PR:000011406glucocorticoid receptorCHEBI:17347testosteroneCL:0000019spermD005298fertilityGO:0004883glucocorticoid receptor activityGO:0042446hormone biosynthetic processGO:0006915apoptotic processGO:0061370testosterone biosynthetic processVT:0002673sperm quantityD005298fertility1increased2decreased8morphological change10116ratWCS_9606human10095mice10090mouse10116Rattus norvegicusGlucocorticoid Receptor Agonist, ActivationGR Agonist, ActivationMolecularCL:0000178Leydig cell2016-11-29T18:41:252017-09-16T10:15:24Repressed expression of steroidogenic enzymes Repressed expression of steroidogenic enzymes CellularCL:0000178Leydig cell2016-11-29T18:41:252017-09-16T10:15:24Increased apoptosis, decreased number of adult Leydig Cells Increased apoptosis, decreased Leydig Cells CellularCL:0000178Leydig cell2016-11-29T18:41:252017-09-16T10:15:24Reduction, Testosterone synthesis in Leydig cellsReduction, Testosterone synthesis in Leydig cellsCellular<p><b>Biological state</b>
</p><p>Testosterone is a steroid hormone from the androgen group and is found in humans and other vertebrates.
</p><p><b>Biological compartments</b>
</p><p>In humans and other mammals, testosterone is secreted primarily by the testicles of males and, to a lesser extent, the ovaries of females and other steroidogenic tissues (e.g., brain, adipose). It either acts locally /or is transported to other tissues via blood circulation. Testosterone synthesis takes place within the mitochondria of Leydig cells, the testosterone-producing cells of the testis. It is produced upon stimulation of these cells by Luteinizing hormone (LH) that is secreted in pulses into the peripheral circulation by the pituitary gland in response to Gonadotropin-releasing hormone (GnRH) from the hypothalamus. Testosterone and its aromatized product, estradiol, feed back to the hypothalamus and pituitary gland to suppress transiently LH and thus testosterone production. In response to reduced testosterone levels, GnRH and LH are produced. This negative feedback cycle results in pulsatile secretion of LH followed by pulsatile production of testosterone (Ellis, Desjardins, and Fraser 1983), (Chandrashekar and Bartke 1998).
</p><p><b>General role in biology</b>
</p><p>Testosterone is the principal male sex hormone and an anabolic steroid. Male sexual differentiation depends on testosterone (T), dihydrotestosterone (DHT), and the expression of androgen receptors by target cells (Manson and Carr 2003). During the development secretion of androgens by Leydig cells is essential for masculinization of the foetus (Nef 2000).
The foetal Leydig cells develop in utero. These cells become competent to produce testosterone in rat by gestational day (GD) 15.5, with increasing production thereafter. Peak steroidogenic activity is reached just prior to birth, on GD19 (Chen, Ge, and Zirkin 2009). Testosterone secreted by foetal Leydig cells is required for the differentiation of the male urogenital system late in gestation (Huhtaniemi and Pelliniemi 1992). Foetal Leydig cells also play a role in the scrotal descent of the testis through their synthesis of insulin-like growth factor 3 (Insl3), for review see (Nef 2000).
</p><p>In humans, the first morphological sign of testicular differentiation is the formation of testicular cords, which can be seen between 6 and 7 weeks of gestation. Steroid-secreting Leydig cells can be seen in the testis at 8 weeks of gestation. At this period, the concentration of androgens in the testicular tissue and blood starts to rise, peaking at 14-16 weeks of gestation. This increase comes with an increase in the number of Leydig cells for review see (Rouiller-Fabre et al. 2009).
</p><p>Adult Leydig cells, which are distinct from the foetal Leydig cells, form during puberty and supply the testosterone required for the onset of spermatogenesis, among other functions. Distinct stages of adult Leydig cell development have been identified and characterized. The stem Leydig cells are undifferentiated cells that are capable of indefinite self-renewal but also of differentiation to steroidogenic cells. These cells give rise to progenitor Leydig cells, which proliferate, continue to differentiate, and give rise to the immature Leydig cells. Immature Leydig cells synthesize high levels of testosterone metabolites and develop into terminally differentiated adult Leydig cells, which produce high levels of testosterone. With aging, both serum and testicular testosterone concentrations progressively decline, for review see (Nef 2000).
</p><p>Androgens play a crucial role in the development and maintenance of male reproductive and sexual functions.
Low levels of circulating androgens can cause disturbances in male sexual development, resulting in congenital
abnormalities of the male reproductive tract. Later in life, this may cause reduced fertility, sexual dysfunction,
decreased muscle formation and bone mineralisation, disturbances of fat metabolism, and cognitive
dysfunction. Testosterone levels decrease as a process of ageing: signs and symptoms caused by this decline
can be considered a normal part of ageing.
</p><p>OECD TG 456 <a rel="nofollow" target="_blank" class="external autonumber" href="http://www.oecd-ilibrary.org/environment/test-no-456-h295r-steroidogenesis-assay_9789264122642-en">[1]</a> is the validated test guideline for an in vitro screen for chemical effects on steroidogenesis, specifically the production of 17ß-estradiol (E2) and testosterone (T).
The testosterone syntheis can be measured in vitro cultured Leydig cells. The methods for culturing Leydig cells can be found in the Database Service on Alternative Methods to animal experimentation (DB-ALM):
Leydig Cell-enriched Cultures <a rel="nofollow" target="_blank" class="external autonumber" href="http://ecvam-dbalm.jrc.ec.europa.eu/beta/index.cfm/methodsAndProtocols/index?id_met=232">[2]</a>,
Testicular Organ and Tissue Culture Systems <a rel="nofollow" target="_blank" class="external autonumber" href="http://ecvam-dbalm.jrc.ec.europa.eu/beta/index.cfm/methodsAndProtocols/index?id_met=515">[3]</a>.
</p><p>Testosterone synthesis in vitro cultured cells can be measured indirectly by testosterone radioimmunoassay or analytical methods such as LC-MS.
</p><p>Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates, including humans.
</p>CL:0000177testosterone secreting cellHighHighLow<p>Chandrashekar, V, and A Bartke. 1998. “The Role of Growth Hormone in the Control of Gonadotropin Secretion in Adult Male Rats.” Endocrinology 139 (3) (March): 1067–74. doi:10.1210/endo.139.3.5816.
</p><p>Ellis, G B, C Desjardins, and H M Fraser. 1983. “Control of Pulsatile LH Release in Male Rats.” Neuroendocrinology 37 (3) (September): 177–83.
Huhtaniemi, I, and L J Pelliniemi. 1992. “Fetal Leydig Cells: Cellular Origin, Morphology, Life Span, and Special Functional Features.” Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 201 (2) (November): 125–40.
</p><p>Manson, Jeanne M, and Michael C Carr. 2003. “Molecular Epidemiology of Hypospadias: Review of Genetic and Environmental Risk Factors.” Birth Defects Research. Part A, Clinical and Molecular Teratology 67 (10) (October): 825–36. doi:10.1002/bdra.10084.
</p><p>Nef, S. 2000. “Hormones in Male Sexual Development.” Genes & Development 14 (24) (December 15): 3075–3086. doi:10.1101/gad.843800.
</p><p>Rouiller-Fabre, Virginie, Vincent Muczynski, Romain Lambrot, Charlotte Lécureuil, Hervé Coffigny, Catherine Pairault, Delphine Moison, et al. 2009. “Ontogenesis of Testicular Function in Humans.” Folia Histochemica et Cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society 47 (5) (January): S19–24. doi:10.2478/v10042-009-0065-4.
</p>2016-11-29T18:41:242017-09-16T10:14:33Reduction, testosterone levelReduction, testosterone levelTissue<p><strong>Biological state</strong></p>
<p>Testosterone (T) is a steroid hormone from the androgen group. T serves as a substrate for two metabolic pathways that produce antagonistic sex steroids.</p>
<p><strong>Biological compartments</strong></p>
<p>Testosterone is synthesized by the gonads and other steroidogenic tissues (e.g., brain, adipose), acts locally and/or is transported to other tissues via blood circulation. Leydig cells are the testosterone-producing cells of the testis.</p>
<p><strong>General role in biology</strong></p>
<p>Androgens, the main male sex steroids, are the critical factors responsible for the development of the male phenotype during embryogenesis and for the achievement of sexual maturation at puberty. In adulthood, androgens remain essential for the maintenance of male reproductive function and behaviour. Apart from their effects on reproduction, androgens affect a wide variety of non-reproductive tissues such as skin, bone, muscle, and brain (Heemers, Verhoeven, & Swinnen, 2006). Androgens, principally T and 5α-dihydrotestosterone (DHT), exert most of their effects by interacting with a specific receptor, the androgen receptor (AR), for review see (Murashima, Kishigami, Thomson, & Yamada, 2015). On the one hand, testosterone can be reduced by 5α-reductase to produce 5α dihydrotestosterone (DHT). On the other hand, testosterone can be aromatized to generate estrogens. Testosterone effects can also be classified by the age of usual occurrence, postnatal effects in both males and females are mostly dependent on the levels and duration of circulating free testosterone.</p>
<p>Testosterone can be measured by immunoassays and by isotope-dilution gas chromatography-mass spectrometry in serum (Taieb et al., 2003), (Paduch et al., 2014). Testosterone levels are measured i.a. in: Fish Lifecycle Toxicity Test (FLCTT) (US EPA OPPTS 850.1500), Male pubertal assay (PP Male Assay) (US EPA OPPTS 890.1500), OECD TG 441: Hershberger Bioassay in Rats (H Assay).</p>
<p>Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates, including humans.</p>
UBERON:0000178bloodHighHighHigh<p>Heemers, H. V, Verhoeven, G., & Swinnen, J. V. (2006). Androgen activation of the sterol regulatory element-binding protein pathway: Current insights. Molecular Endocrinology (Baltimore, Md.), 20(10), 2265–77. doi:10.1210/me.2005-0479</p>
<p>Murashima, A., Kishigami, S., Thomson, A., & Yamada, G. (2015). Androgens and mammalian male reproductive tract development. Biochimica et Biophysica Acta, 1849(2), 163–170. doi:10.1016/j.bbagrm.2014.05.020</p>
<p>Paduch, D. A., Brannigan, R. E., Fuchs, E. F., Kim, E. D., Marmar, J. L., & Sandlow, J. I. (2014). The laboratory diagnosis of testosterone deficiency. Urology, 83(5), 980–8. doi:10.1016/j.urology.2013.12.024</p>
<p>Taieb, J., Mathian, B., Millot, F., Patricot, M.-C., Mathieu, E., Queyrel, N., … Boudou, P. (2003). Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clinical Chemistry, 49(8), 1381–95.</p>
2016-11-29T18:41:242017-09-16T10:14:33Decreased sperm quantity or quality in the adult, Decreased fertility Decreased sperm quantity or quality in the adult, Decreased fertility Individual2016-11-29T18:41:252016-12-03T16:37:50impaired, Fertilityimpaired, FertilityIndividual<p><strong>Biological state</strong></p>
<p>capability to produce offspring</p>
<p><strong>Biological compartments</strong></p>
<p>System</p>
<p><strong>General role in biology</strong></p>
<p>Fertility is the capacity to conceive or induce conception. Impairment of fertility represents disorders of male or female reproductive functions or capacity.</p>
<p>As a measure, fertility rate, is the number of offspring born per mating pair, individual or population.</p>
HighAdult, reproductively matureHighHighHigh2016-11-29T18:41:242016-12-02T09:21:49c09acf09-d02a-4013-a3e8-a70ccf6bbdf529c1c5fb-7530-42d4-b3fe-e1244938d8ee2017-08-11T13:06:292017-08-11T13:06:29c09acf09-d02a-4013-a3e8-a70ccf6bbdf57ad045b8-d7a9-4512-a994-544b207e3e832017-08-11T13:06:472017-08-11T13:06:4729c1c5fb-7530-42d4-b3fe-e1244938d8ee9843284b-d790-46e9-8be2-489a25ead4cd2017-08-11T13:07:122017-08-11T13:07:127ad045b8-d7a9-4512-a994-544b207e3e839843284b-d790-46e9-8be2-489a25ead4cd2017-08-11T13:07:372017-08-11T13:07:379843284b-d790-46e9-8be2-489a25ead4cd92a70f85-6c94-4d73-ba23-7aac358011d2<p>Impairment of testosterone production in testes directly impacts on testosterone levels.</p>
<p>Within the testes, steroid synthesis takes place within the mitochondria of Leydig cells. Testosterone production by Leydig cells is primarily under the control of LH. LH indirectly stimulates the transfer of cholesterol into the mitochondrial matrix to cholesterol side-chain cleavage cytochrome P450 (P450scc, CYP11A), which converts cholesterol to pregnenolone. Pregnenolone diffuses to the smooth endoplasmic reticulum where it is further metabolized to testosterone via the actions of 3β-hydroxysteroid dehydrogenase Δ5-Δ4-isomerase (3β-HSD), 17α-hydroxylase/C17-20 lyase (P450c17, CYP17), and 17β-hydroxysteroid dehydrogenase type III (17HSD3). For review see (Payne & Hales, 2013). Therefore, inhibition or impairment of the testosterone production directly impacts on the levels of testosterone.</p>
<p>There is evidence from experimental work that demonstrates a coordinated, dose-dependent reduction in the production of testosterone and consecutive reduction of testosterone levels in foetal testes and in serum, see Table 1.</p>
<table class="wikitable" id="Event439">
<tbody>
<tr>
<td>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p><strong>KE: testosterone synthesis, reduction</strong></p>
</td>
<td>
<p><strong>KE: testosterone, reduction</strong></p>
</td>
<td>
<p> </p>
</td>
<td>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Compound</p>
</td>
<td>
<p>Species</p>
</td>
<td>
<p>Effect level</p>
</td>
<td>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p>Details</p>
</td>
<td>
<p>References</p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL =300 mg/kg/day</p>
</td>
<td>
<p>testicular testosterone production, reduction (ex vivo)</p>
</td>
<td>
<p>testicular testosterone levels, reduction, no change plasma testosterone</p>
</td>
<td>
<p>testosterone levels at GD 21 in male rat fetuses exposed to 0, 10, 30, 100, or 300 mg /kg bw/day from GD 7 to GD 21 testicular testosterone production ex vivo</p>
</td>
<td>
<p>(Borch, Metzdorff, Vinggaard, Brokken, & Dalgaard, 2006)</p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DBP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL =50 mg/kg/day</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>testicular testosterone levels, reduction,</p>
</td>
<td>
<p>Testicular testosterone was reduced >50 mg/kg/day</p>
</td>
<td>
<p>(Shultz, 2001)</p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=300 mg/kg/day</p>
</td>
<td>
<p>fetal testicular testosterone production, reduction</p>
</td>
<td>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Borch, Ladefoged, Hass, & Vinggaard, 2004)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=300 mg/kg/day</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>testicular testosterone levels, reduction,</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Borch et al., 2004)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=300 mg/kg/day</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>No change plasma testosterone</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Borch et al., 2004)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=100 mg/kg/day</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>Serum testosterone levels, reduction,</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Akingbemi, 2001)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=750 mg /kg /day</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>testicular testosterone levels, reduction, by 60 – 85%</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Parks, 2000)</p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=750 mg /kg/day</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>testosterone levels, reduction, fetuses on GD 17 (71% lower than controls) and 18 (47% lower than controls)</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Parks, 2000)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=750mg/kg/day</p>
<p> </p>
</td>
<td>
<p>ex vivo testosterone production, reduction by 50%</p>
</td>
<td>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Wilson et al., 2004)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=234 mg/kg/day</p>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p>serum testosterone levels, reduction,</p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Culty et al., 2008)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>LOEL=1250 mg/kg/day</p>
</td>
<td>
<p><em>ex vivo</em> foetal testicular production</p>
</td>
<td>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Culty et al., 2008)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DEHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>ED50=444,2 mg/kg/day</p>
</td>
<td>
<p><em>ex vivo</em> foetal testicular production, reduction</p>
<p> </p>
</td>
<td>
<p> </p>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p><br />
(Hannas et al., 2012)</p>
<p> </p>
</td>
</tr>
<tr>
<td>
<p>Phthalates</p>
<p>(DHP)</p>
</td>
<td>
<p>rat</p>
</td>
<td>
<p>ED50=75.25 mg/kg/day</p>
<p> </p>
</td>
<td>
<p><em>ex vivo</em> foetal testicular production, reduction</p>
</td>
<td>
<p> </p>
</td>
<td>
<p> </p>
</td>
<td>
<p>(Hannas et al., 2012)</p>
<p> </p>
</td>
</tr>
</tbody>
</table>
<p>Table 1. Summary table for empirical support for this KER. ED50 - half maximal effective concentration, LOEL- lowest observed effect level, Dibutyl phthalate (DBP), Bis(2-ethylhexyl) phthalate (DEHP), Dihexyl Phthalate (DHP).</p>
HighHighModerate<p>Ses Table 1.</p>
<p>Akingbemi, B. T. 2001. “Modulation of Rat Leydig Cell Steroidogenic Function by Di(2-Ethylhexyl)Phthalate.” Biology of Reproduction 65 (4) (October 1): 1252–1259. doi:10.1095/biolreprod65.4.1252.</p>
<p>Borch, Julie, Ole Ladefoged, Ulla Hass, and Anne Marie Vinggaard. 2004. “Steroidogenesis in Fetal Male Rats Is Reduced by DEHP and DINP, but Endocrine Effects of DEHP Are Not Modulated by DEHA in Fetal, Prepubertal and Adult Male Rats.” Reproductive Toxicology (Elmsford, N.Y.) 18 (1): 53–61. doi:10.1016/j.reprotox.2003.10.011.</p>
<p>Borch, Julie, Stine Broeng Metzdorff, Anne Marie Vinggaard, Leon Brokken, and Majken Dalgaard. 2006. “Mechanisms Underlying the Anti-Androgenic Effects of Diethylhexyl Phthalate in Fetal Rat Testis.” Toxicology 223 (1-2) (June 1): 144–55. doi:10.1016/j.tox.2006.03.015.</p>
<p>Culty, Martine, Raphael Thuillier, Wenping Li, Yan Wang, Daniel B Martinez-Arguelles, Carolina Gesteira Benjamin, Kostantinos M Triantafilou, Barry R Zirkin, and Vassilios Papadopoulos. 2008. “In Utero Exposure to Di-(2-Ethylhexyl) Phthalate Exerts Both Short-Term and Long-Lasting Suppressive Effects on Testosterone Production in the Rat.” Biology of Reproduction 78 (6) (June): 1018–28. doi:10.1095/biolreprod.107.065649.</p>
<p>Hannas, Bethany R, Christy S Lambright, Johnathan Furr, Nicola Evans, Paul M D Foster, Earl L Gray, and Vickie S Wilson. 2012. “Genomic Biomarkers of Phthalate-Induced Male Reproductive Developmental Toxicity: A Targeted RT-PCR Array Approach for Defining Relative Potency.” Toxicological Sciences : An Official Journal of the Society of Toxicology 125 (2) (February): 544–57. doi:10.1093/toxsci/kfr315.</p>
<p>Parks, L. G. 2000. “The Plasticizer Diethylhexyl Phthalate Induces Malformations by Decreasing Fetal Testosterone Synthesis during Sexual Differentiation in the Male Rat.” Toxicological Sciences 58 (2) (December 1): 339–349. doi:10.1093/toxsci/58.2.339.</p>
<p>Shultz, V. D. 2001. “Altered Gene Profiles in Fetal Rat Testes after in Utero Exposure to Di(n-Butyl) Phthalate.” Toxicological Sciences 64 (2) (December 1): 233–242. doi:10.1093/toxsci/64.2.233.</p>
<p>Wilson, Vickie S., Christy Lambright, Johnathan Furr, Joseph Ostby, Carmen Wood, Gary Held, and L.Earl Gray. 2004. “Phthalate Ester-Induced Gubernacular Lesions Are Associated with Reduced insl3 Gene Expression in the Fetal Rat Testis.” Toxicology Letters 146 (3) (February): 207–215. doi:10.1016/j.toxlet.2003.09.012.</p>
2016-11-29T18:41:342016-12-02T10:18:0592a70f85-6c94-4d73-ba23-7aac358011d2ab170e0f-904c-46cf-b31e-a0d3b59bb5f92017-08-11T13:09:112017-08-11T13:09:11ab170e0f-904c-46cf-b31e-a0d3b59bb5f98c0931e5-ca9d-4733-a64f-33493d9087c22017-08-11T13:09:422017-08-11T13:09:42Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male FertilityAdult Leydig Cell DysfunctionUnder Development: Contributions and Comments WelcomeUnder Development1.29<p>Under REACH, information on reproductive toxicity is required for chemicals with an annual production/importation volume of 10 metric tonnes or more. Standard information requirements include a screening study on reproduction toxicity (OECD TG 421/422) at Annex VIII (10-100 t.p.a), a prenatal developmental toxicity study (OECD 414) on a first species at Annex IX (100-1000 t.p.a), and from March 2015 the OECD 443(Extended One-Generation Reproductive Toxicity Study) is reproductive toxicity requirement instead of the two generation reproductive toxicity study (OECD TG 416). If not conducted already at Annex IX, a prenatal developmental toxicity study on a second species at Annex X (≥ 1000 t.p.a.).</p>
<p>Under the Biocidal Products Regulation (BPR), information is also required on reproductive toxicity for active substances as part of core data set and additional data set (EU 2012, ECHA 2013). As a core data set, prenatal developmental toxicity study (EU TM B.31) in rabbits as a first species and a two-generation reproduction toxicity study (EU TM B.31) are required. OECD TG 443 (Extended One-Generation Reproductive Toxicity Study) shall be considered as an alternative approach to the multi-generation study.) According to the Classification, Labelling and Packaging (CLP) regulation (EC, 200; Annex I: 3.7.1.1): a) “reproductive toxicity” includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring; b) “effects on fertility” includes adverse effects on sexual function and fertility; and c) “developmental toxicity” includes adverse effects on development of the offspring.</p>
adjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedNot SpecifiedMaleNot SpecifiedAdult, reproductively matureNot Specified2016-11-29T18:41:162023-04-29T13:02:11