Registration Dossier

Administrative data

Hazard for aquatic organisms

Freshwater

Hazard assessment conclusion:
PNEC aqua (freshwater)
PNEC value:
1.5 µg/L
Assessment factor:
10
Extrapolation method:
assessment factor

Marine water

Hazard assessment conclusion:
PNEC aqua (marine water)
PNEC value:
0.15 µg/L
Assessment factor:
100
Extrapolation method:
assessment factor

STP

Hazard assessment conclusion:
PNEC STP
PNEC value:
10 mg/L
Assessment factor:
100
Extrapolation method:
assessment factor

Sediment (freshwater)

Hazard assessment conclusion:
PNEC sediment (freshwater)
PNEC value:
3 mg/kg sediment dw
Assessment factor:
10
Extrapolation method:
assessment factor

Sediment (marine water)

Hazard assessment conclusion:
PNEC sediment (marine water)
PNEC value:
0.3 mg/kg sediment dw
Assessment factor:
100
Extrapolation method:
assessment factor

Hazard for air

Air

Hazard assessment conclusion:
no hazard identified

Hazard for terrestrial organisms

Soil

Hazard assessment conclusion:
PNEC soil
PNEC value:
0.54 mg/kg soil dw

Hazard for predators

Secondary poisoning

Hazard assessment conclusion:
PNEC oral
PNEC value:
41 mg/kg food
Assessment factor:
90

Additional information

The measured hydrolysis half-life of octamethylcyclotetrasiloxane (D4, CAS 556-67-2) is 3.9 days at pH 7 and 25 °C. The measured water solubility of the substance in pure water is 0.056 mg/l at 23 °C. However, actual functional water solubility differs depending on test media and methods used to prepare test medium. The substance has a measured log Kow of 6.5.

See Section 7.5 for further details of PNEC derivation. This derivation takes a precautionary worst-case approach to the interpretation of the aquatic studies available; the studies are reported accordingly. However, in section 7.6, a weight-of-evidence approach is applied in consideration of the self-classification for the environment to conclude that the effects seen are of low significance.

READ-ACROSS JUSTIFICATION

In order to reduce animal testing, read-across is proposed to fulfil REACH Annex X requirements for sediment ecotoxicity for the registered substance from substances that have similar structure and physicochemical properties.

The registration substance (D4) and the substance used as surrogate for read-across are members of the Reconsile Siloxanes Category. Substances in this category tend to have low water solubility, high adsorption and partition coefficients and slow degradation in the sediment compartment. In the environment, the substances will adsorb to particulate matter and will partition to soil and sediment compartments.

Read-across from decamethylcyclopentasiloxane (D5) to octamethylcyclotetrasiloxane (D4) is considered to be valid for sediment ecotoxicity.

The hypothesis for read-across of sediment ecotoxicity evidence within the Siloxanes Category is that no structure-based or property-based pattern is evident from the Category data set, with read-across proposed on a nearest-neighbour basis within the Category. The registered substance, octamethylcyclotetrasiloxane (D4, CAS 556-67-2) and the surrogate substance decamethylcyclopentasiloxane (D5, CAS 541-02-6) are cyclic siloxanes. D5 is a cyclic siloxane with five dimethylated silicon atoms linked by five oxygen atoms. D4 is a directly analogous structure with four silicon and four oxygen atoms. The substances have similar physicochemical properties: high molecular weight (370 and 296 respectively), low water solubility (both insoluble, at 0.017 and 0.056 mg/l respectively), high log Kow (8.02 and 6.49 respectively) and high log Koc (5.2 and 4.22 respectively).

Environmental toxicity data for siloxanes are consistent with a non-polar narcosis mechanism (Redman, 2012; Peter Fisk Associates 2017). Given the similar properties and structural similarities, it is considered valid to read-across data from decamethylcyclopentasiloxane (D5) to octamethylcyclotetrasiloxane (D4). Additional information is given in Section 7.1.5 and in a supporting report (PFA 2017) attached in Section 13 of the IUCLID 6 dossier.

 

Table7.0.1 Summary of ecotoxicological and physicochemical properties for the registered substance and the surrogate substance(aquatic and terrestrial toxicity)

CAS Number

556-67-2

541-02-6

Chemical Name

Octamethylcyclotetrasiloxane (D4)

Decamethylcyclopentasiloxane (D5)

Si hydrolysis product

Dimethylsilanediol

Dimethylsilanediol

Molecular weight (parent)

296.62

370.78

Molecular weight (hydrolysis product)

92.17

92.17

log Kow (parent)

6.49

8.02

log Kow (silanol hydrolysis product)

-0.38

-0.38

log Koc (parent)

4.22

5.2

Water solubility (parent)

0.056 mg/l

0.017 mg/l

Vapour pressure (parent)

132 Pa

33.2 Pa

Vapour pressure (hydrolysis product)

7 Pa

7 Pa

Hydrolysis t1/2 at pH 7 and 25°C

69-144 hours

1590 h

Short-term toxicity to fish (LC50)

96 h LC50 >22 μg/l;

>16 µg/l

Short-term toxicity to aquatic invertebrates (EC50)

>15 μg/l

>2.9 µg/l

Algal inhibition (ErC50 and NOEC)

ErC50 >22 µg/l and ErC10 22 µg/l

ErC50: >12 μg/l; NOEC: ≥12 μg/l

Long-term toxicity to fish (NOEC)

≥4.4 μg/l

≥14 μg/l

Long-term toxicity to aquatic invertebrates (NOEC)

NOEC ≥15 µg/l

≥15 µg/l

Sediment toxicity (NOEC)

13 mg/kg dry weight, Lumbriculus variegatus
44 mg/kg dry weight, Chironomus riparius

70 mg/kg dwt,C. riparius
≥1272 mg/kg dwtL. variegatus
130 mg/kg dwt, H. azteca

Short-term terrestrial toxicity (L(EC)50)

n/a

(IC50) 209 mg/kg dwt,H. vulgare;
>4054 mg/kg dwt,
T. pratense

Long-term terrestrial toxicity (NOEC)

n/a

≥4074 mg/kg dwt,
E. andrei
377 mg/kg dwt,
F. candida

 

Overview of toxicity to aquatic organisms

This discussion is a new consolidated review of the toxicity to aquatic organisms, and is a necessary step before PNECs and environmental classification are discussed in later sections. It has been prepared by the registrants in 2017 in response to ongoing discussions about the aquatic classification of D4.

Background

An overall WoE evaluation has been performed by the Industry to consider all relevant data including environmental behaviour of the substance, physical-chemical properties and ecotoxicological data and to address some of the uncertainties as well as the technical difficulties resulting from intrinsic physicochemical and partitioning properties of the substance when conducting guideline tests (GHS Revision 6, 2015, sections 4.1.2.5, A9.3.4.2, and A9.3.6.2.3).In addition, recently published expert reviews (Bridges and Solomon, 2016 and Fairbrother et al., 2016) have also been considered and provided as references in this analysis.

Detail

Discussion on Toxicity

GHS Guidance highlights that:

Section A9.3.4.2: apparent effects due to use in closed systems should be weighted accordingly

Section A9.3.4.2: “Substances, which are difficult to test, may yield apparent results that are more or less severe than the true toxicity. Expert judgment would also be needed for classification in these cases.”

Section 4.1.2.5: “There may be circumstances where the lowest toxicity value among taxa is not used for C&L where a WoE approach is used.”

Section A9.3.6.2.3:  “Classification should allow for use of reviews from national authorities and expert panels as long as the reviews are based on primary data.”

D4’s intrinsic properties lead to challenges in testing – Section A9.3.4.2: apparent effects due to use in closed systems should be weighted accordingly and Section A9.3.4.2: Substances, which are difficult to test, may yield apparent results that are more or less severe than the true toxicity. Expert judgment would also be needed for classification in these cases.

D4’s intrinsic properties lead to challenges in testing that must be taken into consideration when assessing the data set for classification and labelling.  D4 is a substance of very low water solubility (approximately 50 micrograms per litre), and its solubility in test media is likely to be lower than its solubility in pure water.  In addition, D4 is volatile with a high Henry’s law constant. These properties led to significant challenges in testing water column species and decisions based on testing under extremely unrealistic conditions should always be cautionary and expert judgement should be used for assessing classification and labelling.

While D4 has exhibited toxicity to water column organisms in the laboratory, toxicity has been demonstrated only in studies performed using closed, hermetically sealed dosing systems having no headspace, which essentially eliminates the predominant intrinsic physical/chemical property of volatilization. All toxicity studies performed using open non-sealed diluter systems that realistically allow equilibration with air, showed no effect at any concentration.

While D4 has exhibited toxicity to water column organisms in the laboratory, given D4’s very low water solubility the methods used to prepare and add stock solutions may have led to unrealistic test conditions. Test systems prepared using over statured stock solutions (prepared at ambient temperatures) can lead to a very high excess of the substance at the point of addition, and when added to a test system operating at the lower temperature of 12 degrees C, the solubility in the test media would remain uncertain.

There may be circumstances where the lowest toxicity value among taxa is not used for C&L where a WoE approach is used - Experts conclude the daphnia chronic NOEC value of 7.9 µg/L of D4 should not be considered the relevant NOEC.

Based on scientific expert analysis by Fairbrother et al., (2016) and Bridges and Solomon (2016), the 21-d Daphnia magna reproduction and survival NOEC value of 7.9 µg/L of D4 should not be considered the relevant NOEC on the following basis:

The study was conducted under closed system, with zero head-space conditions, i.e., the exposure apparatus was all glass, with no openings to the atmosphere to minimize volatilization and loss of D4 from aqueous solution.  This exposure arrangement is extreme and will not be replicated under natural field conditions.

In review of the statistical analysis of the reproduction data, a significant (p ≤ 0.05) difference was observed at the 7.9 µg/L treatment level in comparison with the control. However, this was not a population-relevant effect since the number of offspring per daphnid did not decrease from the control to the highest concentration (15 µg/L), but increased cumulatively from 111 (at control) to 167 (at 15 µg/L) offspring/daphnid. Therefore, the reproduction NOEC should be considered ≥ 15 µg/L.

A significant difference (p ≤ 0.05) was also observed in the survival rate at the 7.9 µg/L treatment level in comparison with the control. The survival rate of parent daphnia changed from 87% to 77% at 7.9 µg/L and 15 µg/L dose levels respectively in comparison with the controls with a survival rate of 93%. However, the survival rate of 77% in the high dose group is the arithmetic mean of just 2 replicates, where in fact only in 1 replicate a survival rate below 80% was observed (replicate 1: 67%; replicate 2: 87%). In addition, the allowable survival rate for controls is 80% so this is considered only a slight reduction in survival, and ultimately the substance did not affect reproduction or neonate size.

Furthermore, Fairbrother et al., (2016), has noted that the “functional water solubility is defined as the maximum achievable solubility under the specific conditions and dilution water quality for a particular study”.  The water solubility of D4 in the 21-d Daphnia magna study is notably lower (15 μg/L) than the actual water solubility of 56 µg/L.

Bridges and Solomon (2016), using a cut-off for environmental concentrations (based on the upper 99.9th centile of the maximum values reported in receiving waters) reported that in the 21-d chronic daphnia study the NOEC was 750 times greater than the water concentration cut-off of 0.02 μg/L and the response was judged to not be adverse (Bridges & Solomon, 2016).

Therefore, based on the above, registrants agree that the overall chronic daphnia D4 NOEC in this study should be considered ≥15 µg/L.

Classification should allow for use of reviews from national authorities and expert panels as long as the reviews are based on primary data – Experts conclude D4 is low risk for Aquatic organisms.

A Weight of Evidence (‘WoE’) analysis of laboratory testing of toxicity to aquatic organism from D4 (Bridges and Solomon, 2016) concluded that: “the overall WoE analysis shows that there is moderate to strong evidence of no adverse effects from concentrations of D4 as measured or expected to be in the environment”.

Mackay et al. (2015) also concluded that super-hydrophobic substances such as D4 often fail to reach a toxic endpoint at their functional solubility limit. As noted by the authors, this is due to the fact that such materials generally act via a narcotic mode of action (MOA), and D4 is unlikely to achieve a body burden at the narcotic MOA level due to limited water concentrations, poor bioavailability, and insufficient time of exposure. In addition, Mackay et al., (2015) have estimated the critical body burden for toxicity as 3 mmol/kg, for a narcotic mode of action.

The estimated time (days) to achieve a critical body residue of 3.0 mmol/kg (888 mg/kg) for D4 is calculated to be 72 to >1000 days for dose levels of reported functional water solubility of 22 down to 4.4 µg/L (See attached Table).

Fairbrother et al., (2016) also indicate that “It is not surprising that D4 has no toxicity or a low level of toxicity in most aquatic species. Like most hydrophobic chemicals, D4 acts via a narcosis mode of action, which requires the accumulation of the chemical in the tissues to achieve a critical (toxic) body burden.” They conclude that “the concepts of narcosis mode of action and chemical activity explain the apparent lack of toxicity of D4 to water column species under environmentally realistic conditions.”

Thus, given the mode of action (narcosis mode of action) and that estimated time (days) to achieve a critical body residue of 3.0 mmol/kg (888 mg/kg) for D4 is calculated to be 72 to >1000 days for the concentration levels used in the 14-day study or up to the functional water solubility of 22 µg/L, the occurrence of mortality in adult rainbow trout after only 14-d exposure is surprising and mortality would not have been expected even if higher concentrations were used in the long-term (93-day) (SEHSC 1991) rainbow trout early life stage toxicity study.

Furthermore, the concentration of D4 in fish following aqueous exposure over a 100-d period has been modelled, assuming a standard kinetic model cfish = (kr/k2)*cw*[1-e(-k2t)]. The uptake (kr¬) and depuration (k2) rates were taken from the D4 BCF study in minnow.

The estimated cfish was then compared with the Critical Body Burden (CBB) of 3 mmol/kg (888 mg/kg), assumed by Mackay et al. (2015) for a non-polar narcosis mode of action. Redman et al. (2012) have concluded that cyclic siloxane compounds, including D4, act through a narcotic mode of action.

Aqueous exposure to 4.4 µg/L, 6.9 µg/L, 12 µg/L, and 22 µg/L D4 in fresh water, as in the prolonged 14-d acute toxicity study with trout, indicates that the steady state cfish which would be reached after approximately 60 days is far below the CBB (See attached Fig. 1). In contrast, exposure at the limit of solubility for D4 in purified water (56 µg/L) indicates that the CBB would be exceeded after approximately 30 days. However, neither 56 µg/L was achieved in the study nor did the study persist for 30 days or longer. Therefore, lethality is not expected in a 14-d fish toxicity test.

See attached Figure 1. Modelled concentrations in fish assuming a standard kinetic model cfish= (kr/k2)*cw*[1-e(-k2t)] and using the re-calculated rate constants from Smit et al.(2012). Red dashed line shows the CBB of 3 mmol/kg (888 mg/kg D4) for a non-polar narcosis mode of action.

These data reinforce the outlier status of the 14-day sub chronic fish study and support that effects are not likely to occur even if higher concentrations were used in the long-term (93-day) rainbow trout early life stage toxicity study (SEHSC 1991).

As noted in the Classification and Labelling dossier there is one toxicity study with algae reported (SEHSC, 1990). As it is a limit test, the validity of the study for use in chronic classification is questioned. In addition, growth in controls was reduced similar to that of the treated flask (this was a limit test so there was only one treatment level at the functional solubility of 22 ug/L). Cell density essentially remained unchanged in all flasks suggesting that D4 is not acutely toxic to the algae. The NOEC for algae (SEHSC, 1990) < 22 µg/L was based on yield/biomass, whereas, in accordance with CLP guidance (ECHA, 2015), it is preferred to base it on growth rate. The OECD TG 201 clearly indicates that the growth rate is preferred and that ErC10 or ErC20 is more scientifically founded than NOEC by saying that “the use of average specific growth rate for estimating toxicity is scientifically preferred” (para 47). Taking this into account it is more appropriate to use ErC10 > 22 µg/L. As raw data have been reported in the study report, Reconsile has conducted a re-analysis revealing an inhibition of the average specific growth rate in the treatment group by less than 7 % after 72 h and 96 h, respectively, when compared to the control. Therefore, the ErC10 > 22 µg/L, which is the maximum water solubility level in the test medium.

It is important to note that although the summarised results above are considered reliable, there are some uncertainties associated with testing a substance such as D4 that must be considered. D4 is a substance of very low solubility in water (56 µg/L), and its solubility in test media is likely to be lower than its solubility in pure water. In addition, D4 is volatile with a high Henry’s law constant. Often in order to meet the requirements of the testing guidelines extra measures must be used to maintain D4 in the test system. These include using closed, sealed systems that have no headspace, test systems prepared using saturated stock solutions (prepared at ambient temperatures) which can lead to an excess of the substance at the point of addition and, when added to a test system operating at the lower temperature of 12 °C the solubility in the test media is uncertain, or solvent addition. Analytical measurement of test solutions is often carried out using GC-MS a method that does not necessarily distinguish between dissolved and dispersed test material. As D4 is a clear liquid, undissolved test material may not be obvious therefore often the solubility in the test media is uncertain.

GHS Guidance clearly highlights the need for WOE and expert judgement when assessing a substance that is difficult to test.

Conclusion on classification

The substance has an EU harmonised classification as follows:

R53: May cause long-term adverse effects in the aquatic environment in Annex I of Directive 67/548/EEC.

Chronic Cat. 4 (aquatic), H413: May cause long lasting harmful effects to aquatic life in Annex VI of CLP Regulation (EC) No 1272/2008.

A weight of evidence (WoE) approach is also recommended to address some of the uncertainties as well as the technical difficulties resulting from intrinsic physicochemical and partitioning properties of the substance when conducting guideline tests (GHS Revision 6, 2015,sections 4.1.2.5, A9.3.4.2, A9.3.6.2.3). Therefore, further scientific analysis of all the available data as well as recent expert reviews follows.

1.1 D4: intrinsic properties lead to challenges in testing - need for expert judgement and review

The GHS Guidance (A9.3.4 Weight of evidence) highlights that “substances, which are difficult to test, may yield apparent results that are more or less severe than the true toxicity. Expert judgement would also be needed for classification in these cases.” It also indicates that “classification should allow for use of reviews from national authorities and expert panels as long as the reviews are based on primary data.”

It is important to evaluate the functional water solubility of each test system under the specific conditions and dilution water quality for a particular study. Evaluation of the main study (the 21-d chronic Daphnia magna), Fairbrother and Woodburn, (2016, Table 1) defined the maximal achievable solubility of D4 as 15 μg/L.

The guidance also suggests that “there may be circumstances where the lowest toxicity value among taxa is not used for C&L where a WoE approach is used” (section 4.1.2.5).

 

1.2 Experts conclude that D4 is not toxic up to its limits of functional water solubility under realistic environmental conditions

a)     Under scientific expert analysis by Fairbrother and Woodburn (2016), and Bridges and Solomon (2016), the 21-d Daphnia magna survival NOEC value of 7.9 µg/L of D4 are not considered relevant data.

                   i.            In review of the statistical analysis of the reproduction data, a significant (p≤ 0.05) difference was observed at the 7.9 µg/L treatment level in comparison with the control. However, this was not an actual effect since the number of offspring per daphnid did not decrease from the control to the highest concentration (15 µg/L), but increased cumulatively from 111 (at control) to 167 (at 15 µg/L) offspring/daphnid. Therefore, the reproduction NOEC should be considered ≥ 15 µg/L.

                 ii.            A significant difference (p≤ 0.05) was observed in the survival rate at the 15 µg/L treatment level in comparison with the control. The survival rate of parent daphnia were reduced to 77% at 15 µg/L in comparison with the controls with a survival rate of 93%. However, the survival rate of 77% in the high dose group is the arithmetic mean of just 2 replicates, where in fact only in 1 replicate a survival rate below 80% was observed (replicate 1: 67%; replicate 2: 87%). In addition, the allowable survival rate for controls is 80% so this is considered only a slight reduction in survival, and ultimately the substance did not affect reproduction or neonate size.

               iii.            The slight reduction in survival was only seen at the level of functional water solubility. Therefore, the survival NOEC should be considered ≥ 15 µg/L, the functional water solubility.

Furthermore,

b)       In the 21-d Daphnia study the original reported NOEC of 7.9 µg/L was significantly greater than the water concentration cutoff of 0.02 μg/L, and therefore the response was given a score of zero for relevance for potential adverse effects under relevant environmental concentrations (Solomon & Bridges, 2016). The cut-off of 0.02 μg/L was based on the upper 99.9th centile of the maximum values reported in receiving waters (Wang et al., 2013).

c)       Mackay et al. (2015) concluded that superhydrophobic substances such as D4 often fail to reach a toxic endpoint in standard laboratory tests due to the difficulty or impossibility of reaching critical body burden (CBR defined as: the lowest observed total body concentration of a contaminant in an organism, which is associated with the occurrence of adverse toxic effects) in aquatic organisms given its high log Kow value and metabolic activity.

d)       Long-term (93 -day) fish early life stage toxicity study was conducted and no adverse effects were seen up to the highest concentration tested (SEHSC 1991).

e)       While D4 has exhibited toxicity to water column organisms in the laboratory, toxicity has been demonstrated only in studies that used a solvent to prepare the test media or were performed using closed, sealed dosing systems having no headspace, which essentially eliminates the predominant intrinsic physical/chemical property of volatilisation. All toxicity studies performed using open non-sealed diluter systems that realistically allow equilibration with air, and those that did not use a solvent to dissolve the test substance, showed no effect at any concentration.

In addition, the conclusion that D4 is non-toxic to water column organisms up to its limits of functional water solubility is further substantiated by Fairbrother and Woodburn, (2016) by use of activity to describe the degree of saturation achieved by D4 in a given medium. The experts note that this approach is particularly useful for substances that display a narcosis mode of action in aquatic organisms, such as D4, as chemical activities may provide valuable estimates of the proximity of measured concentrations to potentially toxic levels. Chemical activities are easy to calculate and allow the comparison of concentration data in various matrices with differing units. Chemical activities are simply the ratio of a concentration and its solubility, adjusted for salinity, amount of particulate matter, and carbon content. Activities of concentrations in biota are the ratio of the lipid-based concentration and the apparent solubility of the chemical in lipid, which is approximated by the substance’s octanolwater coefficient (Kow) and its aqueous solubility value. This allows expression of all data to range from 0 to 1, resulting in easy comparison of biota and environmental matrices. An analysis of the chemical activity of D4 in aquatic systems and aquatic organisms is presented in the equivalent section of the CSR. The NOEC values for aquatic organisms exposed to D4 were calculated as the aqueous concentration divided by the functional solubility for each test, resulting in NOEC D4 activities of 0.021.0, with a mean value of 0.52. Chemical activities for field-collected fish and invertebrates are approximately 107 to 106, based on tissue concentrations in biota collected simultaneously with the water sampling referenced above. The measured chemical activities of D4 in the water samples presented, adjusted for site-specific salinity and organic carbon, are approximately 105 to 103, far lower than the NOEC values. Overall, these data show that chemical activities of D4 in biota cannot reach values that are associated with nonpolar narcosis (i.e., toxicity).

See attached Figure: D4 activities

D4 activities (unitless) in surface water and receiving waters, wastewater treatment plant effluents, invertebrates and fish from different locations in Japan, Europe and North American relation to the maximal activity [a= 1 (red line)] and chronic no observed effect concentrations (NOECs) with aquatic organisms Median concentrations are shown by the black horizontal bar; the yellow boxes show upper and lower quartile concentrations, and the whiskers represent minimal and maximal values.

As described above, modelling was also employed to examine the roles of hydrophobicity, organism size, and metabolism (Mackay et al., 2015). The results demonstrate the difficulty or impossibility of reaching critical body burden (CBB defined as: the lowest observed total body concentration of a contaminant in an organism, which is associated with the occurrence of adverse toxic effects) in aquatic organisms for D4 given its high log Kow value and metabolic activity. In the work of Mackay et al. (2015), a simple first order pharmacokinetic model

 

Cfish = k1/k2*Cw*(1-exp-(k2+km)*time)

 

 is used to estimate fish critical body burden (CBB) levels and compare those CBB levels to those associated with a narcotic mode of action (MOA), under which the cVMS materials are proposed to operate (Redman et al., 2012).

In addition, E.Mihaich (submitted during the consolation on D4 CLH proposal) evaluates the different fish weights in the calculation. As well as uses the pharmacokinetic model of Mackay et al. (2015) to examine the unexplained mortality noted in the D4 14-day prolonged acute study. The Mackay et al. (2015) model was used to calculate the time to achieve critical body burden (CBB) at a given D4 dose concentration of 6.9, 12, and 22 µg/l; the 4.4 µg/l empirical dose level in the 93-d trout ELS study is also presented.

The results of the 93-day trout ELS study at 13 °C with a NOEC of ≥4.4 µg/L indicate that no adverse fish effect was noted at this dose/exposure time combination. These empirical results are consistent with the results of the Mackay et al. (2015) simulation of the exposure, where fish averaged 1.6 g in weight. Four other dose regimes were modelled in addition to 4.4 µg/L: 6.9, 11, 12, 22, and 27 µg/L; the last modelled dose is the functional water solubility for D4 at 13 °C (calculated). As seen in the attached graph, the data indicate that only at dose concentrations of 22 and 27 µg/L did the small trout accumulate sufficient D4 by day 90 of the simulation to exceed the CBB for narcotic mode of action of 3 mmol/kg (Mackay et al., 2015); i.e., the fish achieved body burdens <3 mmol/kg at dose levels of 4.4, 6.9, 11, and 12 µg/L after 90 days of exposure. These results indicate that D4 dose levels up to 12 µg/L could have been successfully used in the D4 93-day trout ELS study without adverse effect.

Graph: Pharmacokinetic modelling of D4 accumulation in fish tissue (Cfish) during up to a 90-d exposure of varying aqueous concentrations. At dose levels 4.4, 6.9, 11, and 12 µg/l, the Cfish is <3 mmol/kg (target narcosis MOA) at 90 days, while Cfish at 22 and 27 µg/L (the functional solubility of D4 at 13 °C) is >3 mmol/kg after 90 days, suggested potential adverse impact.

PLEASE SEE ATTACHED GRAPH

 

The pharmacokinetic model of Mackay et al. (2015) may also be used to examine the unexplained mortality noted in the D4 14-day prolonged acute study. As shown in the table below, the Mackay et al. (2015) model was used to calculate the time to achieve critical body burden (CBB) at a given D4 dose concentration of 6.9, 12, and 22 µg/L; the 4.4 µg/L empirical dose level in the 93-d trout ELS study is also presented. Different weights have been considered in the calculation, also shown in the table below. The results show that the experimental results from the D4 14-day prolonged acute study are anomalous compared to the pharmacokinetic modelled results, which indicate that dose concentrations as high as 22 µg/L should not have produced the observed trout mortality in 14 days or less (see table below).

Table: Simulation results using the Makay et al. (2015) model to calculate time to time to achieve CBB at given D4 dose concentrations during both the 14-d prolonged acute study and 93-d trout ELS study, taking into consideration size of test organisms.

D4 Concentration (µg/L)

Avg. Fish Weight (g)

Time (days) to achieve CBB at D4 concentration and fish size

22 (14-d study)

0.42

27

12 (14-d study)

0.42

52

6.9 (14-d study)

0.42

96

4.4 (93-d ELS)

1.6

269

1.3 Discussion on rapid degradability       

Aside from ready biodegradability in biodegradation screening tests, the CLP Regulation allows for use of other convincing scientific evidence in defining rapid degradation (e.g., hydrolysis), provided that the degradation products do not fulfil the criteria for classification as hazardous to the aquatic environment. D4 meets the current regulatory criteria (as defined in REACH Annex XIII) for Persistence (see Section 8.1.1), however this is on the basis of persistence in sediment. The criteria for persistence in water and soil are not met.

A hydrolysis half-life of 69-144 hours at pH 7 and 25°C has been determined in a reliable study. The substance is considered to be rapidly degradable according to the criteria in PART 4 of Annex I to the CLP Regulation(EC) No 1272/2008.

 

1.     From the available data, D4 has limited potential to be biodegraded. However, abiotic hydrolysis in the water compartment is a key degradation process in the environment. At concentrations less than the solubility limit, D4 degrades to dimethylsilanediol through a series of consecutive pseudo first order reactions involving linear oligodimethylsiloxane-α,ω-diols as transient intermediates. The rates of hydrolysis of the parent substance and intermediates as a function of pH and temperature are well understood based on reliable data from an OECD Test Guideline 111 study (Durham and Kozerski, 2005). The siloxanediol intermediates are not expected to require classification based on their own rapid hydrolysis (Durham and Kozerski, 2005; Kozerski and Durham, 2006), and dimethylsilanediol (CAS 1066-42-8) is not toxic to aquatic organisms and does not fulfil the criteria for classification as hazardous to the aquatic environment.

 

2.     The conditions for use of OECD 111 hydrolysis data to demonstrate rapid degradability are stated clearly in the CLP Regulation guidance (ECHA, 2015), requiring that the longest half-life determined within the pH range 4 to 9 is shorter than 16 days. In the case of D4, the longest observed half-life was for pH 7.0, with an average half-life of 3.9 days at 25°C. For 20°C, the lowest temperature allowed in a standard OECD 301 ready biodegradability study, the calculated hydrolysis half-life for D4 at pH 7.0 is 5.8 ± 1.7 days, which clearly meets the 16 day threshold criterion for rapid degradability.

 

3.     The rates of chemical reactions, whether biochemical or abiotic, depend on temperature. Reaction rates generally decrease with decreasing temperature, giving longer half-lives at lower temperatures. Annex 9 of GHS (UN, 2013; A9.4.1.1) and Annex II of CLP Guidance (ECHA, 2015) suggest that classification of substances should be based on consideration of both intrinsic properties of the substance and the prevailing environmental conditions, which includes parameters such as pH and temperature. However, the recommended decision scheme (GHS A9.4.4, CLP II-4) gives no guidance on extrapolation of laboratory degradation studies to the “real environment” for the purpose of classification. It is recommended only that, “Data from studies employing environmentally realistic temperatures should be used for the evaluation” (A9.4.2.4.3). In the case of hydrolysis by OECD 111, this statement refers to the fact that experiments may be conducted at temperatures of up to 70°C. Clearly, 20-25°C is considered realistic from the standpoint of using OECD 301 ready biodegradability screening data in the assessment of rapid degradability.
Therefore, there is no reason to consider temperatures below 20°C in evaluating the hydrolysis half-life of D4 in the determination of rapid degradability. To do otherwise would introduce a double standard in how the data from different degradation study types are treated. This is also further explained by Matthies and Beulke (2016) with p
articular considerations of temperature in the context of the persistence classification.

 

The data above support the conclusion that D4 is rapidly degradable according to the criteria in GHS Revision 6 and in PART 4 of Annex I to the CLP Regulation(EC) No 1272/2008.

 

A hydrolysis half-life of 69 to 144 hours (average of 3.9 days) at pH 7 and 25ºC has been determined in a reliable study.

Consideration of the pH range of surface water bodies in the EU

Attached Figure 1 shows the dependence of the half-life in water versus the pH of the water body for D4 is presented. The predicted rate constants for each pH/temperature combination have been calculated using the catalytic constants derived from experimental data at pH 4 (H+catalysis, kH) and pH 9 (OH-catalysis, kOH) at 3 temps (10, 25, and 35°C):

 

kpred= kH[10-pH] + kOH[10(pH-Kw)],

 

where Kw is the auto-ionization constant for water at a given temperature. Half-life is 0.693/kpred.

 

 

See attached Fig. 1. Hydrolysis half-life of D4 in surface water at different temperatures (9°C, 12°C, 25°C) as a function of the pH value (range from pH 5 to 8).

 

Bundschuh et al.(2016) identified the median pH value for surface water bodies in the EU to be 7.94. It can be stated that by applying the mean temperature of European surface waters of 12°C and the respective median pH value of 7.94 the hydrolysis half-life of D4 is far below 16 days. Thus, D4 clearly meets the 16-day threshold criterion for rapid degradability.

1.4   GHS Guidance on hazards to the aquatic environment does not include aquatic sediment

GHS Guidance highlights that:

Section A9.1.2: “The hazard classification scheme has been developed with the object of identifying those substances that present, through the intrinsic properties they possess, a danger to the aquatic environment. In this context, the aquatic environment is taken as the aquatic ecosystem, in freshwater and marine, and the organisms that live in it. For most substances, the majority of data available addresses this environmental compartment. The definition is limited in scope in that it does not, as yet, include aquatic sediments, nor higher organisms at the top of the aquatic food chain, although these may to some extent be covered by the criteria selected.”

1.5 Overall conclusion on environmental classification       

NOEC values obtained from the available FELS and chronic daphnia studies, as well as E(L)C50 values from the acute tests, are all equal to or greater than the maximum concentrations achieved during the tests, as described in previous paragraphs. D4 cannot therefore be classified on the basis of aquatic toxicological effects.
The “safety net” classification category Aquatic Chronic 4 is nonetheless assigned, in accordance with CLP Regulation and related guidance, on the basis that D4 is poorly water soluble, is not rapidly degraded under low temperature conditions, and has an experimentally determined BCF ≥500.  
While Registrants have previously assigned a more stringent classification category to D4 for aquatic hazards on a precautionary basis, assessments took place in different jurisdictions which have triggered re-evaluation for global consistency.

 

 

 

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