Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Hazard for aquatic organisms

Freshwater

Hazard assessment conclusion:
PNEC aqua (freshwater)
PNEC value:
5.22 µg/L
Assessment factor:
10
Extrapolation method:
assessment factor
PNEC freshwater (intermittent releases):
0.027 mg/L

Marine water

Hazard assessment conclusion:
PNEC aqua (marine water)
PNEC value:
0.522 µg/L
Assessment factor:
100
Extrapolation method:
assessment factor
PNEC marine water (intermittent releases):
0.027 mg/L

STP

Hazard assessment conclusion:
PNEC STP
PNEC value:
4.787 mg/L
Assessment factor:
10
Extrapolation method:
assessment factor

Sediment (freshwater)

Hazard assessment conclusion:
PNEC sediment (freshwater)
PNEC value:
1.21 mg/kg sediment dw
Extrapolation method:
equilibrium partitioning method

Sediment (marine water)

Hazard assessment conclusion:
PNEC sediment (marine water)
PNEC value:
0.121 mg/kg sediment dw
Extrapolation method:
equilibrium partitioning method

Hazard for air

Air

Hazard assessment conclusion:
no hazard identified

Hazard for terrestrial organisms

Soil

Hazard assessment conclusion:
PNEC soil
PNEC value:
0.239 mg/kg soil dw
Assessment factor:
1
Extrapolation method:
equilibrium partitioning method

Hazard for predators

Secondary poisoning

Hazard assessment conclusion:
no potential for bioaccumulation

Additional information

Of the studies presented, the evidence suggests the chemical may have endocrine disrupting properties (ED). The methods for each study have been previously described and the following outlines the methods for assessing ED and contextualises the results of these studies in terms of ED. There are four well-known MoAs for ED these are comprising of oestrogen, androgen, thyroid and steroidogen modalities (WHO, 2012 & EC, 2016). These will be the focus herein.

Endocrine Disruption:

Firstly, Yang et al. (2014) specifically studied the potential of the test item to dirupt sex hormone regulation and vitellogenin (VTG). VTG is a major precursor of egg yolk, and is synthesized in the liver of females in all oviparous vertebrates. VTG is transported through the blood to the ovary, and ultimately absorbed in the mature oocytes.  VTG in adult male fish can be induced by the presence of oestrogenic compounds. Thus, the induction of VTG gene expression in males or larvae has been used as a sensitive biomarker for oestrogenic disruption. Expression of VTG is under the control of 17beta-estradiol, which can bind to specific endocrine receptors (ERs) in response to the stimulation of endocrine-disrupting chemical. Here the study focuses on the possible disturbance of the oestrogenic (VTG and estradiol; E2), androgenic (testosterone; T) and thyroid (triiodothyronine; T3). Both the oestrogenic and androgenic effects also come under steroidogenic effects. Histological observtions were also made on the gonad. Whole body homogenates of T, E2 and T3 were measured using standard biochemcil assays. VTG was measured indirectly using VTG gene expression. VTG is a standard endpoint under the OECD 234 guideline (2011) which was designed to study perturbations in fish sexual development, and potential ED. However, the study does not rely on gene expression due to the reasons previously mentioned. VTG gene expression was significantly increaed in males, although alone gene expression can not always infer biological alterations, the authors also noted acellular areas in the testis or inhibited oocyte maturation from the histological observations. Furthermore, in males E2 was signifcantly increased, again suggesting an oestrogenic effect. Statistically not significnat dose dependent decreases in T levels and T/E2 ratio. T3 was significantly increaed in female fish. Based on the evidence from the study, the test item is potentially an endocrine disruptor.

Song et al. (2014) studied the oestrogenic activity of the test item. VTG levels and oestrogenic activity were assessed. VTG was measured in the blood of exposed zebrafish and was smeasured in the sreum using comparative enzyme-linked immunoabsorbant assay (ELISA), similar to that described in the OECD guideline (OECD 234, 2011). Oestrogenic activity was direclty measuredin vitrousing the the MCF-7-p-Vit-tk-Luc-Neo assay which measures activity using luminesence. Breifly, This cell line was stably transfected with the luciferase reporter gene and estrogen-responsive element, and ER agonists can induce the production of luciferase. Luciferase activity is then measured on luminescence Microplate Reader after cells were exposed to test compound for 48 h, total protein content was simultaneously measured by the Bradford Blue assay to normalize luminescent units. VTG was significantly increased in a dose-dependent manner in all zebrafish exposed to the test item, the exposure concentrations were 0.5, 1.0 and 1.5 mg/L. During the MVLN assay oestrogenic activity was also increased at 10 µM of test item and showed a dose dependnet response. However, there was no impact at the whole organism level when considering endpoints which may have been due to ED, i.e. in the measured endpoint of hatching rate, although increased oedema was observed this is non-selective mode of action. Although VTG and oestrogen activity were significantly impacted it is unsure on how these shifts will impact the population or individual fish. The study provides some evidence of the test item potentially being an ED but the endpoints can not be linked to biological outcome. According to the WHO/IPCS (2002) definition, a chemical is only an ED if an adversein vivoeffect can be plausibly linked to an endocrine MoA. Further under many regualtory frameworks it is important to establish a plausible biological link between the MoA and the whole organism effect. However, there is no causal link made in this study and as such no plausible links can be directly made. The study shows that the test item is potentially an endocrine disruptor.

Shi et al. (2015) studied oestrogenic (E2) and androgenic (T) pertrubations of zebrafish expsosed to the test item. Furthermore, genes of the hypothalamus-pituitary-gonad axis were studied, which largely controls many of the hormones which may be impacted by ED chemicals (i.e. gonadotropin releasing hormone (GnRH), lutenizing hormone (LH), follicle stimulating hormone (FSH) and oestrogen and testosterone). These measures were taken after 120 -d of exposure. The hormone analysis was taken from blood samples taken from the caudal veins, the RNA was extracted from homogenates of brains, gonads and liver. The study showed that after 120-d of exposre to the test item E2 and E2/T ratio was significantly increased in both males and females in a dose-dependent manner. For males the NOEC was 5 µg/L and for females it was 25 µg/L. T significantly decreaesed in males only with a NOEC of 25 µg/L, again in a dose dependent manner. No such effect was noted in the female fish. In male fish several genes at 125 µg/L were either significantly suppressed or induced in all tissues. In the liver vtg1 significnatly increased at 25 and 1255 µg/L. Minimal gene expression changes were seen in female fish, although there was one gene which was significantly increased and decreaed (fshrandstar) at 125 µg/L. Genes invovled with the regulation of GnRH (e.g.gnrh2), LH (e.g.lh-beta,lhr) and FSH (e.g.fsh-beta,fshr) were all effected, and thus the regualtion of testosterone and oestrogen may be effected. This is shown at the sub-organism level seen in the E2 and T resutls of the study. Further there is a causal link between the disruption of these genes and steriodal hormones with whole levein vivoeffects. The link is also plausable. For the F0 generation there was a decrease in ferilization rate of females, and this was significant at 125 µg/L, however this did not appear dose-dependent, possibly as higher concentrations were not tested, nevertheless, ED chemicals may not present dose-dependent relationships and therefore there is still potential that this is an affect of an ED chemical (EFSA, 2015). Further, malformation rate of offspring was also increaed ar 125 µg/L, survival was also decreaed at the highest concntration (125 µg/L). The study shows that the test item is potentially an endocrine disruptor.

The presented evidence suggests a causal link between ED specific gene and hormone disruption and biological repsonse. Based on the genes and hormones affected the link is also plausable. Considering the evidence presented, the test item is potentially an endocrine disruptor in fish.

Conclusion on classification

No harmonised classification is available on the registered substance.


Based on data available in the present dossier, the substance meets the criteria for classification as Aquatic Chronic 1 (hazardous to the aquatic environment (long-term)) with a M-factor at 1, in accordance with the criteria set in Regulation (EC) No 1272/2008 (CLP).


In acute conditions, the aquatic invertebrates, Daphnia magna is the most sensitive species with a 48h-EC50 value at 2.7 mg/L. As the lowest E(L)C50 value is > 1.0 mg/L, the substance is not classified for short-term aquatic hazard. However, in long-term conditions, the lowest NOEC value was reported at 52.2 µg/L for the algae Pseudokirchneriella subcapitata. As the substance is not readily biodegradable with a lowest NOEC value < 0.1 mg/L, the Category Chronic 1 classification applies for long-term aquatic hazard.