Trimethylamine, N-oxide

Endpoint summary

Description of key information

Acute Oral toxicity: LD50 = 973 mg/kg bw (based on read-across to TMA)

Acute Dermal toxicity: LD50 approximately 973 mg/kg bw (based on acute oral findings)

 

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

973 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Justification for type of information:

The TMAO target substance is a low volatile non-inhalable powder. The vapour pressure of 23.5 Pa at 20 °C is reported with a MMAD of 414.329 µm with a D10 of 161.713 µm. This measured data supports the waiver as a low volatile substance, vapour pressure is less than 0.5 kPa, that is not inhalable, particles with aerodynamic diameters greater than 100 μm (ECHA, 2017).

ECHA, 2017. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7c: Endpoint specific guidance. Version 3.0 June 2017.

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

Data regarding the acute dermal toxicity of the target substance trimethylamine N-oxide is not available; however, there is sufficient data to conclude on classification and the generation of test data is scientifically not necessary. Independent analyses by regulators, associations and industry to understand differences between acute toxicity oral and dermal outcomes all resulted in a similar conclusion that there is little value performing an acute dermal study where an acute oral study is available as the dermal study is not the leading health effect selected for a human health assessment (van der Kamp and Elliot 2021; Moore et al., 2013; Creton et al., 2010; Seidle et al., 2020, 2011). Oral acute toxicity classifications for pure substances were more conservative than dermal data in more than 98% of cases.

Testing reported within the REACH dossier has demonstrated that trimethylamine N-oxide does not present a hazard from dermal exposure due to either irritation or sensitization. Additionally, trimethylamine N-oxide passes through human dermal tissue with little restriction to its movement (Kenyon et al., 2004). As several independent assessments have demonstrated that the results of dermal toxicity assessment will not result is a more sever safety concern than that from oral exposure, following one of the key goals of the REACH Regulation, specially to reduce testing on vertebrate animals, based on the acute oral toxicity data, a dermal LD50 of approximately 973 mg/kg bw is assigned.

References
Creton, S., Dewhurst, I.C., Earl, L.K., Gehen, S.C., Guest, R.L., Hotchkiss, J.A., Indans, I., Woolhiser, M.R. and Billington, R., 2010. Acute toxicity testing of chemicals—opportunities to avoid redundant testing and use alternative approaches. Critical reviews in toxicology, 40(1), pp.50-83.

Kenyon, S., Carmichael, P.L., Khalaque, S., Panchal, S., Waring, R., Harris, R., Smith, R.L. and Mitchell, S.C., 2004. The passage of trimethylamine across rat and human skin. Food and chemical toxicology, 42(10), pp.1619-1628..

Moore, N.P., Andrew, D.J., Bjerke, D.L., Creton, S., Dreher, D., Holmes, T., Prieto, P., Seidle, T. and Rowan, T.G., 2013. Can acute dermal systemic toxicity tests be replaced with oral tests? A comparison of route-specific systemic toxicity and hazard classifications under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Regulatory Toxicology and Pharmacology, 66(1), pp.30-37.

Seidle, T., Prieto, P. and Bulgheroni, A., 2011. Examining the regulatory value of multi-route mammalian acute systemic toxicity studies.

Seidle, T., Robinson, S., Holmes, T., Creton, S., Prieto, P., Scheel, J. and Chlebus, M., 2010. Cross-sector review of drivers and available 3Rs approaches for acute systemic toxicity testing. Toxicological Sciences, 116(2), pp.382-396.

van der Kamp, S. and Elliott, C., 2021. Increasing confidence in waiving dermal toxicity studies: A comparison of oral and dermal acute data with alternative approaches for agrochemicals and products. Regulatory Toxicology and Pharmacology, 121, p.104865.

Reason / purpose for cross-reference:

data waiving: supporting information

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 973 mg/kg bw

Based on:

test mat.

Interpretation of results:

Category 4 based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

ca. 973 mg/kg bw

Additional information

Oral

Based on the hypothesis that the source (TMA) and the target (TMAO) substances have similar toxicological properties because after ingestion by animals or humans, the TMA is metabolized to TMAO in the liver, the acute oral toxicity of TMAO is predicted based on the TMA data. Male and female Sprague-Dawley rats were exposed orally to TMA following a GLP-complaint OECD 401 methodology.  The TMA test substance cause systemic toxicity (including mortality) and local irritation in a dose dependent manner.  The TMA LD50 was reported to be 766 mg/kg bw.  Based on a conversion factor related to the molecular weight of the TMA source and TMAO target substances, the TMAO target substance has a predicted acute oral LD50 of 973 mg/kg bw.

 

Inhalation

The TMAO target substance is a low volatile non-inhalable powder.  The vapour pressure of 23.5 Pa at 20 °C is reported with a MMAD of 414.329 µm with a D10 of 161.713 µm.  This measured data supports the waiver as a low volatile substance, vapour pressure is less than 0.5 kPa, that is not inhalable, particles with aerodynamic diameters greater than 100 μm (ECHA, 2017).  Therefore, the acute inhalation study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

 

Dermal

Data regarding the acute dermal toxicity of the target substance trimethylamine N-oxide is not available; however, there is sufficient data to conclude on classification and the generation of test data is scientifically not necessary.  Independent analyses by regulators, associations and industry to understand differences between acute toxicity oral and dermal outcomes all resulted in a similar conclusion that there is little value performing an acute dermal study where an acute oral study is available as the dermal study is not the leading health effect selected for a human health assessment (van der Kamp and Elliot 2021; Moore et al., 2013; Creton et al., 2010; Seidle et al., 2020, 2011).  Oral acute toxicity classifications for pure substances were more conservative than dermal data in more than 98% of cases.

 

Testing reported within the REACH dossier has demonstrated that trimethylamine N-oxide does not present a hazard from dermal exposure due to either irritation or sensitization.  Additionally, trimethylamine N-oxide passes through human dermal tissue with little restriction to its movement (Kenyon et al., 2004). As several independent assessments have demonstrated that the results of dermal toxicity assessment will not result is a more sever safety concern than that from oral exposure, following one of the key goals of the REACH Regulation, specially to reduce testing on vertebrate animals, based on the acute oral toxicity data, a dermal LD50 of approximately 973 mg/kg bw is assigned.

 

References

Creton, S., Dewhurst, I.C., Earl, L.K., Gehen, S.C., Guest, R.L., Hotchkiss, J.A., Indans, I., Woolhiser, M.R. and Billington, R., 2010. Acute toxicity testing of chemicals—opportunities to avoid redundant testing and use alternative approaches. Critical reviews in toxicology, 40(1), pp.50-83.

 

ECHA, 2017. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7c: Endpoint specific guidance. Version 3.0 June 2017.

 

Kenyon, S., Carmichael, P.L., Khalaque, S., Panchal, S., Waring, R., Harris, R., Smith, R.L. and Mitchell, S.C., 2004. The passage of trimethylamine across rat and human skin. Food and chemical toxicology, 42(10), pp.1619-1628..

 

Moore, N.P., Andrew, D.J., Bjerke, D.L., Creton, S., Dreher, D., Holmes, T., Prieto, P., Seidle, T. and Rowan, T.G., 2013. Can acute dermal systemic toxicity tests be replaced with oral tests? A comparison of route-specific systemic toxicity and hazard classifications under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Regulatory Toxicology and Pharmacology, 66(1), pp.30-37.

 

Seidle, T., Prieto, P. and Bulgheroni, A., 2011. Examining the regulatory value of multi-route mammalian acute systemic toxicity studies.

 

Seidle, T., Robinson, S., Holmes, T., Creton, S., Prieto, P., Scheel, J. and Chlebus, M., 2010. Cross-sector review of drivers and available 3Rs approaches for acute systemic toxicity testing. Toxicological Sciences, 116(2), pp.382-396.

 

van der Kamp, S. and Elliott, C., 2021. Increasing confidence in waiving dermal toxicity studies: A comparison of oral and dermal acute data with alternative approaches for agrochemicals and products. Regulatory Toxicology and Pharmacology, 121, p.104865.

Justification for classification or non-classification

Based on the results of the acute oral study, trimethylamine N-oxide does meet the classification criteria of EC 1272/2008 (as amended) for Category 4 Acute and Dermal toxicity.

 

There are no toxicological effects reported which would indicate there is specific target organ toxicity.