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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for grouping of substances and read-across

There are no data available on the toxicity to reproduction of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters. In order to fulfil the standard information requirements set out in Annex IX, 8.7, 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 toxicity to reproduction is covered on the basis of 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 expected and similar hydrolysis products.

Overview of toxicity to reproduction

CAS#	Chemical name	Molecular weight (range)	Toxicity to reproduction
-- (a)	Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters	258.40 – 330.46	WoE: RA: CAS 75782-86-4 RA: CAS 112-53-8 RA: CAS 112-92-5 RA: 111-27-3 RA: CAS 661-19-8 Data waiving
111-27-3	Hexan-1-ol	102.17	Experimental result: NOAEL = 1127 mg/kg bw/d (90 d study)
112-53-8	Dodecan-1-ol	186.34	Experimental result: NOAEL = 2000 mg/kg bw/d (OECD 422)
112-92-5	Octadecan-1-ol	270.50	Experimental result: NOAEL = 2000 mg/kg bw/d (OECD 422)
661-19-8	Docosan-1-ol	326.6	Experimental result: NOAEL = 1000 mg/kg bw/d (OECD 415)

(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

CAS 112-53-8

In a combined repeat dose and reproductive/developmental toxicity screening tests, performed in Wistar rats according to OECD guideline 422 and under GLP conditions, groups of 12 animals per sex and dose were administered doses of 0, 1500, 7500 & 30,000 ppm (approx. 100, 500, 2000 mg/kg bw/day) Dodecan-1-ol (CAS 112-53-8) in the diet (Hansen 1992a). Females were fed up to 54 days (premating, mating and gestation until post natal day 5), and the males for 41-44 days. No mortality occurred in the F0 generation and no clinical signs of toxicity were reported. No differences between treated and controls of either sex in body weight gain. There were no statistically significant effects on pregnancy rate, length of gestation or numbers of corpora lutea, implantations, resorptions or pups at birth. There were no dose related changes in organ weights, including the testes, epididymides and ovaries; in males only there was a reduction in relative and absolute liver weights at the low dose level and a reduction in relative liver weight at mid doses, the top dose was comparable to controls. At gross pathology, there were no changes attributable to exposure to the test compound and there were no treatment related histopathological changes. Based on the absence of any adverse effects observed the NOAEL was set at 2000 mg/kg bw/day (the highest dose tested).

CAS 112-95-5

The developmental toxicity of Octadecan-1-ol (CAS 112-95-5) was investigated in a combined repeat dose and reproductive/developmental toxicity screening test according to OECD guideline 422 in Wistar rats (Hansen, 1992b). Groups of 12 animals per sex and dose received the test substance ad libitum via the diet at dose levels of 0, 1500, 7500 and 30000 ppm, corresponding to approx. 0, 100, 500, 2000 mg/kg bw/day, respectively. Males were treated for 45 days (including a 14-day premating period), whereas females were administered the test substance up to 54 days (including 14 days prior to mating, then throughout mating and gestation until post natal Day 5). No maternal toxicity and mortality were observed and body weights and food consumption were comparable between treated animals and controls. There was no statistically significant difference in pregnancy rates (confirmed using a Chi-squared test) although they were reduced in treated groups they were within the normal historical control range according to the authors. There were no statistically significant dose related changes in organ weights including the testes, epididymides and ovaries. At gross pathology, there were no changes attributable to exposure to the test compound and there were no treatment related histopathological changes. Duration of gestation was comparable in treated and control dams (mean 22 days for all groups) and no clinical biochemical findings, examined in the males only, were considered of biological significance. Haematological examination in the males only showed changes in plasma free cholesterol, triglycerides and glucose although the significance is unclear. The changes were observed at all doses levels but were not dose related and may be related to differences in dietary composition. There was no significant differences in the numbers of implantations between treated and control groups (Mean 13 in controls and low-dose, 15 in mid- and high-dose groups); resorptions mean for controls and low-dose 0, for mid- and high-dose 1; no significant differences between treated and control groups with respect to number of corpora lutea (mean controls 13, low and mid dose 14, high dose 15). Based on the absence of any adverse effects observed the NOAEL was set at 2000 mg/kg bw/day (the highest dose tested).

CAS 661-19-8

A one-generation study was carried out with Docosanol in rats, following a protocol equivalent to OECD guideline 415 and according to GLP. Groups of 22 animals per sex and dose received the test substance daily by gavage at dose levels 0, 10, 100 and 1000 mg/kg bw/day, respectively. Males: were treated from 71 days prior to mating, during mating and until females were sacrificed. The females were administered the substance from 15 days prior to mating, during mating, and up to day 17 of gestation, they were killed on day 20 of gestation. No mortality occurred in females, in males, one death was seen in the top dose group in week 6, but No effects were seen on body weight gain, food consumption and reproductive function (estrous cycle, sperm measures, reprodictive performance, pregnancy rate. There were no effects on organ weights. At gross pathology, there were no changes attributable to exposure to the test compound. The NOAEL for the parental and the F1 generations was 1000 mg/kg bw/day, the highest dose tested (Iglesias, 2002).

CAS 111-27-3

A supporting subchronic repeated dose feeding study reported a lack of effects on the reproductive organs of rats receiving Hexan-1-ol (CAS 111-27-3). The NOAEL of 1127 mg/kg bw/day (highest dose tested) was based on the fact that no adverse effects were noted at any of the dose levels administered during the study (Sasol 1966).

CAS 75782-86-4

In a supporting subacute repeated dose study performed according to OECD guideline 407 and under GLP conditions, the test material was administered by gavage to male rats up to 1000 mg/kg bw/day for 28 days. No effect on the absolute or relative weight of the testis and no abnormalities were evident on microscopic examination of the testes.

CAS 50-21-5

As already discussed in the section repeated dose toxicity, Lactate is an endogenous substance in man, involved in carbohydrate and amino acid metabolism, and a natural component of very many foods. Furthermore, available developmental toxicity studies conducted with Lactic acid did not indicate any adverse effects on fertility at doses not leading to maternal toxicity. Thus, the nature of the compound, being a part of human metabolism, does not make toxicity studies to fertility necessary.

Conclusions for toxicity to reproduction

There are no data available on toxicity to reproduction of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters. Since hydrolysis of the target substance is expected, hazard assessment is conducted by means of read-across from the hydrolysis product Alcohols, C12-13-branched and linear (CAS 75782-86-4) and other structurally similar substances of the breakdown products.

Overall, the available data provide sufficient evidence to conclude that the Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters has no toxic effects to reproduction.

Short description of key information:
Toxicity to reproduction – fertility: WoE: not toxic to reproduction

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue and based on the weight of evidence from all available studies.

Effects on developmental toxicity

Description of key information

Developmental toxicity: WoE: no developmental toxicant

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for grouping of substances and read-across

There are no data available on the toxicity to reproduction of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters. In order to fulfil the standard information requirements set out in Annex IX, 8.7, 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 developmental toxicity is covered on the basis of 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 expected and similar hydrolysis products.

Overview of developmental toxicity

CAS#	Chemical name	Molecular weight (range)	Developmental toxicity
-- (a)	Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters	258.40 – 330.46	WoE: RA: CAS 75782-86-4 RA: CAS 85566-14-9 RA: CAS 112-53-8 RA: CAS 112-92-5 RA: CAS 50-21-5
75782-86-4 (former CAS 67762-41-8) (b)	Alcohols, C12-13-branched and linear	186.34 - 200.37	WoE: no developmental toxicity expected
85566-14-9	Alcohols, C7-11-branched and linear	116.21 - 172.31	Experimental result: NOAEL ≥1440 mg/kg bw/day
112-53-8	Dodecan-1-ol	186.34	Experimental result: NOAEL ≥2000 mg/kg bw/day
112-92-5	Octadecan-1-ol	270.50	Experimental result: NOAEL ≥2000 mg/kg bw/day
50-21-5	2-Hydroxypropanoic acid	90.08	Experimental result: NOEL < 570 mg/kg bw/day

(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

CAS 75782-86-4

As cited in secondary sources, representative data are available for several alcohols, covering the low (C6, C8, C9), intermediate (C10, C12) and high (C18, C22 and higher) carbon chain lengths of this class. For the essentially linear alcohols, the key data are derived from the supporting substances isoamyl alcohol and Alcohols, C7-11-branched and linear (CAS 85566-14-9), consisting of C7, C9 and C11 alcohols (65% linear). The available test data indicate that for both linear and essentially linear alcohols there is no evidence of fetotoxicity in the absence of maternal toxicity and supports the conclusion that C12-13 alcohols are not expected to be developmental toxicants in the absence of maternal toxicity.

CAS 85566-14-9

In a prenatal developmental toxicity study according to OECD guideline 414, the effects of Alcohols, C7-11-branched and linear on female Wistar Chbb/THOM rats were investigated during Days 6 to 15 of gestation (Hellwig and Jackh, 1997). Once daily, the animals (8-10 per dose group) received the test substance in distilled water with Cremophor EL as emulsifier at dose levels 144, 720 or 1440 mg/kg bw/day via oral gavage. A control group received water alone. On Day 20 of gestation, dams were sacrificed and maternal as well as foetal examinations were performed. No maternal mortalities and no clinical signs of toxicity were observed. No changes in body weighs and food consumption between treated and control dams were noted. Furthermore, uterus, placental and foetal weights and the number of corpora lutea, implantation sites and live foetuses per dam and duration of pregnancy were similar between animals of the treatment and control groups. No embryotoxic effects were detected that were attributed to the treatment. Litter size and weights and the numbers of viable were comparable between treatment and control groups. Similar incidences of abnormalities occurred in the treated and control groups, including bilateral renal pelvis, hydroureter, thoracic vertebral body dumbbell shaped, skeletal variations and skeletal retardations. Since no developmental toxicity was noted up to and including the highest dose level, a NOAEL of ≥ 1440 mg/kg bw/day for rats was derived.

CAS 112-53-8

A combined repeat dose and reproductive/developmental toxicity screening test according to OECD guideline 422 was conducted with Dodecan-1-ol in rats (Hansen, 1992). The test substance was administered ad libitum to 12 animals per sex and group at dietary doses of 1500, 7500 and 30000 ppm, corresponding to approx. 100, 500, 2000 mg/kg bw/day, respectively. Males were treated for a period of 41-44 days (including 14 days premating), whereas females were exposed to the test substance up to 54 days (including premating, mating and gestation until post natal Day 5). In dams, no mortalities, no statistically significant effects on body weight and food consumption as well as organ weights (liver, kidneys, and thymus) and pathology were observed between treated and control animals. Furthermore, no statistically significant effects on numbers of corpora lutea, implantations, resorptions or pups at birth and no statistically significant abnormalities after external and head examinations in pups were noted between treatment and control groups. Based on the results of this study, the NOAEL for developmental toxicity in rats treated with Dodecan-1-ol was considered to be ≥ 2000 mg/kg bw/day.

CAS 112-92-5

The developmental toxicity of Octadecan-1-ol was investigated in a combined repeat dose and reproductive/developmental toxicity screening test according to OECD guideline 422 in Wistar rats (Hansen, 1992). Groups of 12 animals per sex and dose received the test substance ad libitum via the diet at dose levels of 1500, 7500 and 30000 ppm, corresponding to approx. 100, 500, 2000 mg/kg bw/day, respectively. Males were treated for 45 days (including a 14-day premating period), whereas females were administered the test substance up to 54 days (including 14 days prior to mating, then throughout mating and gestation until post natal Day 5). No maternal toxicity and mortality were observed and body weights and food consumption were comparable between treated and control dams. Pregnancy rate, duration of gestation, number of implantations as well as number of corpea lutea was not altered in treated dams compared to controls. In offspring, no effects on litter size and weight, sex and sex ratios, and post natal survival until Day 5 of the study were observed. No treatment-related changes in the incidence of external or visceral malformations visible on macroscopic examination were noted. Based on the results of this study, the NOAEL for developmental toxicity in rats treated with Octadecan-1-ol was considered to be ≥ 2000 mg/kg bw/day.

CAS 50-21-5

A developmental toxicity study is available for 2-Hydroxypropanoic acid (Lactic acid), in which 12 gravid Swiss albino CD-1 mice were dosed once daily with 570 mg/kg bw/day by gavage on Days 6-15 of gestation (Andersen, 1998). A control group of 13 females received distilled water. At sacrifice (Day 18 of gestation), no significant difference was observed in body weight gain between treated and control dams, although food consumption was significantly decreased during Days 6-9, 6-12, and 15-18 of gestation as compared to control values. Furthermore, relative liver weight was significantly decreased in treated dams compared to controls. In foetuses, the only observed effect included a statistically significant increase in delayed ossification of the parietal bones, which is generally considered to be a reversible delay in development, and, thus, not of adverse nature. Based on the results of this study, the NOEL for developmental toxicity in rats was < 570 mg/kg bw/day. At this dose level maternal toxicity occured.

Conclusions for developmental toxicity

There are no data available on the developmental toxicity/teratogenicity of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters. Since hydrolysis of the target substance is expected, hazard assessment is conducted by means of read-across from expected hydrolysis products 2-Hydroxypropanoic acid (CAS 50-21-5, Lactic acid) and Alcohols, C12-13-branched and linear (CAS 75782-86-4) and other structurally similar substances of the breakdown products.

Overall, the available data provide sufficient weight of evidence to conclude that the Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters has no toxic effects on intrauterine development.

Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue and based on the weight of evidence from all available studies.

Justification for classification or non-classification

The available data on toxicity to reproduction/developmental toxicity of Propanoic acid, 2-hydroxy-, C12-13-branched-alkyl esters 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.