Propanoic acid, 2-hydroxy-, C12-13-branched alkyl esters

Endpoint summary

Description of key information

Based on read-across from Tetradecyl 2-hydroxypropionate (CAS No. 1323-03-1): NOAEL (oral, rat, 90d) = 500 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from a reference substance with similar structure and intrinsic properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for grouping of substances and read-across

There are no data available on the repeated dose toxicity of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters. In order to fulfil the standard information requirements set out in Annex VIII, 8.6.1, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity. The endpoint repeated dose toxicity is covered on the basis of read-across to a target substance of a structurally similar lactic acid ester as well as on the metabolism of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters, in particular on the fact that the substance undergoes enzymatic ester hydrolysis resulting in the formation of Alcohols, C12-13-branched and 2-Hydroxypropanoic acid resulting in reading-across to the expected hydrolysis products.

Overview of repeated dose oral toxicity

CAS#	-- (a)	75782-86-4 (former CAS 67762-41-8) (b)	1323-03-1	111-27-3	50-21-5
Name	Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters	Alcohols, C12-13-branched and linear	Tetradecyl 2-hydroxypropionate	Hexan-1-ol	2-Hydroxy-propanoic acid
subacute	WoE: RA: CAS 75782-86-4 RA: CAS 111-27-3	Experimental result: NOAEL ≥300 mg/kg bw/day	--	Experimental result: NOAEL = 1127 mg/kg bw/d
subchronic	RA: CAS 1323-03-1 RA: CAS 50-21-5	--	Experimental result: NOAEL≥500 mg/kg bw/day	--	Experimental result: NOAEL > 1600 mg/kg bw/d

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

Repeated dose toxicity: oral

Subacute

CAS 75782-86-4 (former CAS 67762-41-8)

A GLP- compliant subacute toxicity study according to OECD guideline 407 was conducted with Alcohols, C12-13-branched and linear (CAS 740817-83-8), which was former registered under CAS 67762-41-8 (Alcohols, C10-16) (Wijnands, 1999). Groups of male and female rats (5 per dose) received the test substance diluted in corn oil once daily at dose levels of 100, 300 and 1000 mg/kg bw/day via oral gavage for a period of 28 days. A similar constituted group of animals was treated with the vehicle only and served as control group. At the high dose (1000 mg/kg bw/day), clinical signs of toxicity in most of the males (80%) and all females involved thinly haired areas of skin and regurgitation of the test substance immediately after dosing. At the same dose level, 3/5 males showed weakness, thin appearance and respiratory disorders, and one of these animals died on study Day (SD) 27, which, however, was presumably due to a dosing error. During the first and last weeks of the study, high dose males showed a significant reduction in mean body weight compared to the concurrent control animals. On SD 27, mean body weight in males of the high dose was reduced by ca. -14% compared to controls, which corresponded to a decrease in food consumption (ca. -17% compared to controls) of these animals. No effects on body weights and food consumption were noted in males of the other dose groups and in any of the treated females, respectively. Haematology revealed a significantly reduced thrombocyte count (-10%) in females of the high dose group compared to controls, whereas the absolute number of monocytes was increased in these animals. Although a slight (-6%), but significant reduction in mean corpuscular haemoglobin was observed in males treated at 300 mg/ kg bw/day, this isolated effect was considered fortuitous due to the lack of any dose-response relationship. In high dose female, significant changes in clinical chemical parameters indicative of an adverse effect on the liver (increase in ALP (+49%), ALAT (+ 44%), and cholesterol (+28%)) were observed. However, there were no accompanying histopathological changes observed in the liver in females of this dose group. In males, the decreased albumin/globulin ratio at 1000 mg/kg bw/day was of questionable biological significance given that total protein and albumin was comparable in all groups. Determination of organ weights revealed a significant increase (+7.5% and +14%) in relative kidney weights in males at 300 and 1000 mg/kg/day, which however, was not accompanied by any adverse histopathological changes in the kidney. Thus, the increase in relative kidney weights in males was not considered to be toxicologically significant. At necropsy and microscopic examination, pathological changes associated with the dosing procedure, but no test substance-related abnormalities were observed.

Based on the significant reduction in food consumption and body weights in males and the significant changes in clinical chemistry and haematological parameters in females at 1000 mg/kg bw/day, the subacute oral NOAEL was considered to be 300 mg/kg bw/day for male and female rats, respectively.

CAS 111-27-3

In a subacute oral toxicity study conducted with Hexan-1-ol (CAS 111-27-3), 10 rats per sex and dose received the test substance continuously administered to the basal diet at concentrations of 0.25%, 0.50%, 1.0-6.0% (w/w) for a period of 13 weeks (Faurot and Pennisi, 1985). The dose levels in the high dose group were 1% from week 1 to week 10, 2% in week 11 and 4% in week 12 and 6% in week 13. An additional group of 20 untreated animals served as control.group. Fresh diets were prepared each week. Body weights and food consumption were recorded weekly. Hematology parameters and urine analyses were measured at day 30 and day 90. Organ and body weight measurements were made for all animals in each test group at termination of the study after 13 weeks. Selected tissues were obtained from each animal and preserved for possible microscopic examination. All of the selected tissues from the control and the high dosage groups were examined microscopically. One male in the low dose group died during week 9 of the study, however the death was considered to be unrelated to treatment. Although there was a significant increase in relative heart weight in mid dose males, this did not correlate with any histopathological change and was not dose related. It was therefore not considered to be biologically significant. The NOAEL (males: 1127 mg/kg bw/d, females: 1243 mg/kg be/d) was therefore based on a lack of toxicological significance at any of the dose levels tested and represents the highest dose tested.

Subchronic

CAS 1323-03-1

In a subchronic oral toxicity study with Tetradecyl 2-hydroxypropionate, 10 Sprague Dawley rats per sex and group received undiluted test substance 5 days/week at dose levels of 500; 2500 and 5000 mg/kg bw/day for a period of 13 weeks (Faurot and Pennisi, 1985). An additional group of 10 animals per sex were sham-exposed and served as control group. All animals survived until study termination and their appearance and behaviour were relatively unaffected by treatment. In males, body weight gain was significantly decreased at 5000 mg/kg bw/day, whereas no effects on body weights were noted in treated males of any other dose group and treated females, respectively. A few statistically significant changes in haematological parameters were observed in treated animals, but these fell within the normal ranges observed in control animals, and were thus not toxicologically relevant. At 2500 and 5000 mg/kg bw/day, serum glutamate pyruvate transferase (SGPT) values were significantly increased in males and females. In addition, serum alkaline phosphatase (SAP) and serum glutamic oxaloacetic transaminase (SGOT) values in males were significantly elevated at 5000 mg/kg bw/day. At necropsy, three males of the high dose group and one male of the mid dose group showed slightly enlarged livers with a prominent lobular pattern and three females of the high dose group had slightly enlarged livers with paleness of all lobes. The observed liver enlargement correlated with the significantly increased liver weight in males and females of the mid- and high dose groups compared to controls. In addition to adverse effects on the liver, necropsy revealed dose-related effects in the gastrointestinal tract, including enlargement or thickening of the walls of the stomach and duodenum. The gross pathological findings in stomach and liver were accompanied by respective histopathological findings in these organs. These involved inflammatory and/or proliferative lesions in the non-glandular portion of the stomach at 2500 and 5000 mg/kg bw/day as well as liver changes, primarily related to Kupffer cell hypertrophy, at 5000 mg/kg bw/day. Furthermore, diffuse mucosal hyperplasia primarily in the duodenum was observed at the two highest dose levels.

Based on the changes in liver, stomach, and intestine (duodenum) at the higher dose levels, the lowest administered dose of 500 mg/kg/day was selected as the NOAEL in male and female rats.

CAS 50-21-5

Data is available from secondary sources where Lactic acid did not show significant toxicity in dogs, rats pigs and hamsters in oral subchronic toxicity studies (Andersen, 1998): Two dogs were given 600-1600 mg/kg Lactic Acid orally 42 times over a 2.5-month period. No ill effects were observed (Faust, 1910). A group of white rats was fed 10% Lactic Acid at a dose of 4 mL/20 g of meal and a control group was given untreated feed. No differences in appearance, gross observations at necropsy, or organ weights were observed between the test and control animals. Changes in blood carbon dioxide were slight (Wysokinska, 1952). No overt toxic effects were observed in pigs given approximately 3.6-18 g/kg Lactic Acid in feed or water for up to 5 months (Lamb and Evvard, 1919; Kershaw et al., 1966). Groups of 15 Syrian hamsters, 8 males and 7 females per group, were dosed with Lactic Acid by adding 0.057 mL Lactic Acid (80%) to 100 g of feed or by adding 0.050 mL Lactic Acid (80%) to 100 mL distilled water for 100 days; the amount of Lactic Acid added to the feed and water provided the same daily ingested dose for the two groups. A third group was given untreated feed and water. All animals were killed for necropsy at study termination. No differences in appearance or growth rate were noted between the groups, and no gross changes were observed at necropsy. Various degrees of alveolar resorption were reported for several animals, but no significant difference was observed between the groups (Granados et al., 1949).

Lactate is an endogenous substance (in carbohydrate and amino acid metabolism) and a natural component of very many foods. Under conditions of heavy energy demand and high oxygen need, skeletal muscles convert glucose anaerobically into lactic acid, which is excreted from the muscle cells into the blood. In the liver this lactic acid is reduced to glucose. Ultimately any absorbed lactic acid will be oxidised to give carbon dioxide and water (EFSA 2011). In 1973 the Joint FAO/WHO Expert Committee on Food Additives (JECFA) derived an Acceptable Daily Intake (ADI) “not limited” for lactate and several salts (JECFA, 1974). In 1991, this view (ADI “not specified”) was also supported by the Scientific Committee of Food (SCF) (SCF, 1991); and in 2006 and 2011 iterated by the European Food Safety Authority (EFSA) in the evaluation of lactate and sodium lactate for poultry carcass treatment (EFSA, 2008) and in the evaluation of the safety and efficacy of lactic acid for the removal of microbial surface contamination of beef carcasses, cuts and trimmings (EFSA, 2011). Furthermore, Lactic acid (2-Hydroypropanoic acid), has been approved for use as direct food additive with generally recognised as safe (GRAS) status for use beyond infancy at concentrations that do not exceed good manufacturing practices (GMP) (FDA, 1980).

Repeated dose toxicity: inhalation and dermal routes

This information is not available.

For the purpose of hazard assessment of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters, the NOAEL of 500 mg/kg bw/day from the subchronic (90-day) oral toxicity study performed with the source substance Tetradecyl 2-hydroxypropionate was selected as most appropriate dose descriptor. This effect level serves as the most conservative dose descriptor starting point for derivation of the long-term systemic DNELs for the oral, inhalation and dermal route. The respective DNELs are provided in section 7, Toxicological information.

Conclusions for repeated dose toxicity

There are no data available on the repeated dose oral toxicity of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters. Therefore, hazard assessment is conducted by means of read-across to a target substance of a structurally similar lactic acid ester as well as on the metabolism of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters, in particular on the fact that the substance undergoes enzymatic ester hydrolysis resulting in the formation of Alcohols, C12-13-branched and linear and 2-Hydroxypropanoic acid resulting in reading-across to the expected hydrolysis products and structurally similar substances of the breakdown products.

Overall, the available data provide sufficient weight of evidence to conclude that the substance Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters is not toxic after long-term repeated exposure.

There are no data available on repeated dose toxicity by the inhalation and dermal route.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

The available data on repeated dose toxicity of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters via the oral route do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.