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Description of key information

Taking into account all available data, PEMB possesses a low acute toxicity and is not expected to accumulate in

biological systems. However, account needs to be taken of the fact that PEMB is systemically bioavailable after repeated oral administration, although most of the compound-related effects observed after 28 and 90 days of treatment seem to be reversible during recovery.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

PEMB (3-[(3-sulfanylbutanoyl)oxy]-2,2-bis{[(3-sulfanylbutanoyl)oxy]methyl}propyl 3-sulfanylbutanoate) is a mono-constituent substance in which the percentage range for the main constituent overlaps the 80% criterion and the main constituent is only occasionally ≤ 80%. PEMB contains as impurities:

- 14% PE3MB (3-hydroxy-2,2-bis{[(3-sulfanylbutanoyl)oxy]methyl}propyl 3-sulfanylbutanoate),

- 0.95% 2,2-bis(hydroxymethyl)propane-1,3-diyl bis(3-sulfanylbutanoate),

- 0.84% 3-[(3-sulfanylbutanoyl)oxy]-2,2-bis([(3-sulfanylbutanoyl)oxy]methyl)propyl 3-[(3-sulfanylbutanoyl)sulfanyl]butanoate and

- 1.21% multiple unknown impurities.

 

There are no experimental studies available in which the toxicokinetic properties of PEMB were investigated. Therefore, whenever possible, toxicokinetic behaviour was assessed taking into account the available information on physicochemical and toxicological characteristics of PEMB according to “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014)”.

In its pure state, PEMB is a pale yellow liquid which is almost insoluble in water (0.76 mg/L) and has a very low vapour pressure (8.8E-10 Pa at 25 °C). The molecular mass of PEMB is 544.8 g/mol and the partition coefficient (log Kow) was determined to be 3.99.

 

Absorption and distribution

Acute oral toxicity of PEMB was tested in the fixed dose procedure according to OECD 420 (Pooles, 2009). Female rats received the test substance in a single dose at 2000 mg/kg bw by gavage. No deaths and no signs of toxicity were noted during the study period. Macroscopic examinations at necropsy did not reveal any abnormalities. The LD50 of the test substance was > 2000 mg/kg bw. With respect to the dose administered and as no effects were observed, it can be presumed that after single oral administration systemic bioavailability of PEMB is rather low or/and PEMB is not toxic up to 2000 mg/kg bw.

An oral repeated dose toxicity study performed in rats similar to OECD 407 (28 -day treament) showed treatment-related effects in the highest dose group tested with PEMB (Miyata, 2009). At 1000 mg/kg bw/day, pathological and histopathological findings were noted in the livers of females and in the kidneys of males, indicating that PEMB is systemically bioavailable after repeated oral administration. However, as male rats are susceptible to chemically induced renal toxicity involving alpha-2µ-globulin, it is not clear whether the effect is mediated by alpha-2µ-globulin.Clinical signs observed were assessed as incidental occurrence. No toxicologically relevant changes in hematology parameters and no treatment-related effects on body weight and food consumption were found. In the recovery group, histopathological examinations displayed reversible effects in liver and kidney, but organ weights of liver and kidney were statistically significantly increased. Similar effects were observed in an oral repeated dose toxicity study performed in rats similar to OECD 408 (90 -day treatment) (Jun, 2010).

Therefore, after repeated oral administration, PEMB is systemically bioavailable as treatment-related effects in liver and kidney were found.

 

No data on acute inhalation toxicity are available. However, as the physical state of PEMB is liquid and the vapour pressure is very low (8.8E-10 Pa at 25 °C), inhalation is not considered to be a relevant route of exposure. Moreover, the use of PEMB will not result in spray applications. Thus, exposure to humans via the inhalation route will be unlikely to occur.

 

For acute dermal toxicity, PEMB was applied to the intact skin of female and male rats at a dose level of 2000 mg/kg bw, according to OECD 402 (Pooles, 2009). No deaths and no signs of toxicity were observed during the study period. At necropsy, no abnormal findings were noted and the LD50 was determined to be > 2000 mg/kg bw. The data suggest that after single dermal application skin penetration of PEMB is rather low or/and PEMB is not toxic up to 2000 mg/kg bw.

For PEMB a QSAR based modelling published by Potts and Guy (1992), taking into account molecular mass and log Kow, estimated a dermal permeability constant Kp of 5.83E-04 cm/h. Similar to the approach taken by Kroes et al. (2007), the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated, resulting in dermal absorption of 0.00044 µg/cm²/h PEMB. Usually, this value is considered as indicator for a dermal absorption of 1% (Mostert and Goergens, 2011). This is in accordance with the result of the acute dermal toxicity study in which no systemic toxicity was found up to 2000 mg/kg bw. This could be an indication that skin penetration is low. However, the partition coefficient (log Kow) for PEMB was determined to be 3.99, thus indicating thatPEMB can penetrate the skin. It is generally accepted that substances with logKow ranging from 0.1 to 6 penetrate the skin easily (Vermeire et al., 1993). Furthermore, also the skin sensitisation study showed a positive result.

 

Taking into consideration all available information, PEMB is systemically bioavailable after repeated oral administration as treatment-related effects in liver and kidney were observed. No systemic effects were found after single oral or dermal administration. No experimental data are available on distribution after oral, inhalation or dermal doses of PEMB. However, it can be assumed that absorbed PEMB will only show a low volume of distribution based on the partition coefficient (log Kow) of 3.99, which indicates a low potential to accumulate in biological systems.

 

Metabolism and excretion

There are no data available on metabolism and excretion of PEMB. By calculating potential metabolites via OECD QSAR toolbox v.2.3 (2012), metabolites generated by the microbial and liver metabolism simulator indicated hydrolysis of PEMB. It can be deduced from the potential metabolites that PEMB is hydrolysed into PE3MB, mercaptobutanoic acid and other hydrolysis products followed by oxidation. The microbial metabolism simulator also predicted numerous forms of thiol and propane compounds. No relevant metabolites were generated by the skin metabolism simulator.

With respect to the positive result of the local lymph node assay (LLNA), interactions of PEMB with skin proteins cannot be excluded.

Studies on genetic toxicity (in-vitro Ames test and in-vivo micronucleus assay) were negative, indicating that there is no evidence of the generation of chemically reactive metabolites of PEMB. Solely an in-vitro chromosome aberration test yielded an ambiguous result. However, based on all available data, metabolism of PEMB into chemically reactive compounds seems to be unlikely.

Considering the potential metabolites generated via QSAR modelling, PEMB will be hydrolysed in the gastrointestinal tract. This means that absorption of smaller and more water-soluble molecules of the parental compound via the gastrointestinal tract is possible. If absorption occurs, subsequent methylation of the thiol groups seems rather likely. The fraction which is systemically bioavailable will be excreted via urine and/or bile acids. The fraction of PEMB which is not absorbed via the gastrointestinal tract will be excreted with the feces.

 

In conclusion, taking into account all available data, PEMB possesses a low acute toxicity and is not expected to accumulate in biological systems. However, account needs to be taken of the fact that PEMB is systemically bioavailable after repeated oral administration, although most of the compound-related effects observed after 28 and 90 days of treatment seem to be reversible during recovery.

 

References not cited in the IUCLID:

Potts, R. and Guy, R. (1992) Predicting skin permeability. Pharm. Res. 9(5): 663-669

Kroes, R. et al. (2007) Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem. Toxicol. 45, 2533–2562

Mostert, V. and Goergens, A. (2011) Dermal DNEL setting: using QSAR predictions for dermal absorption for a refined route-to-route extrapolation. Society of Toxicology, Annual Meeting, ISSN 1096-6080 (http://www.toxicology.org/AI/PUB/Toxicologist11.pdf), 120(2): 107

ECHA guidance document, endpoint specific guidance, Chapter R.7c, November, 2012

Vermeire, T.G. et al.(1993) Estimation of consumer exposure to chemcials: application of simple models.The Science of the Total Environment 136: 155-176