1,1,3,3-tetramethylbutyl 2-ethylperoxyhexanoate

Long-term toxicity to fish

Link to relevant study record(s)

Reference

Endpoint:

fish early-life stage toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

The study does not need to be conducted for the reasons of adaptation rules of section 1 (scientifically not necessary) of Annex XI to Regulation (EC) 1907/2006 (REACH).

There are no indications from the short-term toxicity studies on aquatic species that the fish would be substantially more sensitive than aquatic invertebrates or algae. The algae study was the only study where effects were seen. The 72-h EL10 and EL50 of 1,1,3,3-tetramethylbutyl 2-(ethylperoxy)hexanoate were determined based on growth rate to be 20.2 mg/L and > 838 mg/L (nominal), respectively. In a supporting Algal Growth Inhibition study the effects of 1,1,3,3-tetramethylbutyl peroxy-2-ethylhexanoate and its degradation products was evaluated. The 72- ErC10 (72h) was calculated as 2.9 mg/L (growth rate). The 72-h ErC50 was estimated as 7.1 mg/L (growth rate) expressed as degraded parent material derived from average measured initial concentrations of 2,2-Dimethylpropan-1-ol and 2-Ethylhexanoic acid and the available decomposition mechanism (please refer to IUCLID section 6.1.5). The chronic toxicity of 1,1,3,3-tetramethylbutyl peroxy2-ethyl hexanoate to aquatic invertebrates was investigated in a Daphnia magna Reproduction Test according to OECD 211. The 21-d NOELR was found to be 10 mg/L (see IUCLID section 6.1.4).

With regard to the short-term fish toxicity, a read across to the source substance 1,1,3,3-tetramethylbutylperoxypivalate (CAS 22288-41-1) was performed. The read across source substance has a higher water solubility and is thus regarded worst case. However, no toxicity up to the maximum water solubility was found. Consequently, the EL50 of the source substance is considered to be higher than its water solubility limit. In addition, a semi-static 96-hour Fish Embryo Acute Toxicity Test according to OECD 236 was performed both with 1,1,3,3-tetramethylbutylperoxypivalate (CAS 22288-41-1) and 1,1,3,3-tetramethylbutyl 2-(ethylperoxy)hexanoate in order to demonstrate a comparable toxic potential of the source and the target substance. In this study loading of 10 mg test material/L did not result in any significant alterations to Danio rerio embryos for both substances. The results hence support that 1,1,3,3-tetramethylbutyl 2-(ethylperoxy)hexanoate is unlikely to be toxic to fish.

Moreover, due to its rapid hydrolysis and ready biodegradability a long-term exposure to the parent material in the aquatic environment can be considered negligible. In a hydrolysis study according to OECD 111 at 12 °C in natural surface water (containing 2-3 mg/L DOC and 15 mg/L TSS) and in deionized water with humic acid (containing 2-3 mg/L DOC) half-lifes decreased to 11.5 h and 11.9 h, respectively. Because half-lifes are < 12h under environmental conditions hydrolysis products have been identified in a separate tier 3 study according to OECD guideline 111. 2-Ethylhexanoic acid (CAS 149-57-5, log Kow = 2.64), 2,2-Dimethylpropan-1-ol (CAS 75-84-3, log Kow = 1.31) and Acetone (CAS 67-64-1, log Kow = -0.24) were formed in natural surface water, deionized water as well as standard pH 7 buffer. The presence of organic material did not affect formation of hydrolysis products (please refer to IUCLID section 5.1). Therefore, from a scientific point of view, it is justified to determine the long-term toxicity to fish using data for the hydrolysis products.

In accordance with the disseminated ECHA REACH dossier for the hydrolysis product 2-Ethylhexanoic acid (CAS 149-57-5) available ecotoxicological data on this substance are conclusive but not sufficient for classification for environmental hazards following the criteria outlined in Regulation (EC) 1278/2008 (CLP). In analogy, Acetone has not been classified for environmental hazards, as stated in its disseminated ECHA REACH dossier (last accessed: 2021-05-04). 2,2-Dimethylpropan-1-ol, (CAS 75-84-3) is not considered to be toxic to aquatic organisms either based on the notified classification and labelling according to CLP criteria (source: ECHA Summary of Classification and Labelling: last accessed: 2021-05-04).

Nevertheless, the long-term toxicity of the hydrolysis products 2-Ethylhexanoic acid, 2,2-Dimethylpropan-1-ol and Acetone to fish was additionally estimated using the (Q)SAR model ECOSAR v2.0. As a result, the ChV value for 2,2-Dimethylpropan-1-ol was calculated to be 27.4 mg/L. The long-term toxicity ChV value for 2-Ethylhexanoic acid was calculated to be 29.4 mg/L and for Acetone to be 372 mg/L. All three hydrolysis products were within the applicability domain of the model. A description of the applied prediction model and the assessment of the estimation domain were documented in QSAR Model Reporting Format (QMRF) files and QSAR Prediction Reporting Format files (QPRF), respectively (please refer to IUCLID section 6.1.2). The high significance of the used model has also been proven in a published study of Staples (2001) (please refer to IUCLID section 6.6) where ECOSAR predictions for 2-ethylhexanoic acid were compared to measured data. It was concluded that ECOSAR calculated chronic values for fish are good estimates of chronic toxicity for this substance.

In addition, reliable published information on the acute toxicity of Acetone to fish as well as its long-term toxicity to aquatic invertebrates and cyanobacteria are reported as separate IUCLID Endpoint Study Records. In an experimental study Acetone showed a very low acute toxicity towards Oncorhynchus mykiss (96-h LC50: 5540 mg/L nominal). In an assay comparable to OECD 211, the 28-day NOEC for Daphnia magna based on reproduction was found to be 2212 mg/L (nominal). The 28-day NOEC (MATC) and 28 -day LOEC based on mortality of parent individuals was >1106 and <2212 mg/L and 2212 mg/L (nominal), respectively. Further, Acetone showed a low toxicity to Microcystis aeruginosa (8 d TT (NOEC)=530 mg/L based on biomass) in a study according to the German national method DIN 38412 part 9.

Furthermore, the substance is only used in controlled industrial settings where waste water is discharged to a STP. Considering residence time of the parent material the substance will be degraded abiotically as well as biotically and will not reach the aquatic environment. Hydrolysis products reveal neither a need to classify as dangerous to the environment, nor are they PBT or vPvB substances, nor are there any further indications that the substances may be hazardous to the environment. They are considered to be rapidly degraded in aquatic compartments; the bioaccumulation potential is regarded to be insignificant (low log Kow).

Therefore, long-term toxicity testing on fish with 1,1,3,3-tetramethylbutyl 2-(ethylperoxy)hexanoate is considered scientifically not necessary, as it is clearly shown in the technical dossier that algae is the most sensitive species towards. Additionally, proof has been given that the hydrolysis products 2-Ethylhexanoic acid, 2,2-Dimethylpropan-1-ol and Acetone bear no long-term toxicity to fish. Effect values for a long-term fish test with the registration substance are expected to be well above the effect values obtained in algae tests. Therefore, long-term toxicity studies in fish with the registration substance are not expected to provide more relevant information in regards to hazard conclusion.

Taken together the points outlined above, it is concluded, that the criteria of Annex XI section 1 are fulfilled justifying the adaptation of the information requirements, accordingly. Therefore, and considering animal welfare reasons, further studies on long-term toxicity to fish are neither scientifically, nor from a regulatory point of view justified.

Reference: Staples, C.A., 2001, A review of the environmental fate and aquatic effects of a series of C4 and C8 oxo-process chemicals, Chemosphere 45 p. 339-346

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Description of key information

The study on long-term toxicity to fish does not need to be conducted for the reasons of adaptation rules of section 1 of Annex XI to Regulation (EC) 1907/2006 (REACH). Based on results for the acute toxicity to fish, the physicochemical properties and hydrolysis behaviour, long-term toxicity testing on fish is not considered scientifically justified.

Additional information

Non-submission justification

The study does not need to be conducted for the reasons of adaptation rules of section 1 (scientifically not necessary) of Annex XI to Regulation (EC) 1907/2006 (REACH).

 

There are no indications from the short-term toxicity studies on aquatic species that the fish would be substantially more sensitive than aquatic invertebrates or algae. The algae study was the only study where effects were seen. The 72-h EL10 and EL50 of 1,1,3,3-tetramethylbutyl 2-(ethylperoxy)hexanoate were determined based on growth rate to be 20.2 mg/L and > 838 mg/L (nominal), respectively. In a supporting Algal Growth Inhibition study the effects of 1,1,3,3-tetramethylbutyl peroxy-2-ethylhexanoate and its degradation products was evaluated. The 72- ErC10 (72h) was calculated as 2.9 mg/L (growth rate). The 72-h ErC50 was estimated as 7.1 mg/L (growth rate) expressed as degraded parent material derived from average measured initial concentrations of 2,2-Dimethylpropan-1-ol and 2-Ethylhexanoic acid and the available decomposition mechanism (please refer to IUCLID section 6.1.5). The chronic toxicity of 1,1,3,3-tetramethylbutyl peroxy2-ethyl hexanoate to aquatic invertebrates was investigated in a Daphnia magna Reproduction Test according to OECD 211. The 21-d NOELR was found to be 10 mg/L (see IUCLID section 6.1.4).

 

With regard to the short-term fish toxicity, a read across to the source substance 1,1,3,3-tetramethylbutylperoxypivalate (CAS 22288-41-1) was performed. The read across source substance has a higher water solubility and is thus regarded worst case. However, no toxicity up to the maximum water solubility was found. Consequently, the EL50 of the source substance is considered to be higher than its water solubility limit. In addition, a semi-static 96-hour Fish Embryo Acute Toxicity Test according to OECD 236 was performed both with 1,1,3,3-tetramethylbutylperoxypivalate (CAS 22288-41-1) and 1,1,3,3-tetramethylbutyl 2-(ethylperoxy)hexanoate in order to demonstrate a comparable toxic potential of the source and the target substance. In this study loading of 10 mg test material/L did not result in any significant alterations to Danio rerio embryos for both substances. The results hence support that 1,1,3,3-tetramethylbutyl 2-(ethylperoxy)hexanoate is unlikely to be toxic to fish.

 

Moreover, due to its rapid hydrolysis and ready biodegradability a long-term exposure to the parent material in the aquatic environment can be considered negligible.  In a hydrolysis study according to OECD 111 at 12 °C in natural surface water (containing 2-3 mg/L DOC and 15 mg/L TSS) and in deionized water with humic acid (containing 2-3 mg/L DOC) half-lifes decreased to 11.5 h and 11.9 h, respectively. Because half-lifes are < 12h under environmental conditions hydrolysis products have been identified in a separate tier 3 study according to OECD guideline 111. 2-Ethylhexanoic acid (CAS 149-57-5, log Kow = 2.64), 2,2-Dimethylpropan-1-ol (CAS 75-84-3, log Kow = 1.31) and Acetone (CAS 67-64-1, log Kow = -0.24) were formed in natural surface water, deionized water as well as standard pH 7 buffer. The presence of organic material did not affect formation of hydrolysis products (please refer to IUCLID section 5.1). Therefore, from a scientific point of view, it is justified to determine the long-term toxicity to fish using data for the hydrolysis products.

 

In accordance with the disseminated ECHA REACH dossier for the hydrolysis product 2-Ethylhexanoic acid (CAS 149-57-5) available ecotoxicological data on this substance are conclusive but not sufficient for classification for environmental hazards following the criteria outlined in Regulation (EC) 1278/2008 (CLP). In analogy, Acetone has not been classified for environmental hazards, as stated in its disseminated ECHA REACH dossier (last accessed: 2021-05-04). 2,2-Dimethylpropan-1-ol, (CAS 75-84-3) is not considered to be toxic to aquatic organisms either based on the notified classification and labelling according to CLP criteria (source: ECHA Summary of Classification and Labelling: last accessed: 2021-05-04).

 

Nevertheless, the long-term toxicity of the hydrolysis products 2-Ethylhexanoic acid, 2,2-Dimethylpropan-1-ol and Acetone to fish was additionally estimated using the (Q)SAR model ECOSAR v2.0. As a result, the ChV value for 2,2-Dimethylpropan-1-ol was calculated to be 27.4 mg/L. The long-term toxicity ChV value for 2-Ethylhexanoic acid was calculated to be 29.4 mg/L and for Acetone to be 372 mg/L. All three hydrolysis products were within the applicability domain of the model. A description of the applied prediction model and the assessment of the estimation domain were documented in QSAR Model Reporting Format (QMRF) files and QSAR Prediction Reporting Format files (QPRF), respectively (please refer to IUCLID section 6.1.2). The high significance of the used model has also been proven in a published study of Staples (2001) (please refer to IUCLID section 6.6) where ECOSAR predictions for 2-ethylhexanoic acid were compared to measured data. It was concluded that ECOSAR calculated chronic values for fish are good estimates of chronic toxicity for this substance.

 

In addition, reliable published information on the acute toxicity of Acetone to fish as well as its long-term toxicity to aquatic invertebrates and cyanobacteria are  reported as separate IUCLID Endpoint Study Records. In an experimental study Acetone showed a very low acute toxicity towards Oncorhynchus mykiss (96-h LC50: 5540 mg/L nominal). In an assay comparable to OECD 211, the 28-day NOEC for Daphnia magna based on reproduction was found to be 2212 mg/L (nominal). The 28-day NOEC (MATC) and 28 -day LOEC based on mortality of parent individuals was >1106 and <2212 mg/L and 2212 mg/L (nominal), respectively. Further, Acetone showed a low toxicity to Microcystis aeruginosa (8 d TT (NOEC)=530 mg/L based on biomass) in a study according to the German national method DIN 38412 part 9.

 

Furthermore, the substance is only used in controlled industrial settings where waste water is discharged to a STP. Considering residence time of the parent material the substance will be degraded abiotically as well as biotically and will not reach the aquatic environment. Hydrolysis products reveal neither a need to classify as dangerous to the environment, nor are they PBT or vPvB substances, nor are there any further indications that the substances may be hazardous to the environment. They are considered to be rapidly degraded in aquatic compartments; the bioaccumulation potential is regarded to be insignificant (low log Kow).

 

Therefore, long-term toxicity testing on fish with 1,1,3,3-tetramethylbutyl 2-(ethylperoxy)hexanoate is considered scientifically not necessary, as it is clearly shown in the technical dossier that algae is the most sensitive species towards. Additionally, proof has been given that the hydrolysis products 2-Ethylhexanoic acid, 2,2-Dimethylpropan-1-ol and Acetone bear no long-term toxicity to fish. Effect values for a long-term fish test with the registration substance are expected to be well above the effect values obtained in algae tests. Therefore, long-term toxicity studies in fish with the registration substance are not expected to provide more relevant information in regards to hazard conclusion.

 

Taken together the points outlined above, it is concluded, that the criteria of Annex XI section 1 are fulfilled justifying the adaptation of the information requirements, accordingly. Therefore, and considering animal welfare reasons, further studies on long-term toxicity to fish are neither scientifically, nor from a regulatory point of view justified.

 

 

Reference: Staples, C.A., 2001, A review of the environmental fate and aquatic effects of a series of C4 and C8 oxo-process chemicals, Chemosphere 45 p. 339-346