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Administrative data

Description of key information

Acute toxicity: Oral LD50 (rat, m/f): > 2000 mg/kg bw (OECD 401, GLP)

Acute toxicity: Dermal LD50 (rat, m/f): > 2000 mg/kg bw (OECD 402, GLP, category approach)

Acute toxicity: Inhalation LC50 (rat, m/f): > 2.916 mg/L air (OECD 403, category approach)

 

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

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).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

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).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

 

Acute oral toxicity

CAS 627-83-8

The acute toxicity via the oral route of ethylene distearate has been investigated in rats and mice in several studies (CAS 627-83-8).

A study for acute oral toxicity of ethylene distearate was performed in rats in accordance with OECD guideline 401 (Wnorowski, 1991). A group of 10 Wistar rats (5 males and 5 females) was treated with the limit dose of 5000 mg/kg bw of the test substance in carboxymethyl cellulose by gavage. The observation period following administration was 14 days. During the study period, no mortality and no clinical signs of toxicity were observed in any animal. All test animals showed normal body weight gain. Therefore, the oral LD50 in male and female rats was greater than 5000 mg/kg bw.

Further studies in which the acute oral toxicity of ethylene distearate was studied in rats and mice similar to OECD guideline 401 are available. The test material was administered by gavage at doses of 5000 or 2000 mg/kg bw (Wnorowski, 1991; Bouffechoux, 1995). No mortalities were observed and no abnormalities in body weight were recorded during the 14-day observation period in the studies. No signs of toxicity were observed in the studies by Bouffechoux and Wnorowski (1995, 1991).

Furthermore, four independent acute oral toxicity studies in doses up to 16000 mg/kg bw in rats with glycol distearate are reported (Elder, 1982). Doses above 13000 mg/kg bw were noted to produce diarrhoea, wet oily coats and nasal haemorrhage being reversible within 10 days. In one study, at gross necropsy the stomach contained residues which appeared to be the test material.

In summary, the oral LD50 of ethylene distearate is greater than 5000 mg/kg bw.

CAS 68583-51-7

Several studies investigating the acute toxicity via the oral route of Decanoic acid mixed diesters with octanoic acid and propylene glycol are available (CAS 68583-51-7).

A study for acute oral toxicity of Decanoic acid, mixed diesters with octanoic acid and propylene glycol was performed in rats in accordance with EU Method B.1 under GLP conditions (Potokar, 1988). A group of 10 Wistar rats (5 males and 5 females) was dosed with 2000 mg/kg bw of the test material in peanut oil by gavage. The animals were observed for a period of 14 days following administration. During the study period, no mortality and no clinical signs of toxicity occurred in any animal. No effect on body weight was noted. During necropsy, in 1/5 males a tightly filled urinary bladder and in 1/5 females a mild hydrometra was observed. These findings were not considered to be substance-related. Therefore, under the conditions of this study, the oral LD50 in male and female rats was greater than 2000 mg/kg bw.

Further studies are available, in which the acute oral toxicity of Decanoic acid, mixed diesters with octanoic acid and propylene glycol was studied in rats and mice according to OECD guideline 401.

In each case, the test material was administered by gavage at a dose of 5000 mg/kg bw or 5 mL/kg bw (Blackwell, 1989; Blackwell, 1988; Consultox Laboratories Ltd., 1972; Masson, 1985). No mortalities were observed during the 14-day study periods. No substance related signs of toxicity were observed in the studies. Moreover, no abnormalities in body weight (gain) were observed during the observation period and macroscopic examinations at termination revealed no treatment-related changes (Blackwell, 1989; Blackwell, 1988).

In summary, the oral LD50 of Decanoic acid mixed diesters with octanoic acid and propylene glycol is greater than 2000 mg/kg bw.

CAS 84988-75-0

No studies are available investigating the acute oral toxicity of Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol. In order to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006 read-across from the structurally related category members ethylene distearate (CAS 627-83-8), Decanoic acid, mixed diesters with octanoic acid and propylene glycol; CAS 68583-51-7) and Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) was conducted.

In addition to the already discussed studies from the category members ethylene distearate, Decanoic acid, mixed diesters with octanoic acid and propylene glycol (described under the respective CAS numbers), an additional study evaluating the acute oral toxicity of Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) is available (Potokar, 1989). The study was performed equivalent to OECD guideline 401 under GLP conditions in a group of 10 Wistar rats (5 males and 5 female), treated with the limit dose 2000 mg/kg bw of the test substance in peanut oil by gavage. No mortality occurred and no clinical signs of toxicity were observed up to the end of the 14-day observation period in male animals. In one female a slightly coloured red nose was observed 4-24 h after treatment. No further clinical signs were observed. No effect on body weight was noted and pathology of male animals revealed no substance-related findings. In one female hydrometra was observed but was considered to be not substance-related.

Therefore, under the conditions of this study, the oral LD50 in male and female rats was greater than 2000 mg/kg bw.

In summary, based on the available data on acute oral toxicity of the category members, the oral LD50 of Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol is considered to be greater than 2000 mg/kg bw.

CAS 624-03-3

No studies are available investigating the acute oral toxicity of ethane-1,2-diyl palmitate. In order to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006 read-across from the structurally related category members ethylene distearate (CAS 627-83-8) and Decanoic acid, mixed diesters with octanoic acid and propylene glycol; CAS 68583-51-7) was conducted.

The studies from the category members ethylene distearate and Decanoic acid, mixed diesters with octanoic acid and propylene glycol are already described under the respective CAS numbers.

Based on the available data on acute oral toxicity of the category members the oral LD50 of ethane-1,2-diyl palmitate is considered to be greater than 2000 mg/kg bw.

Acute inhalation toxicity

CAS 627-83-8, CAS 68583-51-7, CAS 84988-75-0 and CAS 624-03-3

For acute inhalation toxicity, two studies are available within the Glycol ester category and were considered for assessment of all category members by read-across and a weight of evidence approach. The acute inhalation toxicity of Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) was evaluated in two studies similar to OECD guideline 403 in a limit test (Re, 1978 a,b). A group of 10 male Sprague-Dawley rats and a group of 10 male and female guinea pigs and 3 control animals, respectively, were exposed whole body to 200 ppm (equivalent to 2.916 mg/L air) for 6 h. The animals were observed for a period of 7 days following administration.

No mortality occurred and no clinical signs of toxicity were apparent during the study period in any animal. Necropsy revealed no substance-related findings in both studies.

Therefore, the LC50 for male rats and male and female guinea pigs was greater than 200 ppm (2.916 mg/L).

Acute dermal toxicity

CAS 627-83-8, CAS 68583-51-7, CAS 84988-75-0 and CAS 624-03-3

Data from the category members Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0), Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8) and Octanoic acid ester with 1,2-propanediol, mono- and di (CAS 31565-12-5) investigating the acute toxicity via the dermal route are available and were considered for assessment of all category members by read-across and weight of evidence approach.

The acute dermal toxicity of Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol, Butylene glycol dicaprylate / dicaprate and Octanoic acid ester with 1,2-propanediol, mono- and di were evaluated in rats in accordance with OECD guideline 402 under GLP conditions (Potokar, 1989; Mürmann, 1992a,b).

Groups of 10 rats (5 males and 5 females) were treated with the undiluted test substance at the limit dose of 2000 mg/kg bw under occlusive or semiocclusive conditions for 24 h. The animals were observed for a period of 14 days following administration. During the study period, no mortality and no clinical signs of toxicity occurred in any animal. Furthermore, no effects on body weight were noted.

No substance-related findings during necropsy were observed in any animal (Mürmann, 1992a,b). In 3 animals, scaling was observed after 48 h, being no longer apparent at the 72 h observation time point (Mürmann, 1992b).

The results of the three studies of the category substances consistently showed no effects at the limit dose 2000 mg/kg bw. Therefore, the dermal LD50 is considered to be greater than 2000 mg/kg bw.

Conclusion for acute toxicity

In summary, 14 studies are available studying the acute oral toxicity of Glycol Ester category members resulting in oral LD50 values greater than 2000 mg/kg bw. For acute inhalation toxicity, two studies are available within the Glycol Ester category. From these studies a LC50 value for male rats and male and female guinea pigs of greater than the limit dose of 200 ppm (2.916 mg/L) was obtained. Acute dermal toxicity data from three category members consistently showed no effects at the limit dose 2000 mg/kg bw.

Thus, the available data indicate a very low level of acute toxicity for the category members and thus no hazard for acute oral, inhalative and dermal toxicity was identified.

 

References

Agency for Toxic Substances and Disease Registry (ATSDR) (1997): Toxicological Profile for Propylene Glycol. US Department of Health and Human Services. Atlanta, US.

Agency for Toxic Substances and Disease Registry (ATSDR) (2010): Toxicological Profile for Ethylene Glycol. US Department of Health and Human Services. Atlanta, US.

Gubicza, L., Kabiri-Badr, A., Keoves, E., Belafi-Bako, K. (2000): Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

Heymann, E. (1980): Carboxylesterases and amidases. In: Jakoby, W.B., Bend, J.R. & Caldwell, J., eds., Enzymatic Basis of Detoxication, 2nd Ed., New York: Academic Press, pp. 291-323.Gubicza, L. et al. (2000). Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

International Programme on Chemical Safety (IPCS) (2001): Ethylene Glycol. Poisons Information Monograph. PIM 227.

Lilja, J. et al. (2005). Esterification of propanoic acid with ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst. Chemical Engineering Journal, 115(1-2): 1-12.

Liu, Y. et al. (2006). A comparison of the esterification of acetic acid with methanol using heterogeneous versus homogeneous acid catalysis. Journal of Catalysis 242: 278-286.

Miller, O.N., Bazzano, G. (1965): Propanediol metabolism and its relation to lactic acid -metabolism. Annals of the New York Academy of Sciences 119, 957-973.

Radzi, S.M. et al. (2005). High performance enzymatic synthesis of oleyl oleate using immobilised lipase from Candida antartica. Electronic Journal of Biotechnology 8: 292-298.

Ritchie, A.D. (1927): Lactic acid in fish and crustacean muscle. Journal of Experimental Biology 4, 327-332.

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.

Tocher, D.R. (2003): Metabolism and Functions of Lipids and Fatty Acids in Teleost Fish. Reviews in Fisheries Science 11(2), 107-184.

WHO (2002): Ethylene Glycol: Human Health Aspects. Concise International Chemical Assessment Document 45.

Zhao, Z. (2000). Synthesis of butyl propionate using novel aluminophosphate molecular sieve as catalyst. Journal of Molecular Catalysis 154(1-2): 131-135.

 


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 group concept is applied to the members of the Glycol Ester Category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, all available data on acute oral and dermal 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.

Since the available acute inhalation studies provided LC50 values for male rats and male and female guinea pigs of greater than the limit dose of 200 ppm (2.916 mg/L), the data is inconclusive according to the classification criteria of Regulation (EC) 1272/2008 or Directive 67/548/EEC.