Fatty acids, C10-12, esters with polylactic acid, sodium salts

Endpoint summary

Description of key information

Oral: Calculated LD50 (rat) = 4880 mg/kg bw

Weight-of-Evidence approach based on data for structural similar substances, publically available information on food additives, results of a short-term repeated dose toxicity study and a reproductive/developmental toxicity screening test with the registered substance.

Inhalation: No study required as the inhalation route of exposure is considered less relevant than the dermal route.

Dermal: According to the REACH Regulation (EC) No. 1907/2006, Annex VIII, Section 8.5, Column 2, no study is required as fatty acids, C10-12, esters with polylactic acid, sodium salts (Dermosoft decalact, CAS No. 1312021-45-6, EC No. 700-937-1) does not meet the criteria for classification for acute toxicity or Specific Target Organ Toxicity after Single Exposure (STOT SE) by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

other: Expert statement

Adequacy of study:

weight of evidence

Study period:

2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: refer to 'Remarks'

Remarks:

According to Annex XI, Item 1.2, of Regulation (EC) No. 1907/2006 (REACH), testing is not necessary if sufficient weight of evidence from several independent sources of information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, while the information from each single source alone is regarded insufficient to support this notion. The Weight-of-Evidence assessment accounts for all relevant data from (i) the public domain, (ii) information derived from the toxicokinetic assessment of the registered substance, (iii) hazard data on the metabolites of the registered substance, and (iv) results of the repeated dose toxicity study with the registered substance. The influence of unidentified minor components of the registered substance cannot be assessed. This is considered acceptable because such components are contained in amounts below 1% or below 0.1% for known dangerous substances, such as CMR substances and are not expected to have an impact on the outcome of an acute oral toxicity study with the registered substance.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline available

Principles of method if other than guideline:

The acute oral toxicity was assessed from the available data on single constituents, related substances and on the metabolites of enzymatic ester hydrolysis as well as results of the short-term repeated dose toxicity study with the registered substance.

GLP compliance:

no

Test type:

other: Weight-of-Evidence assessment that compiles various tests on metabolism and acute oral toxicity on related substances and metabolites

Limit test:

no

Species:

rat

Strain:

other: data on several rat strains are used

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

other: Studies using various vehicles were assessed

Doses:

Depending on the substance and duration of the studies, the maximum doses ranged between 2400 and 6000 mg/kg bw. Details are given in the expert statement.

No. of animals per sex per dose:

variable

Control animals:

other: in some studies control animals are included

Preliminary study:

Based on bibliographical knowledge and on current valid ADI (acceptable daily intake) of 20 mg/kg bw/day for sodium stearoyl lactylate which is approved to be used in food and feed, the oral LD50 is predicted to be higher than 2000 mg/kg bw. No mortality and no findings of necropsy are expected.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 880 mg/kg bw

Based on:

other: calculated by conservative mathematical approach

Remarks on result:

other: weight of evidence

Mortality:

None expected

Clinical signs:

other: No unusual signs predicted

Gross pathology:

No effects on gross pathology are predicted

Other findings:

None

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.

Conclusions:

Result by weight of evidence: The calculated LD50 (oral, rat) : 4.88g/kg bw

Executive summary:

The registered substance was assessed for its acute oral toxicity by means of a weight-of-evidence approach. The oral LD50 values of structural similar compounds exceed 5 g/kg bw. Additional long-term toxicity data of the lactylic ester of stearic acid lead to an acceptable daily intake (ADI) of 20 mg/kg bw/day for that substance. Moreover, lactylic esters of fatty acids may be safely used in food per 21 CFR 172.848. Lactylic acid esters of long and short chain fatty acids are metabolised in the same way, hence it can be assumed that the registered substance shows no long-term toxicity potential. This is further supported by the results of the short-term repeated dose toxicity study with the registered substance. The impurity sodium lactate, which the registered substance contains up to approx. 10%, has an ADI that is not limited. Hence, a negative effect on the oral LD50 can be ruled out.

In summary, the acute oral toxicity of the registered substance is assumed to be very low. The presented data from several independent sources of information are considered sufficient to evaluate the acute oral toxicity of the registered substance. According to Annex XI, Item 1.2, of Regulation (EC) No. 1907/2006 (REACH), further testing on vertebrate animals shall be omitted if sufficient weight of evidence for the presence or absence of a particular dangerous property is available.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The hazard assessment is based on a Weight-of-Evidence approach taking into account data from several independent sources, e.g. publically available data on structurally similar food additives and data from a short-term repeated dose toxicity study and a reproductive/developmental toxicity screening test with the registered substance. The database is, therefore, sufficient to fulfil the standard information requirements set out in Annex VII, Item 8.5, in accordance with Annex XI, Item 1.2, of Regulation (EC) No. 1907/2006 (REACH).

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Weight-of-Evidence assessment of acute oral toxicity

According to Annex XI, Section 1.2, of the REACH Regulation (EC) No. 1907/2006, testing is not necessary if there is sufficient weight of evidence from several independent sources of information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, while the information from each single source alone is regarded insufficient to support this notion.

The Weight-of-Evidence (WoE) assessment of the acute oral toxicity of fatty acids, C10-12, esters with polylactic acid, sodium salts (Dermosoft decalact, CAS No. 1312021-45-6, EC No. 700-937-1) accounts for all relevant data from

(i)       the public domain of structural similar substances (Schäfer, 2012; expert statement reported in IUCLID section 7.2.1),

(ii)       information derived from the toxicokinetic assessment of Dermosoft decalact (endpoint summary of IUCLID section 7.1), and

(iii)       results of studies with repeated dose administration performed with Dermosoft decalact (Longobardi, 2020, reported in IUCLID section 7.5.1 and Longobardi, 2021, reported in IUCLID section 7.8.1).

Data obtained with other alkanoyl lactyl lactates (lactylates)

In addition to the data obtained with fatty acids, C10-12, esters with polylactic acid, sodium salts (Dermosoft decalact, CAS No. 1312021-45-6, EC No. 700-937-1), studies performed with the following lactylates

•       sodium stearoyl lactylate (SSL, esterification product of C16-C18 even numbered, saturated fatty acids and lactic acid, sodium salt, CAS No. 25383-99-7, EC No. 246-929-7),

•       sodium caproyl lactylate (SCL, CAS No. 29051-57-8, EC No. 608-308-2)

•       sodium lauroyl lactylate (SLL, CAS No. 13557-75-0, EC No. 236-942-6), and

•       calcium stearoyl-2-lactylate (CSL, E 482)

are considered in the expert statement and the toxicokinetic assessment. This formally constitutes an analogue read-across approach according to REACH Annex XI, Section 1.5. The adequacy of this approach needs to be demonstrated based on the scientific principles laid down in the Read-Across Assessment Framework (RAAF; ECHA, 2017a&b). The main principle in the RAAF is the demonstration of structural similarity between target and source substances. In order to decide on the structural similarity, detailed information on the qualitative and quantitative composition is needed. The similarities and differences in the composition of target and source substances must be considered and the 'compounds test organisms are exposed to' need to be discussed. It must be established to what extent the prediction of toxicological properties of the target substance (here Dermosoft decalact) is affected by compounds present in the source substances (here the other lactylates) but not in the target substance. Similarly, it must be clear how compounds present in the target but not in the source substance have an effect on the prediction. In summary, the exact composition of target and source substances is a prerequisite for a robust analogue read-across approach. This conclusion is all the more important as the target and source substances are of UVCB nature (Unknown or Variable composition, Complex reaction products or Biological materials).

It must be noted that the toxicological information on the lactylates are only briefly summarised in reviews prepared by regulatory authorities (JECFA, 1974a&b; EFSA, 2013; 21 CFR 172). No detailed compositional information in terms of the qualitative and quantitative composition of the tested lactylates is provided in the reviews. A detailed discussion of the similarities and differences in composition and their potential implications for the prediction and of the 'compounds test organisms are exposed to' is, therefore, not possible. However, in this particular case the lack of compositional information is not considered to affect the prediction of the acute oral toxicity of Dermosoft decalact. Lactylates (i.e. lactyl lactate esters of fatty acids), including their reasonably expected constituents, are used for several decades as direct food additives in regulatory areas around the globe and the prediction of no acute oral toxicity (i.e. LD50 > 2000 mg/kg bw) is fully supported by all available data obtained with Dermosoft decalact. The analogue read-across is based on the structural similarity that can be derived from the general chemical characterisation of the lactylates given in the reviews.

The main structural feature of both the target and source substances is the lactylate (lactyl lactate) moiety. Since lactyl lactate contains a hydroxyl (OH) group, esterification with acidic compounds is possible. The most abundant acid moieties in the lactylates considered are

•       capric acid (C10 carboxylic acid) in Dermosoft decalact,

•       lauric acid (C12 carboxylic acid) in SLL and Dermosoft decalact,

•       palmitic acid (C16 carboxylic acid) and stearic (C18 carboxylic acid) in SSL and CSL.

Sodium (in Dermosoft decalact, SLL and SSL) and calcium (in CSL) are endogenous cations without toxicological relevance for the present evaluation of the acute oral toxicity. In addition to C10, C12, C16 and C18 alkanoyl moieties, it is expected that further carboxylic acid moieties are present to a lesser extent. However, the presence of additional alkanoyl lactylates in the source and target substances is not expected to affect the WoE assessment of the acute oral toxicity of Dermosoft decalact.

In conclusion, it is considered appropriate to use toxicological data of SSL, SLL and CSL as one of the independent sources of information in the WoE assessment of acute oral toxicity of Dermosoft decalact. It is reasonable to assume that the result of the overall WoE assessment is not adversely affected by the lack of detailed compositional information for the lactylate source substances.

Expert statement on the acute oral toxicity of Dermosoft decalact

Fatty acids, C10-12, esters with polylactic acid, sodium salts (Dermosoft decalact, CAS No. 1312021-45-6, EC No. 700-937-1) was assessed for its acute oral toxicity using several sources of publically available information on food additive substances (Schäfer, 2012). As discussed in the previous section, Dermosoft decalact is structurally closely related to the approved food additives esterification product of C16-C18 even numbered, saturated fatty acids and lactic acid, sodium salt (sodium stearoyl lactylate, SSL, E 481, CAS No. 25383-99-7, EC No. 246-929-7) and calcium stearoyl-2-lactylate (CSL, E 482). The oral LD50 values of these structural similar compounds exceed 5000 mg/kg bw. In addition, long-term toxicity data of SSL lead to an acceptable daily intake (ADI) of 20 mg/kg bw/day for that substance. Moreover, lactylic esters of fatty acids may be safely used in food per 21 CFR 172.848. One of the constituents present in Dermosoft decalact is sodium lactate (sodium 2-hydroxypropanoate, CAS No. 72-17-3, EC No. 200-772-0) which has an ADI that is not limited. Hence, a negative effect on the oral LD50 of that and other similar constituents can be excluded. Lactylic acid esters of long and short chain fatty acids are metabolised in the same way (refer also to the toxicokinetics statement in IUCLID section 7.1). Hence, it can be assumed that Dermosoft decalact shows no long-term toxicity potential.

Based on the available acute oral toxicity data from the lactylates considered and taking the differences in molecular weight into account, an acute oral LD50 value of 4880 mg/kg bw was calculated for Dermosoft decalact.

Information derived from the toxicokinetic assessment (IUCLID section 7.1)

The available information, the physicochemical properties and molecular weight of Dermosoft decalact suggest that the substance is orally absorbed. After absorption, alkyl esters are hydrolysed in the gastrointestinal tract, blood and liver to the corresponding alcohols and fatty acids by the enzymatic activity of ubiquitous carboxylesterases. Therefore, Dermosoft decalact is ultimately expected to be enzymatically hydrolysed to the linear capric (C10) and lauric (12) acids and lactic acid. Free fatty acids and the lactate moiety are readily absorbed by the intestinal mucosa.

The metabolism of the hydrolysis products following their absorption is expected to follow the well-established pathway of β-oxidation for energy generation. In this multi-step process, fatty acids are esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of C2 units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2.

In conclusion, the absorption and metabolism of Dermosoft decalact do not give rise to any concerns in relation to systemic toxicity. The metabolic breakdown of the substance leads to the formation of physiological metabolites feeding into naturally occurring pathways. No systemic toxicity is expected to result from the absorption and metabolism of Dermosoft decalact.

Studies with repeated dose administration performed with Dermosoft decalact

The lack of systemic toxicity expected based on the anticipated toxicokinetic behaviour is fully supported by the findings of the studies with repeated administration of Dermosoft decalact. A short-term (28-day) repeated dose toxicity study according to OECD guideline 407 (Longobardi, 2020, IUCLID section 7.5.1) and a reproductive/developmental screening test according to OECD guideline 421 (Longobardi, 2021, IUCLID section 7.8.1) are available for Dermosoft decalact. In both studies the test substance was administered by oral gavage.

The results of the two studies are very similar: Treatment-related changes were seen in the stomach and/or intestines of animals at macroscopic and microscopic examination. The findings of epithelial hyperplasia of the non-glandular region of the stomach were considered to reflect the irritant effect of the test substance. Since humans lack a non-glandular stomach, these changes were deemed irrelevant for humans. It is important to note that no indication of a systemic toxicity was observed in either of the two studies. The No-Observed-Adverse-Effect-Levels determined in both studies was 750 mg/kg bw/day, corresponding to the highest dose tested. Therefore, the findings of these studies with repeated administration of Dermosoft decalact indicate a lack of systemic toxicity and fully support the overall conclusion of the WoE assessment of the acute oral toxicity.

Conclusion of the WoE assessment

The acute oral toxicity of Dermosoft decalact is assumed to be very low. The presented data from several independent sources of information are considered sufficient to evaluate the acute oral toxicity of the registered substance. According to Annex XI, Item 1.2, of Regulation (EC) No. 1907/2006 (REACH), further testing on vertebrate animals shall be omitted if sufficient weight of evidence for the presence or absence of a particular dangerous property is available. Based on all available independent sources of information, incl. a repeated dose toxicity study and a reproductive/developmental toxicity screening study, conducted with Dermosoft decalact, it is reasonable to expect an acute oral LD50 value for Dermosoft decalact of > 2000 mg/kg bw, the threshold for classification for acute toxicity. All available information indicates a lack of systemic toxicity.

References

Code of Federal Regulations (CFR) - Title 21: Food and Drugs; Part 172: Food additives permitted for direct addition to food for human consumption; 172.848: Lactylic esters of fatty acids

ECHA (2017a). Read-Across Assessment Framework (RAAF), ISBN 978-92-9495-758-0, European Chemicals Agency, 2017

ECHA (2017b). Read-Across Assessment Framework (RAAF), ISBN 978-92-9495-811-2, Considerations on multi-constituent substances and UVCBs, European Chemicals Agency, 2017

EFSA (2013). Scientific Opinion on the re-evaluation of sodium stearoyl-2-lactylate (E 481) and calcium stearoyl-2-lactylate (E 482) as food additives, EFSA Journal 2013;11(5):3144

JECFA (1974a). Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents, 539. Stearoyl lactylic acid, calcium and sodium salts. In: Seventeenth Report of the Joint FAO/WHO Expert Committee on Food Additives, WHO Food Additive Series 5

JECFA (1974b). Evaluation of Certain Food Additives. In: Eighteenth Report of the Joint FAO/WHO Expert Committee on Food Additives, WHO Technical Report Series, No. 557.

Justification for classification or non-classification

Based on a Weight-of-Evidence assessment of the acute oral toxicity of fatty acids, C10-12, esters with polylactic acid, sodium salts (Dermosoft decalact, CAS No. 1312021-45-6, EC No. 700-937-1) accounting for several independent sources of information (data for structural similar substances, publically available information on food additives, information on toxicokinetic assessment and results of a short-term repeated dose toxicity study as well as a reproductive/developmental toxicity screening test), the available data on acute toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP). Data are therefore conclusive but not sufficient for classification.

No information on acute toxicity via the inhalation and dermal routes of exposure are available for Dermosoft decalact because the inhalation route is considered less relevant than the dermal route and the substance does not meet the criteria for classification for acute toxicity or Specific Target Organ Toxicity after Single Exposure (STOT SE) by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation).