Dimethylcyclohex-3-ene-1-carbaldehyde

Bioaccumulation: terrestrial

Description of key information

Terrestrial organisms: The BCF in earthworms was estimated with the equation from Jager (1998) which is incorporated in the EUSES model and is applicable to substances with a log Kow value ranging from 1-8: BCFworm = (Fwaterworm + Flipidworm*Kow)/RHOworm where Fwaterworm = 0.84, Flipidworm = 0.012 and RHO worm = 1000. Entering the log Kow value of 3.1 for Vertoliff results in a BCFearthworm of 15.9 L/kg ww.

Vertoliff bioaccumulation assessment for air-breathing organisms using data from DRAFT OECD TG 309

Vertoliff fulfils the screening criteria for concern for bioaccumulation in air breathing organisms: log Kow (3.1: >2) and log Koa (5.1: >5). Such bioaccumulation in air-breathing organisms may occur for non-metabolising substances because the lungs may present a less effective route for elimination compared to e.g. gills. Based on meeting the screening criteria for bioaccumulation in air-breathing organisms a water-simulation test (OECD TG 309) was performed to address the persistency of the substance and the bioaccumulation of the transformation products. In the OECD TG 309 study, Vertoliff degraded within minutes. Several transformation products were found and their log Kow were determined (HPLC using OECD TG 117). In total 8 regions of interest (ROI) were found. All ROIs were further characterised using log Kow. These log Kow decreased from ROI 8 (closest to Vertoliff) towards ROI 1, more polar products. The bioaccumulation assessment focussed on those ROIs which were exceeding the 10% at day 63 and were not transient. ROI 8, 7, 6, and 5 were all <10% after 63 days. ROIs 4 exceeded the 10% level at the high treatment group (100 µg/l) and ROI 3 at the low treatment group (10 µg/l). ROI 2 and 1 were increasing and >10% after day 63. ROI 4 to 1 all had log Kow values <2. This means that for all transformation products there is no concern for bioaccumulation in air-breathing organism either because of presence <10% or log Kow <2. In addition, there is information that Vertoliff metabolises in air-breathing organisms (see toxico-kinetic section) and the excretion pathway is via the kidneys further assuring absence of such bioaccumulation.

Key value for chemical safety assessment

BCF (terrestrial species):

15.9 L/kg ww

Additional information

Vertoliff and bioaccumulation for air-breathing organisms - based on DRAFT OECD TG 309

Introduction

Vertoliff fulfils the screening criteria for concern for bioaccumulation in air breathing organisms: log Kow (3.1: >2) and log Koa (5.1: >5). This is based on its measured log Kow of 3.1, vapour pressure of 66.1 Pa and water solubility of 381.8 mg/l. Based on meeting these screening criteria for air-breathing organisms a water-simulation test (OECD TG 309) was performed to address first the persistency of the substance and its transformation products as well as the bioaccumulation of the transformation products using measured log Kow (HPLC, OECD TG 117). Below background information on bioaccumulation for air-breathing organisms is outlined and how Vertoliff meets this potential. Thereafter the information on the transformation products of Vertoliff found in the OECD TG 309 is incorporated in this assessment.

Background: The concern for bioaccumulation in air breathing organisms is related to their distinct respiratory pathways and their ability to accumulate substances primarily through dietary exposure (Armitage and Gobas, 2007, Kelly et al., 2004). It is understood that chemicals that may not necessarily bioaccumulate in water respiring organisms can potentially bioaccumulate in air breathing organisms. Water respiring organisms such as fish and aquatic invertebrates readily exchange chemicals to water via gill ventilation and/or skin to soil via pore-water contact. Elimination of chemicals through lungs via the lipid-air exchange process in air breathing organisms (e.g., mammals, birds and reptiles) is a much slower elimination pathway. This can result in a potential underestimation of bioaccumulation when considering fish studies.

While the physiological differences between water breathing and air breathing organisms lead to differences in chemical clearance, the same principals apply; bioaccumulation concerns only exist if the substance is not readily metabolized and/or excreted (Gobas et al., 2020). Based on the terrestrial bioaccumulation model developed by Armitage and Gobas (2007), the bioaccumulation potential of a contaminant is effectively negated if it possesses a biological elimination rate constant of 0.3 d^-1 or a biological half-life of < 2.5 days in an air breathing organism. Furthermore, Armitage and Gobas (2007), in agreement with Hendriks et al. 2001, state that, “as the size of the organism increases, the elimination rate constant required to counteract the bioaccumulative potential of the contaminant in question drops”.[1] Rodents and other small mammals are therefore conservative indicators of the extent chemicals need to be biotransformed and/or eliminated to reduce their inherent bioaccumulation potential. Goss et al. (2013) demonstrate that the elimination rate constant, k2, can be used to derive the elimination half-life, EL_0.5 and for air breathing mammals, an EL_0.5 <70 days will keep the biomagnification factor at a safe level of <1. The thresholds reported by these authors represent points of comparison for Vertoliff toxicokinetic and in particular elimination rates in relevant biological compartments.

Vertoliff and bioaccumulation for air-breathing organisms

There is several available information that can shed light on the potential for air breathing organisms to bioaccumulate for this substance. 1) The log Koa is a screening tool for possible bioaccumulation in air-breathing organism only based on physico-chemical parameters. A log Koa of >5 and absence of metabolism would possibly indicate a bioaccumulation potential for air-breathing organisms. Vertoliff has log Koa of 5.1 and further information is needed. Instead of the log Koa, a better estimate is the log Pblood/air partition coefficient (see Toxico-kinetic section for formula) based on human and rat data as derived by Buist et al (2012). This value for Vertoliff is 2.73 and is well below the log Koa criterion of 5 and based on this no bioaccumulation is expected; 2) The presence of metabolism presents absence of this bioaccumulation: a) The aldehyde functionality of Vertoliff, will be oxidised, reduced and/or hydroxylated during Phase 1 metabolism as presented by O’Brien et al. (2005, EFSA, 2013); b) the hydroxylation is presented in ECHA’s guidance on Henry C, where the aldehydes are explicitly mentioned (Table R.7.1–17); c) The formation of the Vertoliff-acid in water is supported with the degradation of Vertoliff into its acid/alcohols within minutes (DT50 is 5.9 minutes, <1 day) in the water simulation study (OECD TG 309). It can be seen in the Reproscreen study that kidney effects in males indicate excretion via kidneys.

Vertoliff relevant transformation products as found in the OECD TG 309 (Table 1): Vertoliff-parent rapidly underwent biotransformation to ROI 7 which are considered to be Vertoliff acid/alcohol(s). Vertoliff-parent had a calculated DT50 <1 day and is considered not persistent. ROI 7 further underwent biotransformation (oxidation) to products that were either similar in polarity or more polar (Table 1). Generally, transformation products corresponding to ≥10% applied radioactivity (AR) should be identified unless justified otherwise. For the assessment of Vertoliff-parent transformation products, structure identification was considered not needed if the transformation products were either:

1. Decreasing throughout the course of the study to <10% AR at test termination; or


2. if they failed to meet octanol-water partitioning coefficient screening criteria for bioaccumulation in air breathing organisms (i.e, log Kow >2).

The products that were transient (i.e., decreasing) and were present at <10% AR at test termination (i.e., ROI 8, 7, 6, and 5) were not assessed further for their bioaccumulation potential (Table 1) for the low treatment group. Transformation products that were present at ≥10% and increasing in both treatment groups are ROI 2 and 1. Others (i.e., ROI (4 at the high treatment group only), 3 (at the low treatment group only) remained below 10% AR and were not assessed further. ROI 2 and 1 are increasing during the study and have measured log Kow below the threshold for bioaccumulation in air breathing organisms. The range of measured log Kow values of Vertoliff’s transformation products along with their % AR at various timepoints are presented in Table 1 for the low treatment group (10 µg/l).

Table 1 The percentage parent and its transformation products that were found in the OECD TG 309 at the low concentration of 10 ug/l (Table 6 in the report)^

ROI of parent and transformation products	Parent	ROI 8	ROI 7	ROI 6	ROI 5	ROI 4	ROI 3	ROI 2	ROI 1
% after 28 days	0	10.6	7.1	13.2	3.8	10.4	17.5	13	24.1
% after 63 days	0	7.5	5.0	2.3	8.9	6.0	10.2	22.4	36.9
Log Kow (in this test)	2.88	2.78	<2*	2.20	2.08	1.95	1.82	1.77	1.5

^In the high treatment group (100 µg/l) ROI 4 is exceeding the 10% level but has a log Kow of 1.95 and is therefore of no concern for bioaccumulation in air-breathing organisms

*Samples are acidified and therefore in the non-conjugated form. At pH 7 the acid will be dissociated and have a much lower log Kow. The Vertoliff-acid undissociated has a log Kow of 2.75

Conclusion: Vertoliff fulfils the criteria for the screening of bioaccumulation in air-breathing organisms but is not persistent in surface water with a primary biodegradation half-life of <1 day. The aldehyde functionality of this substance is transformed to ROI 7 within minutes into Vertoliff-acid/alcohol(s). These undergo further biotransformation to mostly more polar products (ROI 6, 5, 4, 3, 2 and 1) or the product was transient: ROI 8. The transformation products ROI 8, 7, 6, 5 were present <10% at test termination (63 days) and do not need further assessment (OECD TG 309). Transformation products, ROI 4 and 3 was >10% only at 100 or 10 µg/l, respectively and seemed to be transient. ROI 2 and 1, were > 10% AR and increasing upon test termination. ROI 4, 3, 2 and 1, all have measured log Kow values <2 and are considered to have a low potential for bioaccumulation in air-breathing organisms (Table 1).

 

References

Armitage, J.M., and Gobas, F.A.P.C, 2007, A terrestrial food-chain bioaccumulation model for POPs, Environ. Sci. Techn., 41, 4019-4025.

EFSA, 2013, Annex III, https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2013.3091).

Gobas, F.A.P.C., Lee, Y-S, Lo, J.C., Parkerton, T.F, Letinski, D.J., 2020, A Toxico-kinetic framework and analysis tool for interpreting organization for economic co-operation and development guideline 305 dietary bioaccumulation tests, Environ. Tox. Chem., 39, 171-188.

Goss, B. and Endo, 2013, Elimination half‐life as a metric for the bioaccumulation potential of chemicals in aquatic and terrestrial food chains, Environ. Tox. Chem. 32, 1663-1671. Hendriks, A. J. et al. , 2001, The power of size. 1. Rate constants and equilibrium ratios for accumulation of organic substances related to octanol‐water partition ratio and species weight, Environ. Tox. Chem., 20, 1399-1420.

Kelly, Gobas, F.A.P.C, and McLachlan (2004). "Intestinal absorption and biomagnification of organic contaminants in fish, wildlife, and humans, Environ. Tox. Chem., 23,2324-2336.

O’Brien, P.J., Siraki, A.G., Shangari, N., 2005, Aldehyde sourced, metabolism, molecular toxicity mechanism, and possible effects on human health, Critical Rev. Tox., 35, 609-662