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Ecotoxicological information

Long-term toxicity to fish

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Description of key information

 There are four key studies (all reliability 1, reliable without restriction) available which address the long-term toxicity of Bisphenol A to fish. The most sensitive endpoint was egg hatchability in F2 of a 444 day-multigeneration study with fathead minnow (Pimephales promelas) according to EPA OPP 72-5 method which  reported a NOEC of 16 µg/L (Caunter et al., 2000, published in Staples et al., 2011, Ecotox Environ Safety 74:1548-1557). Results reported from a fish early life stage study (OECD 210) with P. promelas led to significantly higher NOECs based on hatchability, survival, and growth at 640 µg/L in all cases (Caunter et al., 1999, published as Staples et al., 2011, Ecotox Environ Safety 74:1548-1557). With the same test species there were no statistically significant effects in males or females with respect to growth, gonad weight, gonadosomatic index (GSI), or reproduction variables (e.g., number of eggs and spawns, hatchability) at any Bisphenol A concentration in the third key study by Rhodes et al.  (2008, published in Mihaich et al., 2012, Environ Toxicol Chem, 31: 2525-2535) which was conducted in accordance with EPA OPP 72-5 method. However, Rhodes et al., 2008, reported of reduced survival with male fish at 640 µg/L (NOEC = 160 µg/L). For marine species, a NOEC for reproductive success (egg/female/day) was observed in a key study investigating the life-cycle exposure to sheepshead minnow (Cyprinodon variegatus) at 66 µg /L and according to EPA OPPTS 850.1500 method (York, 2010, published in Mihaich et al., 2018, Environ Toxicol Chem, 37:398-410). 

Key value for chemical safety assessment

EC10, LC10 or NOEC for freshwater fish:
0.016 mg/L
EC10, LC10 or NOEC for marine water fish:
0.066 mg/L

Additional information

There are three key long-term toxicity studies for freshwater fish, all with the fathead minnow (Pimephales promelas), and one life-cycle study with an estuarine fish, the sheepshead minnow (Cyprinodon variegatus). Caunter et al. (1999, published in Staples et al., 2011, Ecotox Environ Safety 74:1548-1557) reported the results of a 36-day early life stage study with fathead minnow which were exposed to 1.0, 10, 100, 320, and 640 µg/L nominal concentration. The NOEC determined in that study based on hatchability, survival and growth was 640 µg/L. Caunter et al. (2000, published in Staples et al., 2011, Ecotox Environ Safety 74:1548-1557) reported on a multigeneration study exposing the fathead minnow (Pimephales promelas) for 444 days, through two generations, to a dilution water control and nominal Bisphenol A concentrations of 1.0, 16, 160, 640, and 1280 µg/L. Daily observations of mortality, behaviour and appearance were made and any abnormal effects recorded for the F0, F1, and F2 generation fish. Survival, growth, reproduction, gonadal size, vitellogenin, and gonadal histology were evaluated. Gonadal evaluations and vitellogenin concentrations were reported in the companion study (Sumpter et al., 2001) but the results did not reveal an even more sensitive outcome than observed in the Caunter et al. (2000) study which was hatchability in F2. Due to weaknesses of the spermatogenesis assessment in the supporting study by Sumpter et al. (2001) (e.g. quality of histopathology sections/slides, number of fields counted, number of cell types assessed) it was not possible for the authors to derive a NOEC based on the histology data alone. The reported NOEC of 16 µg/L for vitellogenin in males (Sumpter et al., 2001) supports the same NOEC value for hatchability in F2 (Caunter et al., 2000, published in Staples et al., 2011, Ecotox Environ Safety 74:1548-1557).

Rhodes et al., 2008, the third key study, is a follow-up study to Caunter et al. (2000) and the Sumpter et al. (2001) and aimed to evaluate the possible effects of Bisphenol A on gonadal cell growth (Rhodes, 2008). In this 164 day study with exposure to 0, 1, 16, 64, 160, and 640 µg/L BPA, Rhodes et al. (2008, published in Mihaich et al., 2012, Environ Toxicol Chem, 31: 2525-2535) reported of no statistically significant effects at any treatment level in males or females with respect to growth, gonad weight, gonadosomatic index, or reproduction variables (e.g., number of eggs and spawns, hatchability), with the exception of reduced survival in males at 640 µg/L (NOEC = 160 µg/L). With respect to supplemental endpoints evaluated in this study, there was a statistically significant increase in vitellogenin at 64 µg/L and higher in both males and females, compared to controls. Gonadal histopathology showed a statistically significant increase in intravascular proteinaceous fluid in females, with minimal to mild changes at 640 µg/L, and in males with minimal to moderately-severe changes at 160 and 640 µg/L. A statistically significant shift towards less mature gametogenic cell types (relative cell frequency as compared to controls) was observed in females at 640 µg/L and in males at 160 µg/L and 640 µg/L. In summary, population relevant reproduction endpoints of growth, fecundity and hatchability were not impacted at any concentration. Contrary to previous study results (Sumpter et al., 2001), changes to the distribution of testicular cell types only occurred at the highest treatment levels tested in this robust study. The ecologically relevant NOEC based on male survival was 160 µg/L.

There is one key estuarine/marine life-cycle study with the sheepshead minnow (Cyprinodon variegatus; York, 2010, published in Mihaich et al., 2018, Environ Toxicol Chem, 37:398-410). The objective of this 116-day study was to evaluate the long-term (chronic) effects of exposure to Bisphenol A on marine water fish, the sheepshead minnow. Data were compiled on the effects of exposure on hatching success, survival, growth (total length and wet weight) and reproductive success of first generation (F0) fish (eggs/female/day) and the hatching success, survival and growth (total length and wet weight) of their progeny (F1). No effects were noted in any of the parameters measured at the highest concentration tested except for reproductive success measured as eggs/female/day. Based on F0 reproductive success (eggs/female/day), the study NOEC was 66 µg/L and the study LOEC was 130 µg/L.

Further supporting studies (Klimisch 1 or 2)) were identified. Sumpter et al., 2001, performed a study according to EPA OPPTS 850.1500 method with P. promelas and reported a NOEC of 16 µg/L (already mentioned before). Yokota et al., 2000, determined a NOEC of 355 µg/L in an OECD 210 study with Oryzias latipes. Bayer AG, 1998, conducted an OECD 215 study with Onchorhynchus mykiss and reported a NOEC of 3.64 mg/L. Kang et al., 2002, an exploratory non-guideline study with O. latipes reported of a LOEC of  837 µg/L. Honkanen et al., 2004, an exploratory study with Salmo salar fish reported of no effect following exposure with 10, 100, and 1000 µg/L (NOEC > 1000 µg/L). Metcalfe et al., 2001, reported of a NOEC of 50 µg/L with O. latipes. Finally, Kinnberg and Toft, 2003, determined no effect up to 500 µg/L with Poecilia reticulate. Thus, there are many supporting studies which report NOEC in the range of 16 to 3.640 µg/L.

In contrast, several other chronic fish studies which are listed and discussed in this chapter were rated as Klimisch 3 (not reliable) due to major short-comings or Klimisch 4 (not assignable) due to e.g. insufficient documentation and disregarded in the risk assessment. Full justifications for disregard are provided in the endpoint study records and the respective robust study summaries (e.g. Lahnsteiner et al., 2005, Chen et al., 2015, Kwak et al., 2001, deKermoysan et al., 2013, Hatef et al., 2012, Keiter et al., 2012).

In conclusion, there were four key and several supporting studies. The key studies which reported of the lowest effect levels were Caunter et al., 2000, who reported a NOEC of 16 µg/L for the freshwater compartment and Rhodes et al., 2008, who reported a NOEC of 66 µg/L for the marine water compartment.