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EC number: 229-722-6 | CAS number: 6683-19-8
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- Aquatic toxicity
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- Short-term toxicity to aquatic invertebrates
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- Endocrine disrupter testing in aquatic vertebrates – in vivo
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Specific investigations: other studies
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Link to relevant study record(s)
Description of key information
The test article's potential to disrupt the endocrine system has been addressed by various studies. The test item was negative in an uterotrophic assay with juvenile rats and did furthermore not show any effect in an uterotrophic assay using mature ovarectomised rats. In addition, the test item was negative in vitro when tested to androgenic and antiandrogenic activity. Various in vitro tests demonstrated further that the test article has no estrogenic activity. No effects on reproduction were observed in a 2-generation study with rats. Also development of fetuses as observed in two developmental toxicity studies with rats and mice were unaffected by treatment with the test item. In addition, the test substance is characterized by a large molecular weight supporting the conclusion that bioavailability will be negligible and therefore preventing proximity to an endocrine receptor.
Additional information
Endocrine Disruption Potential
The endocrine disruption potential of the test article was assessed based on several in vitro and in vivo studies investigating the endocrine activity of the test item and based on in vivo reproduction data.
The estrogenic activity of the test item was addressed in a uterotrophic assay with juvenile female rats. The animals received the test substance as suspensions in 0.5% methylcellulose by gavage for five consecutive days at dose levels of 100, 300 and 1000 mg/kg. The vehicle and EE at 0.001, 0.01 and 0.1 mg/kg served as negative and positive controls, respectively. On completion of the treatment period, i.e. on day 6, animals were weighed and killed. The uterus was weighed wet, immediately after sacrifice, with (full uterus) and without (empty uterus) the uterine fluid. A complete macroscopic post-mortem examination was performed in the abdominal cavity, focused on the reproductive tract. Uterus and vagina were preserved. No unscheduled deaths occurred during the study. No clinical signs were observed in any control, reference or treated animals during the study. No notable differences were observed in mean body weight gain between the reference or treated groups and the control group. No statistically significant differences from control group were observed in animals treated with the test item. The mean absolute and relative uterus weights (with or without uterine fluid) of animals given EE at 0.01 mg/kg/day (respectively, full: +144% and +151%, empty: +137% and +143%, p<0.01) or 0.1 mg/kg/day (respectively, full: +110% and +121%, empty: +111% and +122%, p<0.05) were significantly higher than those of the control group animals. There were no macroscopic post-mortem findings in any group. In conclusion, the administration of the test substance by oral route to juvenile female rats for five days was well tolerated. The absence of differences in uterus weight observed in animals receiving the test item indicated the absence of estrogenic activity under these conditions (CIT, 1999).
The estrogenic activity of the test item was further assessed in an unterotrophic assay in mature ovarectomised rats. Groups of ten ovarectomised female Wistar derived rats (8-10 weeks of age at the start of the study) received a single oral dose of 0 (vehicle control), 250, 500 or 1000 mg/kg body weight of the test item once a day for 3 consecutive days. As a positive control, one group of rats received a single oral dose of 0.4 mg 17ß-estradiol benzoate/kg body weight once a day for 3 consecutive days. The vehicle used for the test substance and 17ß-estradiol benzoate was Arachis oil. The body weight of each rat was recorded daily, and detailed clinical observations were made at the same time. At the end of the study (approximately 24 hours after administration of the final dose), all of the animals were killed. The uterus was then removed from each animal and the blotted weight recorded. There were no adverse clinical signs observed during this study that were considered to be related to administration of the test item. There, was no effect of test substance administration on body weight or body weight gain. There was no effect of test substance administration on blotted uterine weight. In conclusion, there was no evidence of an uterotrophic response with this test substance. As expected, oral gavage administration of 17ß-estradiol benzoate to the mature ovarectomised rat for three consecutive days resulted in increased uterine weight, demonstrating a positive uterotrophic response with this substance (CTL, 2002).
The androgenic receptor activity of the test item was investigated in vitro by Araki et al and published in 2005. The androgenic and antiandrogenic activity of various chemicals were analyzed using a recepoter binding assay. The test item was found to possess no androgenic and no anti-androgenic activity (Araki, 2005).
The thyroid hormone receptor (TR)-binding activities of the test item was examined using a yeast two-hybrid assay by Kitagawa at el. The test item was found to be negative in this assay system (Kitagawa, 2003).
Rotroff et al used a panel of 13 in vitro HTS assays to examine various chemicals. The panel of in vitro assays interrogated multiple end points related to estrogen receptor (ER) signaling, namely binding, agonist, antagonist, and cell growth responses. The results from the in vitro assays were used to create an ER Interaction Score. The test compound was found to have a CSagonist score of 0, a CSantgonist score of 0, CSbinding score of 0 and an overall ER interaction score of 0 (Rotroff, 2014).
In another publication investigating estrogen activity, a yeast two-hybrid assay was performed. The results were evaluated on the basis of the relative activity, expressed as 10% relative effective concentration (REC10), which is the concentration of the test chemical showing 10% of the agonist activity of 10xE-6 mol/L 17-beta-Estradiol, the highest activity level of 17-beta-Estradiol. The REC10 (M) for the test substance were >1.0 x 10E-4 (parent compound) and >5.0 x 10E-5 (metabolite) and therefore it has no activity in regard to binding to the estrogen receptor (Ogawa, 2006)
A negative result regarding estrogenic activity was also reported by Ter Veld et al. In their study the estrogenic potency of several compounds was evaluated using two transfected U2-OS (human osteoblasts devoid of endogenous estrogen receptors) estrogen receptor (ER) alpha and beta cell lines. The test article did not show any estrogenic activity in these assays (Ter Veld, 2006).
The Endocrine activity of 65 compounds migrating from polycarbonate replacement plastic baby bottles was assessed using in vitro cell based assays (reporter gene assays) involving human estrogen receptor (ER), human androgen receptor (AR), human progesterone receptor (PR), human glucocorticoid receptor (GR), human peroxisome proliferator-activated receptor gamma (PPARγ), human thyroid receptor beta (TRβ) and the mouse aryl hydrocarbon receptor (AhR). The test compound displayed no agonistic effects on AR, GR, PR, ER, TRβ and AhR. Furthermore, the test article did not display an antagonistic effect on AR, GR, PR, ER1, ER2 and AhR. A low agonistic effect on PPARγ and a low antagonistic effect on TRβ and PPARγ were reported identified. The potencies of these positive results are described only by two categories without any qualitative data, therefore these results cannot be judged properly.
In a publication by the German federal environmental agency (UBA) the test article was investigated in vitro using the Yeast Estrogen Screen (YES), the Yeast Antiestrogen Screen (YAES) and the E-Screen. The test article was found to be inactive in all assays utilized (Wagner, 2011).
In a 2-generation reproduction toxicity study (see chapter 7.8.1) the effect of the test item on fertility and pup development was investigated in rats. Mating performance was not adversely affected by treatment in either generation. The mean duration of gestation was similar for all groups within and between generations. Routine terminal examination of F0 and Fl adults did not reveal any obvious macroscopic changes attributable to treatment. The reproductive tissues of selected adult males and females of the control and top dose group (10000 ppm) of both generations were examined microscopically. There were no treatment-related changes observed in the sections examined in males or females of either generation. There were no adverse effects on litters of treated parents in either generation, as assessed by the incidence of total litter loss, mean values for litter size, pup mortality, sex ratio, litter and mean pup weights and findings at terminal autopsy. The incidence of morphological anomalies recorded at autopsy of excess Fl weanlings or amongst siblings sacrificed at maturity, together with their F2 progeny, did not indicate any adverse effect of treatment. In conclusion, the test article had no effect on fertility and pup development even at the highest dose level applied.
No teratogenic effect was observed in both mice and rats (see chapter 7.8.2). In rats the NOAEL for maternal and developmental toxicity is considered to be 1000 mg/kg bw with no significant adverse treatment-related effects reported. In mice, the NOAEL for maternal and developmental toxicity is considered to be 1000 and 500 mg/kg bw/d, respectively. Reduced ossification of the sternebrae in high dose mice is considered to reflect some minor non-specific signs of maternal toxicity.
The estrogen receptor binding capability of the test item was further analyzed using the OECD toolbox. The OECD Toolbox v3.3 profiler for Estrogen Receptor Binding classified the test article a Non-ER binder due to high molecular weight. Reasoning: Since the RE-binding is a receptor mediated event, particular organic functional groups, size and shape are critical to binding potency. Chemicals that are too large cannot bind to the receptor regardless of structure or shape. While chemicals with a Molecular Weight of greater that 1000 are reported to be too large to bind to the receptor (Cronin et al, 2008; Tong et al, 2004) a review of the ER-binding database (ERBA OASIS) within the Toolbox reveals that no chemical with a molecular weight greater that 500 has been shown to bind to the ER receptor.
References:
Cronin, M.T.D. and Worth A.P. 2008. (Q)SARs for predicting effects relating to reproductive toxicity. QSAR & Combinational Science 27: 91-100.
Tong, W., Fang, W.D., Hong, H., Xie, Q., Perkins, R. and Sheehan, D.M. 2004. Receptor-mediated toxicity: QSARs for estrogen receptor binding and priority setting of potential estrogenic endocrine disruptors. In: Cronin, M.T.D. and Livingstone D.J. (Eds) Predicting Chemical Toxicity and Fate. CRC Press Boca Raton FL pp.285-314.
In addition, the test article is very large (>1100 g/mol) and based on the physico-chemical parameters penetration of biological membranes is not expected. Therefore, the test article will only be bioavailable at trace amounts, if at all. For detailed information refer to chapter 7.1.1.
Overall conclusion:
The test article's potential to disrupt the endocrine system has been addressed by various studies. The test item was negative in an uterotrophic assay with juvenile rats and did furthermore not show any effect in an uterotrophic assay using mature ovarectomised rats. In addition, the test item was negative in vitro when tested for androgenic and antiandrogenic activity. No effects on reproduction were observed in a guideline compliant 2-generation study with rats. Also development of fetuses as observed in two developmental toxicity studies with rats and mice were unaffected by treatment with the test item. In addition, the test substance is characterized by a large molecular weight which allows for the conclusion that bioavailability will be negligible and binding to endocrine receptor nearly impossible. Therefore, there is no concern regarding endocrine disruption for the test item.
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