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

Endpoint summary

Description of key information

RDT oral (OECD 408), rat: NOAEL = 741/855 (m/f) mg/kg bw/day (RA from CAS 61788-89-4), corresponding NAEL = 801/925 - 1587/1831 (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
RDT oral (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

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

741 mg/kg bw/day

Study duration:

subchronic

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.

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 only limited data available on repeated dose toxicity 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 repeated dose toxicity

CAS	Chemical name	Molecular weight [g/mol]	Repeated dose toxicity Oral	Repeated dose toxicity Inhalation	Repeated dose toxicity Dermal
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	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 = 741/855 (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 forFatty 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 repeated dose 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 productsPropylidynemethanol (CAS 77-99-6) and Fatty acids, C18-unsaturated, dimers (CAS 61788-89-4) was applied.

Repeated dose toxicity (oral route)

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 of Propylidynetrimethanol (TMP) (MW 134.18 g/mol) and Fatty 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 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 3642 - 7214 mg/kg bw/day ((610.99/134.18)*800) - ((1209.97/134.18)*800).

 

CAS 61788-89-4

A reliable repeated dose toxicity (90-day) study with Fatty acids, C18-unsaturated, dimers (CAS 61788-89-4) is available and was performed equivalent or similar to OECD TG 408 and in compliance with GLP (Environmental Safety Laboratory, 1993).Three groups of 20 Sprague-Dawley rats of each sex were fed the test material at 0, 0.1, 1 and 5% (w/w) corresponding to 74.1, 740.9, 3591.2 mg/kg bw/day (males) and 90.5, 854.9, 4085.5 mg/kg bw/day (females) in purified diet for 90 consecutive days. The animals were observed for clinical signs up to two times per day. Food and water consumption was determined twice weekly. Body weights were determined weekly. Ophthalmoscopy was carried out before the start of the study and during the last week of the feeding period. Before necropsy, blood samples were taken for clinical pathology determinations. At necropsy, a full range of tissues were taken for histological examination. All tissues from the control and 5% groups were examined. Liver, adrenals, eyes, mesenteric lymph nodes, spleen and thyroids (females) from all groups were also examined. There were no decedents and no treatment-related clinical signs in rats fed the test substance for thirteen weeks. The lower food intake during the first four weeks of the study in rats fed the test material at 5% in diet may reflect an initial reluctance of the rats to eat the diet. Decreases in organ weight and/or relative organ weight of spleen, kidney and liver were observed, mainly after feeding the test material at 1.0% and 5.0%, but bore no relation to any effect which might have been expected on the basis of the histopathology findings. Plasma alkaline phosphatase activity (ALP) was increased in males and females fed the test material at 1.0% or 5.0%. An increase in plasma ALP activity may reflect induction (increased synthesis) in liver cells rather than increased release from damaged cells. Another plasma enzyme derived from the liver in the rat, alanine aminotransferase (ALT) was also increased in male and female rats fed at 5.0%. In addition to increases in plasma ALP level derived from the liver, treatment-related effects were observed on microscopic examination of that organ. Histological examination of liver from animals in the 5.0% treatment group revealed an increase in biliary hyperplasia. Interference in bile flow could be related to the observed increase in ALP, which is a sensitive indicator of cholestasis. Changes in ALP develop before there are any detectable increases in plasma bilirubin levels. It should be noted that while a very small increase in plasma bilirubin was observed in male rats fed the test material at 5.0% or 1.0%, the levels measured were below the sensitivity of the method and must be viewed with caution. Although the bile duct proliferation and sclerosis recorded in the liver may correlate with the increase in ALP, it should be noted only very minor biliary changes were seen in a few female rats. A small reduction in plasma calcium was observed in male and female rats fed the test material at 5.0%. Small reductions in both total serum protein and albumin were also observed in male and female rats in the 5.0% groups. It is possible the calcium and serum protein changes may be connected. However, reduction in plasma calcium was not always accompanied by a parallel reduction in plasma albumin. The changes in plasma calcium and serum proteins are small, probably representing a physiological rather than a pathological response to treatment with the test material. The plasma lipids cholesterol and triglyceride were reduced in male and female rats in the 5.0% and 1.0% treatment groups. It is possible that the test material blocks the absorption of lipid and other nutrients from the gut. Such activity could also explain changes in plasma electrolytes and intermediate metabolites. The reduction in periportal hepatocyte vacuolation seen on histological examination of the liver could correlate with the reduced plasma lipids, indicating some alteration in lipid metabolism, another possible explanation for the plasma lipid, serum protein and calcium changes. The pigment present in the macrophages in the mesenteric lymph nodes and spleen did not stain with Perls' stain for haemosiderin or aldehyde fuchsin for lipofuscin, but did stain with Schmorl's stain for lipofuscin. Lipofuscin is derived from oxidation of unsaturated lipids or lipoproteins. The test material is composed of a mixture of monomers, dimers and trimers of various fatty acids. It is likely that the pigment represents either lipofuscin produced by oxidation of some component of the test material, or that the test material itself stains positively. There was no evidence of any degenerative effect associated with pigmented macrophages. It is probable that they represent a physiological response to dietary administration of lipid materials such as the test material. Accumulations of macrophages in the mesenteric lymph nodes commonly occur as a result of ageing, or following administration of pigmented or lipid substances in the diet. Although the pigment appeared darker in the spleen than in the mesenteric lymph node, this may reflect a difference in density. The pigment was present alongside normal levels of haemosiderin which appeared tinctorially distinct. The coloured nature of the compound is also likely to have been responsible for the alteration in the colour of the caecal contents that was observed at necropsy. Increased cortical vacuolation in the adrenals, coupled with decreased cytoplasmic rarefaction probably indicates altered steroidogenesis. This was not accompanied by any evidence of degenerative change. The significance of the reduced extramedullar haemopoiesis in the adrenals is uncertain, but may possibly correlate with the reduction in neutrophil count in females fed the test material at 5.0% and 1.0%. All of the changes in the adrenal are minor in nature and of limited importance. In summary, based on clinical chemistry parameters and histopathological findings a NOAEL for 1% (w/w) test material in diet can be derived, corresponding to a dose of 741 and 855 mg/kg bw/day for males and females, respectively. The molecular weight ratio of Fatty acids, C18-unsaturated, dimers (MW 564.93 g/mol) and Fatty 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 801 - 1587 mg/kg bw/day ((610.99/564.93)*741) - ((1209.97/564.93)*741) for males and 925 - 1831 mg/kg bw/day ((610.99/564.93)*855) - ((1209.97/564.93)*855) for females, respectively.

Repeated dose toxicity (inhalation route)

There are no data available. Due to the physicochemical properties (low vapour pressure) exposure to Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol via inhalation is considered to be unlikely.

 

Repeated dose toxicity (dermal route)

There are no studies available in which potential toxic effects after long-term dermal exposure have been studied. However, the whole body of evidence on the toxicokinetic behaviour and toxicological activity of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanolindicate that both systemic bioavailability and toxic effects are unlikely to occur upon repeated dermal exposure.

Conclusion for repeated dose toxicity

No studies investigating repeated dose toxicity 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). 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 possible to a limited extend, it will most likely be the hydrolysis products that are absorbed, thus a worst case approach considering the repeated dose toxicity of the potential hydrolysis products was performed. None of the potential hydrolysis products Propylidynetrimethanol (CAS 77-99-6) and Fatty acids, C18-unsaturated, dimers (CAS 61788-89-4) poses a risk for human health effects. Since no significant 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. For Fatty acids, C18-unsaturated, dimers a NOAEL of 741 and 855 mg/kg bw/day for male and female Sprague-Dawley rats, respectively, was derived. The lowest long-term NOAEL of 741 mg/kg bw/day for Fatty acids, C18-unsaturated, dimers is selected for hazard assessment of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol. In order to account for differences in molecular weight, full enzymatic hydrolysis of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol into Fatty acids, C18-unsaturated, dimers and Propylidynetrimethanol is assumed in a worst case approach. Thus, a resulting estimated long-term NOAEL ranging from 801 - 1587 mg/kg bw/day was established for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol. However, even the lowest long term NOAEL used for hazard assessment represents an overestimation, as the registered substance is not anticipated to be absorbed and hydrolysed in any significant amounts. Having regard to the fact that the NOAEL was near to the conventional limit dose of 1000 mg/kg bw/day, no adverse effects for humans are expected and thus no DNEL was derived.

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 repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.