Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynetrimethanol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422), rat: NOAEL ≥800 mg/kg bw/day (RA from CAS 77-99-6), corresponding NAEL = 3643 - 7214 mg/kg bw/day for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol Waiving – Extended one-generation reproductive toxicity study

Reproduction/Developmental Toxicity Screening Test (OECD 421), rat: NOAEL (parental/developmental) ≥1450/1692 (m/f) mg/kg bw/day (RA from CAS 61788-89-4), corresponding NAEL = 1568/1830 - 3106/3624 (m/f) mg/kg bw/day for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on the structural similarity between the source and target substances, as the source substances comprise hydrolysis products (CAS 77-99-6 and CAS 61788-89-4) of the target substance. Refer to endpoint discussion for further details. 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.

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 only limited data available on toxicity to reproduction of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 162353-70-0). In order to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was 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 substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of toxicity to reproduction

CAS	Chemical name	Molecular weight [g/mol]	Toxicity to reproduction	Developmental toxicity/teratogenicity
162353-70-0(a)	Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol	610.99 - 1209.97	RA: CAS 77-99-6 RA: CAS 61788-89-4	Data waiving
77-99-6 (b)	Propylidynemethanol	134.18	Experimental result: NOAEL≥800 mg/kg bw/day (rat)	--
61788-89-4 (b)	Fatty acids, C18-unsaturated, dimers	564.93	Experimental result: NOAEL (P) ≥1450/1692 (m/f) mg/kg bw/day; NOAEL (developmental toxicity) ≥1692 (m/f) mg/kg bw/day (rat)	--

(a) The substance subject to registration 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 “--“.

The above mentioned substances are considered to be the possible hydrolysis products of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 162353-70-0). The available endpoint information is used to predict the same endpoints for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 162353-70-0). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

No data on reproductive toxicity are available with Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 162353-70-0). Therefore, read across from the possible hydrolysis products Propylidynemethanol (CAS 77-99-6) and Fatty acids, C18-unsaturated, dimers (CAS 61788-89-4) was applied.

Toxicity to reproduction

CAS 77-99-6

A reliable combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with Propylidynetrimethanol (TMP, CAS 77-99-6) is available and was performed according to OECD TG 422 (MHLW, 1994). Groups of 12 Slc:SD rats of each sex were administered the test material at doses of 12.5, 50, 200 and 800 mg/kg bw/day or vehicle alone (distilled water) once daily for 45 consecutive (2 weeks prior to mating, throughout mating and until sacrifice on day 4 of lactation) days via oral gavage. Animals were observed for mortalities and clinical signs at least once a day. Body weights and food consumption were recorded.Haematology parameters such as hemoglobin (Hb), hematocrit (Hct), red blood cell count (RBC), blood clotting and different leucocyte counts were evaluated. Clinical chemistry included glucose, total bilirubin, blood urea nitrogen, creatinine, total protein, albumin, ratio albumin/globulin, potassium, chloride, calcium, inorganic phosphorus, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and gamma-glutamyl transferase (gamma-GTP). Organ weights of thymus, liver, kidneys, testes, epididymides and ovaries were determined. Gross pathology examination included all major organs and tissues. Histopathology was performed in animals of the control and high dose group including heart, spleen, lung, kidney, adrenal gland, thymus and liver. No mortality and no clinical signs were observed during the study period. During the 14-day pre-mating period, the absolute body weights in males and the body weight gain in females was statistically significantly decreased at 800 mg/kg bw/day compared to the controls. However, no effects on the body weights were observed in treated animals during the remainder of the study. No effect on food consumption was observed in male and females of any treatment groups compared to controls. Clinical chemistry analysis in males revealed a slight, but statistically significant increase in total bilirubin and chloride at 800 mg/kg bw/day compared to controls. At 800 and 200 mg/kg bw/day, a slight increase (stat. significant) in total protein, albumin, and albumin/globulin ratio was observed in males compared to the control group. The values of blood urea nitrogen were statistically significantly increased in males of the 50, 200 and 800 mg/kg bw/day dose groups. Haematological examination revealed a statistically significant decrease in the values of mean corpuscular haemoglobin (MCH) and the mean corpuscular haemoglobin concentration (MCHC) at all dose levels in males compared to the control group. In addition, haemoglobin concentration was statistically significantly reduced at 800 mg/kg bw/day. Due to the absence of any correlating effects, changes in clinical chemistry and haematological parameters were considered to be non-adverse. All other significant changes in clinical chemistry and haematology parameters were not dose-related and thus of no toxicological relevance. A significant increase in absolute and relative liver weight in males was observed at 800 mg/kg bw/day. In females of the same dose group, only a slight and not statistically significant increase in absolute and relative liver weight was noted. At necropsy, enlargement of the liver was found in 3/10 males, which correlated with the observed increase in liver weight in this gender. In females, the increase in the incidence of macroscopic findings in the lungs (red patch/zone) at all dose levels was not considered to be of toxicological relevance, since they were not unequivocally attributable to the test substance administration due to a lacking dose-response relationship. Histopathological examination revealed basophilic alteration of the renal tubular epithelial cells which was observed in 1/11 females receiving 50 mg/kg bw/day, in 2/10 females receiving 200 mg/kg bw/day and in 5/10 females (stat. significant) receiving 800 mg/kg bw/day. However, these changes were not unequivocally attributable to the test substance administration, because of their limited distribution and limited degree, and because similar lesions were observed in male rats of all groups including the controls. Although necropsy revealed liver enlargement in 3/10 male rats receiving 800 mg/kg bw/day, histopathological examination did not show any definite morphological lesions in the liver. All other histopathological alterations in treated animals were also observed to a similar degree in the corresponding control animals, and were thus of no toxicological significance. Since no adverse effects were observed up to and including the highest dose level, a NOAEL of 800 mg/kg bw/day was derived for Propylidynetrimethanol (TMP) in male and female Slc:SD rats.The molecular weight ratio ofPropylidynetrimethanol (TMP)(MW 134.18 g/mol) andFatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol(MW 610.99 - 1209.97 g/mol) is ~4.55 (610.99/134.18) and ~9.02 (1209.97/134.18). Thus, based on this molecular ratio factor the NAEL forFatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol(CAS 167353-70-0) was calculated to be 3643 - 7214 mg/kg bw/day ((610.99/134.18)*800) - ((1209.97/134.18)*800).

 

CAS 61788-89-4

A reliable reproduction/developmental toxicity screening test performed according to OECD TG 421 and in compliance with GLP with Fatty acids, C18-unsaturated, dimers (CAS 61788-89-4) is available (Pine Chemicals Association, 2004). Groups of 10 Sprague-Dawley rats of each sex per dose were administered doses of 200, 2000 and 20000 ppm with the diet corresponding to a test substance intake of 14.5, 147 and 1450 mg/kg bw/day and 16.5, 166 and 1692 mg/kg bw/day for males and females, respectively. Males were treated for at least 4 weeks, starting from 2 weeks prior to mating; females were treated for 2 weeks prior to mating, during mating and gestation until at least day 4 of lactation. The animals were monitored for clinical signs, body weight, food consumption, mating and litter performance. All animals were submitted to necropsy, which included weighing of testes and epididymides. Histopathology was conducted on male and female reproductive organs of the control and high dose group. The observed effects were limited to the 20000 ppm males and included slightly decreased body weight gain during the first week of treatment and an increased incidence of piloerection. However, weight gain for males at 20000 ppm was essentially similar to control animals for the rest of the study on weeks 2-4 and the incidence of piloerection lacked any dose-relationship. There were no effects on testes, epididymides and ovaries and on reproductive performance between control and test animals. The fertility index was 100% for males and females in all dose groups. A NOAEL (reproductive toxicity/fertility) of ≥1450 mg/kg bw/day and ≥1692 mg/kg bw/day for males and females, respectively, was determined based on no toxicologically significant effects at the highest dose tested. Moreover, a NOAEL (developmental toxicity) of ≥1692 mg/kg bw/day for both sexes was determined.The molecular weight ratio of Fatty acids, C18-unsaturated, dimers (MW 564.93 g/mol) andFatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol(MW 610.99 - 1209.97 g/mol) is ~1.08 (610.99/564.93) and ~2.14 (1209.97/564.93). Thus, based on this molecular ratio factor the NAEL for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 167353-70-0) was calculated to be 1568 - 3106 mg/kg bw/day ((610.99/564.93)*1450) - ((1209.97/564.93)*1450) for males and 1830 - 3624 mg/kg bw/day ((610.99/564.93)*1692) - ((1209.97/564.93)*1692) for females, respectively.

 

Conclusion for toxicity to reproduction (fertility)

No studies on toxicity to reproduction (fertility) are available for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 162353-70-0). However, oral, dermal or inhalative absorption of the registered substance is deemed unlikely due to its very high MW and physico-chemical properties. As hydrolysis is deemed possible to a limited extend, it will most likely be the hydrolysis products that are absorbed, thus a worst case approach considering the reproduction toxicity of the potential hydrolysis products was performed. Hazard assessment is conducted by means of read-across from the available data on the hydrolysis products Propylidynetrimethanol (CAS 77-99-6) and Fatty acids, C18 -unsaturated, dimers (CAS 61788 -89 -4), which did not show any adverse effects on reproductive parameters and post-natal offspring development up to and including the highest dose tested in a combined repeated dose and reproductive/developmental toxicity screening test in rats. In summary, the available data provide sufficient evidence to conclude that the substance Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 167353-70-0) is not toxic to reproduction.

 

Effects on fertility

A waiver for the requirement to perform an extended one-generation reproduction toxicity study (standard configuration or with additional modules) was included, as the study is not scientifically necessary and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

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

Conclusions for toxicity to reproduction (development)

There are no data available for the prenatal developmental toxicity of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 167353-70-0). As oral, dermal or inhalative absorption of the registered substance is deemed unlikely due to its very high MW and physico-chemical properties and hydrolysis is not anticipated to occur in significant amounts, a very low bioavailability in humans is anticipated for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 167353-70-0) and its hydrolysis products after any route of exposure. However, data from reproduction/developmental screening tests with the hydrolysis products Propylidynetrimethanol (CAS 77-99-6) and Fatty acids, C18-unsatd., dimers (CAS 61788-89-4) do not indicate any adverse effects on intrauterine development up to the highest dose tested (NOAEL (developmental toxicity) ≥800 mg/kg bw/day and NOAEL (developmental toxicity) ≥1692 mg/kg bw/day, respectively). Furthermore, all available data on Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 167353-70-0) and structurally related substances show that the substance is of low acute toxicity after oral exposure. In addition, data on the oral repeated dose toxicity of the hydrolysis products Fatty acids, C18-unsatd., dimers (CAS 61788-89-4) and Propylidynetrimethanol (CAS 77-99-6) demonstrate no adverse systemic effects after oral exposure. Thus, based on the physicochemical (high molecular weight, low water solubility and high lipophilicity) and toxicological properties (low acute and repeated systemic toxicity), there is sufficient weight of evidence provided leading to the assumption/conclusion that the substance is not toxic to reproduction. Therefore, further testing on vertebrate animals for (pre-natal) development shall be omitted.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 162353-70-0), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the analogue read-across approach, the available data on toxicity to reproduction do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.