal plasma as its proximate source of Zn. Therefore, a decrease in the concentration of Zn in plasma may lead to a decrease in Zn to the embryo. This seundary effect could cause adverse effecs in development of embryo.