Oleic acid, monoester with oxybis(propanediol)

Endpoint summary

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f): >1000 mg/kg bw/day (OECD 407 and 408, analogue approach)

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) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details). The selected studies are 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 for the repeated dose toxicity of Oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6). In order to fulfil the standard information requirements set out in Annex IX, 8.6.2, 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, oral

CAS No.	NO(A)EL [mg/kg bw/day]
49553-76-6 (a) Target substance	RA: deca-glycerol deca-oleate RA: CAS 111-03-5 RA: CAS 24800-44-0 RA : CAS 25265-71-8
111-03-5 (b)	1000 (m, f)
Decaglycerol decaoleate	10 % (m, f) (27780 (m) and 28985 mg/kg bw/day (f))
24800-44-0	200 (m, f)
25265-71-8	1450 (m) and 2860 (f) (14-day study) 460 (m) and 425 (f) (90-day study)  115 (m) and 530 (f) (2-year study)

(a) Substances subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

 (b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6).

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

 

Discussion

Since no studies investigating the repeated dose toxicity, oral are available Oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6), in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from the structurally related analogue substances 2,3-dihydroxypropyl oleate (CAS# 111-03-5), decaglycerol decaoleate and [(methylethylene)bis(oxy)]dipropanol (CAS# 24800-44-0) and oxydipropanol (CAS# 25265-71-8).

 

CAS 111-03-5

2,3-dihydroxypropyl oleate (CAS# 111-03-5) was tested for subacute oral toxicity in a screening study according to OECD Guideline 422 under GLP conditions (Yamaguchi, 2005).

Prior to the main study, two dose range finding studies were performed. Based on the results of the preliminary studies, 1000 mg/kg bw/day was selected as the highest dose level for the main study. Groups of 12 Sprague-Dawley rats per sex were given the test substance by gavage at dose levels of 100, 300 and 1000 mg/kg bw/day including 5 males of the control and high-dose groups which were allowed 14 days of recovery. Additionally, 5 females were added to a satellite control and high-dose group (recovery group). A concurrent negative control group receiving the vehicle corn oil only was included in the testing as well.

Male rats were administered with test substance for 42 days (14 days before mating and 28 days thereafter). Female rats were treated with the test item for 42-52 days (from 14 days before mating to Day 4 of lactation).

No clinical signs or mortality occurred in relation to the test substance. No changes in body weight and weight gain were observed during the treatment period. In recovery males of the high-dose group, a significant increase in body weight was noted during recovery. This increase was considered to be of no toxicological relevance since a tendency of the control animals to lose body weight was observed. No toxicological relevant differences in food consumption were observed during the administration period in the test groups. No changes in the haematological parameters were noted which were considered to be of toxicological relevance. Observations of clinical chemistry showed a significant decrease in inorganic phosphate in females of the low- and high-dose group. However, this change was not regarded as treatement-related, since no dose-relationship was observed and most of the individual data were within the reference ranges. No significant changes in urine parameters were found during the administration and recovery period. No abnormalities were observed for the tested neurobehavioural parameters during the administration period. In low-dose males, a significant decrease in absolute weight of seminal vesicles and in the low-dose female group a significant decrease in the relative weight of spleen was observed. These changes were considered not to be treatment-related as no corresponding findings were apparent in the histopathological examination and no dose-relationship was observed. Moreover, gross pathology and histopathology showed no substance-related changes in any animal. Furthermore, no differences were found regarding spermatogenic cycle and no abnormalities were found in the uterus and ovaries in the non-pregnant females and the unsuccessful copulation females of the control and high-dose groups, respectively.

Based on the lack of toxicological relevant effects, a NOAEL of 1000 mg/kg bw/day for males and females was identified in this study.

Decaglycerol decaoleate

A 90-day oral feeding study (King, 1971) was performed with the structurally related analogue substance decaglycerol decaoleate according a method equivalent to OECD Guideline 408. Test substance was administered via diet to 20 Sprague-Dawley rats per dose group at specified dose levels (2.5, 5, and 10% corresponding to approx. 6944, 13890 and 27780 mg/kg bw/day for males and 7246, 14493 and 28985 mg/kg bw/day for females ). Soyabean oil was used as the control fat. All animals appeared to be in excellent health during the duration of the study, and no adverse effects were observed with regard to survival, growth, absolute and relative organ weights, and histopathology. With regard to food consumption, it was found thatmales fed 10% PGE consumed more food and had a poorer feed efficiency value than male control animals. However despite decreased feed efficiency those animals consumed enough food to maintain normal growth.

Concerning hematology and clinical chemistry the values fell within normal ranges, and there were no indications of any blood disorder. Some values were significantly different from SBO controls, however differences were usually quite small and in no case established any trend or pattern indicative of a dose-related effect. Urine collected from each animal appeared to be normal in regard to color clarity, sediment, specific gravity and pH, total nitrogen excretion during the third and ninth week by females fed PGE at the 10% level was significantly greater than the control value and appears to be related to dietary treatment, the highest nitrogen excretion (male and female) was from the animals fed the highest dose PGE, the reason for this difference is not understood but it should be recognized that other parameters, including three derived from histologic examination of the urinary tract were normal

The only gross observation of significance was what appeared to be very mild, chronic murine pneumonia in 18% of the animals, but the affected animals were scattered throughout all the groups and the effect was not related to the feeding of PGE.

The percentage of dietary fatty acids absorbed decreased as the level of PGE in the diet was increased. In all cases fat absorption by animals fed PGE at the 5 and 10% dietary levels was significantly less than corresponding SBO control values. Absorption in animals fed the lowest dose was also less but not significantly different. Values from the group fed oleic acid and glycerol fell between those of the 5% PGE and SBO control.

Gas-liquid Chromatography analyses of fetal fatty acids showed that excretion of oleic acid increased in a dose-related fashion: the oleic acid content of fecal fatty acids from animals fed the SBO control diet was 23% compared to 32, 41 and 51% when PGE was fed at levels of 2.5, 5, and 10%. The increased excretion of fatty acids in general and oleic acid in particular shows that absorption of dietary PGE was not complete. The fecal oleic acid may have resulted from the excretion of intact PGE or from hydrolyzed or partially hydrolyzed but unabsorbed material. The oleic acid content of fecal fatty acids from animals fed free oleic and glycerol was 41% corresponding exactly to the 5% PGE group.

 

The 90-day oral NOAEL was determined to be 10% test substance, which refers to approximately 27780 mg/kg bw/day for males and 28985 mg/kg bw/day for females when administered by daily feeding to rats for 90 days.

CAS 24800-44-0

 

[Methylethylene)bis(oxy)]dipropanol (CAS# 24800-44-0) was tested for oral toxicity in rats in an OECD 422 combined repeated dose and reproductive toxicity screening test under GLP conditions (MHW, 1993). Groups of 12 male and female rats per dose were administered with 8, 40, 200 and 1000 mg/kg/day via gavage. The animals were mated. The test material was administered to females from 14 days before mating until day 3 post-partum and to males for 14 days prior mating and 2 weeks days thereafter. The test substance showed no general toxicological effects in either sex. No mortality was observed in any of the groups. However increased in salivation was observed in males treated with 1000 mg/kg bw/day. No treatment related effects were observed in terms of body weights, food consumption, hematology, blood chemistry. With regard to organ weights males belonging to 1000 mg/kg bw/day showed significant higher absolute and relative liver weights and increase relative kidney weights. At the same dose levels, females showed higher relative liver weight. Therefore, under the experimental conditions of the study the NOAEL for [(methylethylene)bis(oxy)]dipropanol for repeated dose toxicity after oral administration resulted to be 200 mg/kg bw/day in both sexes.

 

CAS 25265-71-8

Studies with the structurally related substance to the predicted metabolite oxydipropanol (CAS# 25265-71-8), are available. In a 14-day subacute, a 90-day subchronic and a 2-year chronic drinking water studies in rats, the repeated dose toxicity of oxydipropanol was assessed (NTP, 2004).

In the 14-day subacute study 5000, 10000, 20000, 40000 and 80000 ppm (corresponding to 635, 1450, 2650, 5850 and 13000 mg/kg bw/day in males and 850, 1670, 2860, 5420 and 11100 mg/kg bw/day in females) of test substance were administered in groups of 5 Fischer 344 rats in the drinking water.

During the study period no mortality occurred and clinical signs (such as hypoactivity, piloerection and perinasal staining) were only evident in high-dose males. The final mean body weights and body weight gains of animals belonging to the mid- and high-dose group were significantly lower in comparison to control animals. No treatment-related differences in water consumption were noted. Kidney weights of males were significantly increased from the 5850 mg/kg bw/day group and higher and liver weights were increased from the 2650 mg/kg bw/day group and higher. Likewise, females exposed to dose levels of 5420 mg/kg bw/day showed increased relative kidney weights and increased absolute and relative higher liver weights. Microscopically minimal focal fatty change was observed in livers of some males exposed to 2650 mg/kg bw/day or greater. 

Based on the effects on liver and kidney weights in females and males and on histopathology results of liver and kidney in males, the NOAEL resulted to be of 2860 mg/kg bw/day for females and 1450 mg/kg bw/day for males.

In a 90 day study conducted with a method similar to OECD Guideline 408 and GLP compliant, groups of 10 animals per sex were dosed with 5000, 10000, 20000, 40000 and 80000 ppm (corresponding to 425, 890, 1840, 3890 and 12800 mg/kg bw/day in males and 460, 920, 1690, 3340 and 8950 mg/kg bw/day in females) oxydipropanol administered in the drinking water.

No mortality occurred during the study period. In the male high-dose group, clinical signs as hypoactivity and poor hair coats were observed. The mean body weights of all exposed groups of males and 1690 mg/kg females and higher were significantly lower than those of the control groups. In the high-dose groups water consumption increased during the second week of the study and was greater than that of the controls for the remainder of the study. In males dosed with 890 mg/kg bw/day and higher, the treatment induced a minimal erythron decrease at Week 14. Furthermore, an increase in serum alanine aminotransferase and sorbitol dehydrogenase activities and/or total bile acid concentrations was observed in males (1840 mg/kg bw/day) and females (from 1690 mg/kg bw/day) suggesting a hepatic effect in males and females.

Liver weights of rats receiving 890 and 920 mg/kg bw/day and kidney weights of rats receiving 3890 and 3340 mg/kg bw/day and higher were greater when compared to controls. Histopathological examinations showed that the incidences of liver and kidney lesions were significantly increased in males dosed with 1840 mg/kg bw/day group and higher and in high-dose females. Focal olfactory epithelial degeneration was present in all high-dose rats. Male rats in the high-dose group had small testes, preputial glands, seminal vesicles, and prostate glands. The left testis, cauda epididymis, and epididymis weights of the high-dose males were significantly decreased. The incidences of testicular atrophy, epididymal hypospermia, preputial gland atrophy, and seminal vesicle depletion were generally increased in the high-dose group. However, the effects in the genital system of males occurred only in the high-dose group (dosed with 12800 mg/kg bw/day). For these animals a final mean body weight of 53% when compared to controls was observed.

Based on the effects on organ weights of liver and kidney in females and males, a NOAEL of 460 mg/kg bw/day and a NOAEL of 425 mg/kg bw/day were identified for females and male animals respectively.

In the chronic study, groups of 50 animals per sex were dosed with 2500, 10000 and 40000 ppm (corresponding to 115, 470 and 3040 mg/kg bw/day in males and 140, 530 and 2330 mg/kg bw/day in females) oxydipropanol in drinking water for 105 weeks.

Survival of the high-dose males was significantly reduced when compared to controls group. However, the mortality was mainly due to chronic progressive nephropathy and subsequent renal insufficiency. Mean body weights of the high-dose groups decreased in comparison to the respective control groups during the study period. In high-dose males water consumption increased from week 53 on. The higher average water consumption in comparison to the control group implies renal insufficiency. The histopathological examination confirmed the renal insufficiency: the incidences of nephropathy were significantly increased in 470 (50/50) and 3040 (48/48) mg/kg bw/day males, and the severities were greater than that in the controls. Increased incidences of focal histiocytic (470 mg/kg (46/49), 3040 mg/kg bw/day (48/48)) and focal granulomatous inflammation of the liver in males (470 mg/kg bw/day (42/49), 3040 mg/kg bw/day (27/48)), bile duct hyperplasia of the liver in males (470 mg/kg bw day (43/49), 3040 mg/kg bw/day(44/48)) and females (530 mg/kg bw/day(7/50), 2330 mg/kg bw/day(18/49)), olfactory epithelium degeneration of the nose in males (3040 mg/kg bw/day(7/48))and females (2330 mg/kg bw/day(9/49)), and olfactory epithelium atrophy (470 mg/kg bw/day(3/50), 3040 mg/kg bw/day(34/49)) and thrombosis of the nose in males (470 mg/kg bw/day(4/50), 3040 mg/kg bw/day(9/49)) were considered related to dipropylene glycol exposure. The incidence of minimal to mild suppurative inflammation of the salivary gland was significantly increased in 3040 mg/kg bw/day males (3040 mg/kg (22/50)). There was no evidence of carcinogenic activity of dipropylene glycol in male and female rats.

Based on the overall effects, a NOAEL of 530 mg/kg bw/day for female rats and a NOAEL of 115 mg/kg bw/day for male rats was identified in this study.

There is no data available on the repeated dose toxicity after dermal application and inhalation of the category members.

 

Conclusions

In conclusion, the overall weight of evidence from the available data on repeated dose toxicity via the oral route of the surrogate and structurally related substances showed no adverse effects in animals treated orally with doses from 100 up to 28,985 mg/kg bw/day. Exposure with the surrogate Oxydipropanol which is a structurally related substance of the predicted metabolite Oxybis(propanediol) did increase the rate and severity of kidney nephropathy and inflammation of the liver and salivary gland in male rats and some atrophy of the epithelial tissue of the nose in male and female rats. However these effects are not considered to be adverse to human health.

The results of the intact fatty acid esters which are structurally closely related to the source substance indicate a very low evidence of toxicity after repeated oral exposure. Thus, for hazard assessment, read-across was based on data from the intact ester 2,3-dihydroxypropyl oleate and decaglycerol decaoleate were taken in consideration following an analogue approach. Therefore, an oral NOAEL > 1000 mg/kg bw/day is considered for oleic acid, monoester with oxybis(propanediol).

Justification for classification or non-classification

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from structural analogues. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from structurally similar substances, the available data on oral repeated dose toxicity 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.