methyl 2-hydroxybut-3-enoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert statement based on physicochemical and toxicity data

Adequacy of study:

key study

Study period:

2022-03-18

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement based on physicochemical and toxicity data

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2022

Report date:

2022

Applicant's summary and conclusion

Conclusions:

Methyl-2-hydroxy-3-butenoate was found to be a locally acting substance in all available in vivo studies. However, damage to skin/mucosal surfaces may enhance penetration and based on physicochemical characteristics, absorption, especially by the oral route might take place. In acute and subacute toxicity studies, adverse local effects in the stomach were accompanied by an onset of systemic effects at higher doses. This effect was also seen in two in vivo genotoxicity assays where systemic distribution to the bone marrow and kidneys was shown which was likely secondary to the local effects in the stomach. Bioaccumulation is not expected. Methyl-2-hydroxy-3-butenoate potentially reaches metabolic organs but no predictions on metabolic transformation can be made. On the basis of the molecular substance characteristics and study results, excretion via urine is favoured.

Executive summary:

Methyl-2-hydroxy-3-butenoate is a mono-constituent substance. It is a colourless to yellowish liquid with a molecular weight of 116.117 g/moL. The substance shows complete solubility in water. The log Pow was determined to be <0.3. The test substance has a vapour pressure of 123 Pa at 25 °C.

 

 

Absorption

According to the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c (Endpoint specific guidance), oral absorption is favoured for molecules with molecular weights of less than 500 g/moL. The substance is assumed to readily dissolve in gastrointestinal fluid due to its good water solubility and the log Pow of < 0.3 (the extrapolated log Pow was determined to be 0.13) favours absorption by passive diffusion. Taken together, the physiochemical properties indicate that Methyl-2-hydroxy-3-butenoate becomes bioavailable following the oral route. Some clinical effects were observed in an acute oral toxicity test (convulsions, irregular respiration and lethargy) which might, however be secondary to the local effects observed by gross pathological examination (frothy discharge and red and haemorrhaged mucous membranes in the stomach). This assumption was confirmed by the fact that local effects observed in a 14-day dose-range finding test were followed by some clinical signs (e.g. salivation), decreased body weight gain and hematological changes. Here, local effects were confirmed also by histopathological examination (squamous cell hyperplasia accompanied with hemorrhages, occasionally with erosion and inflammatory cell infiltration in the nonglandular part of stomach) and by elevated white blood cell counts, elevated percentages of reticulocytes and platelet counts which were considered to be related to the gastric effect (irritation and inflammation) of the test item. This finding was confirmed in the main study (Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test) where adverse local gastric effects induced an early onset of adverse systemic changes. Also in both in vivo genotoxicity studies, irritating effects on the stomach were observed. Cytotoxicity assessment also showed signs of systemic toxicity (decreased number of PCEs in the MNT and increased number of ghost cells in stomach and kidney tissues in the Comet Assay) which occurred delayed to the local effects (dose-dependent local effects at all doses, cytotoxicity effects at the highest (Comet: stomach) or in the mid and high dose (Comet: kidney, MNT: bone marrow)). For this reason, it is concluded that the Methyl-2-hydroxy-3-butenoate acts mainly locally at the site of first contact and systemic effects occur secondary to local effects, e.g. by absorption though damaged mucous membranes.

 

Due to the low volatility (vapour pressure of 123 at 25 °C) and high boiling point between 164.5 °C and 178.1 °C of Methyl-2-hydroxy-3-butenoate, it is unlikely that the substance will be available as a vapour. As the substance is a liquid, no particle formation is expected. Hydrophilic substances are likely to be retained within the mucus and thus, because of the good water solubility of the substance, penetration may be reduced. Although the Log Pow of < 0.3 (extrapolated: 0.13) would favour uptake through the respiratory tract epithelium by passive diffusion, it is very unlikely that the substance reaches the respiratory tract due to the previously mentioned properties. Again, rather respiratory irritating effects are expected and systemic uptake might occur where mucous membranes or the lung epithelium is damaged.

 

Methyl-2-hydroxy-3-butenoate is a non-volatile liquid with a log Pow < 0.3 (extrapolated: 0.13) but the molecular weight of approx. 116.117 g/moL of Methyl-2-hydroxy-3-butenoate might be slightly too high to favour dermal uptake. As the substance is completely miscible in water, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Thus, low dermal absorption is expected. Again, local effects are considered to be the predominant mode of action which is confirmed by highly corrosive effects observed in an acute dermal toxicity study and irritating effects observed in two in vitro skin irritation studies. Systemic absorption might occur to a certain extend through the damaged skin barrier. As skin sensitisation was predicted by the Integrated Testing Strategy Defined Approach (ITSv2 DA), some systemic uptake is expected although it may be small. Thus, dermal absorption cannot be excluded but may not be the preferential route of entry into the body.

 

 

Distribution

As mentioned above, Methyl-2-hydroxy-3-butenoate is mainly a locally acting substance. However, after damaging mucosal/skin barriers, the substance might penetrate the body to a certain extend. After being absorbed into the body, Methyl-2-hydroxy-3-butenoate is most likely well distributed due to its relatively low molecular weight. An early onset of systemic effects was observed in acute and repeated dose toxicity studies which can be attributed to a systemic distribution. Furthermore, in vivo genotoxicity studies showed distribution to the bone marrow and kidneys.

 

The log Pow of Methyl-2-hydroxy-3-butenoate indicates no potential for bioaccumulation.

 

 

Metabolism

There is no direct experimental data to characterise the metabolism of Methyl-2-hydroxy-3-butenoate. Instead, the anticipated metabolism is derived from expert judgement and reapplication of metabolic properties of related substances.

 

Genotoxicity studies do not indicate a genotoxic potential of the purified and stabilised substance. No pronounced differences in cytotoxicity were observed with or without metabolic activation. Thus, no predictions on the metabolisation of Methyl-2-hydroxy-3-butenoate by liver enzymes and resulting toxification or detoxification can be made. An early onset of systemic effects were observed in the acute and repeated-dose toxicity studies. Furthermore, in vivo genotoxicity studies indicate a systemic distribution of the test substance at least to the bone marrow and kidneys. Thus, Methyl-2-hydroxy-3-butenoate is in principle capable to reach metabolic organs and their metabolic capacities.

 

 

Excretion

The physicochemical properties of the substance favour excretion via urine (low molecular weight and high water solubility) which is supported by the fact that Methyl-2-hydroxy-3-butenoate was shown to reach the kidneys in an in vivo Comet Assay.