Reaction mass of 4,4'-isopropylidenediphenol and phenol

Long-term toxicity to fish

Link to relevant study record(s)

Reference

Endpoint:

long-term toxicity to fish, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol can be predicted by studies conducted with the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol, because the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol contains phenol (40-45%, typical concentration ca. 40%) and 4,4’-isopropylidenediphenol (BPA) (20-40%, typical concentration ca. 33%) as main constituents. Both constituents are data rich substances with distinct hazard properties, so that mainly data on the constituents have been applied to characterize the Reaction mass of phenol and 4,4’-isopropylidenediphenol. Since this is a common approach in mixture hazard assessment, is reasonable to apply it also to multi-constituent substances.
Additionally, some data from a structurally related substance (2-acetone, polymer with phenol) containing the same constituents/impurities at different concentrations are available, which are applied to characterize the environmental fate and ecotoxicity of the impurities present in the Reaction mass of phenol and 4,4’-isopropylidenediphenol.

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol are predicted to be similar to those of the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol.

Therefore, read-across from the available studies with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
please refer to justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
please refer to justification for read-across attached to Iuclid section 13

4. DATA MATRIX
please refer to justification for read-across attached to Iuclid section 13

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Duration:

444 d

Dose descriptor:

NOEC

Effect conc.:

16 µg/L

Conc. based on:

test mat.

Basis for effect:

other: F2 hatchability

Remarks on result:

other: BPA

Key result

Duration:

60 d

Dose descriptor:

NOEC

Effect conc.:

77 µg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

other: survival, wet weight

Remarks on result:

other: Phenol

Conclusions:

For Bisphenol A, the F2 hatchability NOEC of 16 µg/L from the 2-generation fathead minnow study and the NOEC of 66 µg/L from the life-cycle sheepshead minnow study are the most conservative endpoints and will be used in the deriving aquatic PNEC for use in risk assessment.
The most sensitive endpoint for Phenol was the NOEC of 77 µg phenol/L, based on nominal concentrations, obtained in a 60 day study with Cirrhina mrigala under semi-static conditions with a 24 hour renewal period.
Due to the physicochemical properties of phenol, this major constituent of the reaction mass is capable of targeting aquatic and terrestrial wildlife through a different exposure route than 4,4’-isopropylidenediphenol. Therefore, to adequately characterize the hazard of the reaction mass toward ecotoxicology endpoints, the toxicity and fate of both major constituents of the reaction mass of phenol and 4,4’-isopropylidenediphenol were considered and two sets of PNECs (one for phenol one for 4,4’-isopropylidenediphenol) were derived and an assessment entity approach was applied.

Description of key information

For Bisphenol A, the most sensitive effect endpoint that is relevant to fish populations is egg hatchability in the fathead minnow. The NOEC based on egg hatchability from a fathead minnow life-cycle study is 16 µg/L (Caunter et al., 2000).  For marine species, a NOEC for reproductive success (egg/female/day) was observed in a life-cycle exposure to sheepshead minnow at 66 µg a.i./L (York, 2010).

The most sensitive endpoint for Phenol was the NOEC of 77 µg phenol/L, based on nominal concentrations, obtained in a 60 day study with Cirrhina mrigala under semi-static conditions with a 24 hour renewal period.

Key value for chemical safety assessment

Fresh water fish

Fresh water fish

Dose descriptor:

NOEC

Remarks:

BPA

Effect concentration:

0.016 mg/L

Fresh water fish

Dose descriptor:

NOEC

Remarks:

Phenol

Effect concentration:

0.077 mg/L

Marine water fish

Marine water fish

Dose descriptor:

NOEC

Remarks:

BPA

Effect concentration:

0.066 mg/L

Additional information

No experimental data are available for the target substance reaction mass of phenol and 4,4’-isopropylidenediphenol. The toxicity to fish was assessed by examination of the properties of the constituents and impurities of the multi-constituent substance. A justification for read-across is attached to Iuclid section 13.

 

Studies with Bisphenol A

There are three key freshwater long-term toxicity studies, all with the fathead minnow, and one life-cycle study with the estuarine fish, the sheepshead minnow. Caunter et al. (1999) reported the results of a 36-day early life stage study with fathead minnow. The NOEC determined in that study based on hatchability, survival and growth was 640 µg/L. Caunter et al. (2000) 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 they did not impact the most sensitive effect determined in the Caunter et al. (2000) study of F2 hatchability. Weaknesses in the spermatogenesis portion of the Sumpter et al. (2001) study (e.g. quality of histopathology sections/slides, number of fields counted, number of cell types assessed) result in not being able to use that data to set a NOEC based on the histology data alone. The NOEC for vitellogenin production in males was 16 µg/L. Overall, the NOEC established based on F2 hatchability in this multigenerational exposure was 16 µg/L. The other longer-term key study is a follow-on to the Caunter et al. (2000) and the Sumpter et al. (2001) studies to evaluate the possible effects of Bisphenol A on gonadal cell growth (Rhodes, 2008). In this 164 days study, there were no statistically significant effects at any treatment level in males or females with respect to survival, growth, fecundity, hatchability, and gonadosomatic index, with the exception of reduced survival in males at 640 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 survival, 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 (York, 2010). The objective of this 116-day study was to evaluate the long-term (chronic) effects of exposure to Bisphenol A on the marine fish, sheepshead minnow (Cyprinodon variegatus). 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 a.i./L and the study LOEC was 130 µg a.i/L. 

 

Studies with Phenol

Toxic effects of phenol on survival and growth of Cirrhina mrigala larvae were examined. 30 larvae (age of 4 days, 4.5 ± 0.4 mm length; 51 ± 3 mg wet weight), were exposed to 9 graded phenol concentrations (between 44 and 175 µg/L) in duplicate in a semi-static test for 60 days. The test concentrations were not analytically verified. However, due to the daily renewal of the test water (method according to Verma et al. 1981) the exposure concentrations are regarded as stable. At test end survival and wet weight of the surviving larvae was recorded. Detailed data on wet weight and survival. oxygen and pH during the test are not reported. Based on these results a MATC was deduced.

From the MATC of 77 - 94 µg/l a NOEC of 77 µg/l can be derived. The 60 d NOEC obtained with larvae of Cirrhina mrigala is confirmed by the 60 d NOEC obtained with Cyprinus carpio from the same authors (Verma et al. 1981).

 

Reliable study results are available from 8 long-term studies with six fish species. The tests were conducted under flow-through or semi-static conditions and the exposure concentrations were analytically verified in the six flow-through studies. In the semi-static tests (Verma et al. 1981, 1984) the interval for test water renewal was 24 h and the phenol concentrations are regarded as stable, since Colgan et al. (1982) demonstrated the stability of phenol under semi-static conditions (48 h interval).
The most sensitive endpoint was the NOEC of 77 µg phenol/L, based on nominal concentrations, obtained in a 60 day study with Cirrhina mrigala under semi-static conditions with a 24 hour renewal period (Verma et al 1984).

 

Conclusion 

For Bisphenol A, the F2 hatchability NOEC of 16 µg/L from the 2-generation fathead minnow study and the NOEC of 66 µg/L from the life-cycle sheepshead minnow study are the most conservative endpoints and will be used in the deriving aquatic PNEC for use in risk assessment.

The most sensitive endpoint for Phenol was the NOEC of 77 µg phenol/L, based on nominal concentrations, obtained in a 60 day study with Cirrhina mrigala under semi-static conditions with a 24 hour renewal period.

Due to the physicochemical properties of phenol, this major constituent of the reaction mass is capable of targeting aquatic and terrestrial wildlife through a different exposure route than 4,4’-isopropylidenediphenol. Therefore, to adequately characterize the hazard of the reaction mass toward ecotoxicology endpoints, the toxicity and fate of both major constituents of the reaction mass of phenol and 4,4’-isopropylidenediphenol were considered and two sets of PNECs (one for phenol one for 4,4’-isopropylidenediphenol) were derived and an assessment entity approach was applied.