Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral NOAEL (rat, m/f): 1000 mg/kg bw/day (OECD 422, GLP)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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 on the acute toxicity of "Reaction mixture of glycerol-1,3-di(acetate), glycerol acetate and triacetin".

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 a structurally related substance 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 substances may be predicted as similar provided that their physicochemical and toxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of Repeated dose toxicity via the oral route.

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EC 905-964-4

CAS 102-76-1

Chemical name

"Reaction mixture of glycerol-1,3-di(acetate), glycerol acetate and triacetin"

Triacetin

Molecular weight

134.13 - 218.20 g/mol

218.20 g/mol

Repeated dose toxicity, oral

RA: CAS 102-76-1

NOAEL ≥ 1000 mg/kg bw/day (m,f)

 

The above mentioned substances are considered to be similar on the basis of the structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for "Reaction mixture of glycerol-1,3-di(acetate), glycerol acetate and triacetin".

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

No studies are available investigating the repeated dose toxicity of "Reaction mixture of glycerol-1,3-di(acetate), glycerol acetate and triacetin".

In order to fulfil the standard information requirements set out in Annex IX, 8.6.2, in accordance with Regulation (EC) No 1907/2006 Annex XI, 1.5 read-across from the structurally related analogue substance Triacetin (CAS 102-76-1) is conducted.

A combined repeated dose toxicity study with the reproduction / developmental toxicity screening test was performed with Triacetin (CAS 102-76-1) according to OECD Guideline 422 and under GLP conditions (JECDB, 1998). Groups of twelve CD rats received oral gavage doses of 40, 200 and 1000 mg/kg bw/day of Triacetin (vehicle: 3% gum arabicum in purified water) for 44 days from 2 weeks prior to mating (males) and for 41-48 days from 14 days before mating to Day 3 postpartum (females). Concurrent control animals received the vehicle only. Triacetin had no effects on clinical signs, body weight, food consumption, and organ weight or necropsy findings. No abnormalities in haematological or blood chemical parameters in males were found. No histopathological changes were observed in either sex. Only one male animal of the high dose group died 32 days after start of the study. The death was not considered to be treatment related. The NOAEL for repeated dose oral toxicity was thus considered to be ≥ 1000 mg/kg bw/day for both sexes.

A 90-day oral feeding study in Sprague-Dawley rats was performed with a mixture of glycerol and Triacetin (CAS 102-76-1) to investigate nutritional needs during long-duration space missions (Shapira et al., 1969). Triacetin was mixed at concentrations of 16 and 30% to the diet. Groups of 8 male weanling Sprague-Dawley rats were fed the diet ad libitum for a period of up to 90 days. Assuming an average daily food consumption of 50 g/kg bw this approximates to 8000 and 15000 mg/kg bw/day. Control animals received the plain diet only. The authors concluded that growing rats could tolerate up to 20% Triacetin in the diet whereas higher amounts caused a decrease in weight gain. This corresponds to a NOAEL of 10000 mg/kg bw/day for Triacetin in male rats based on clinical signs and body weight gain.

In another study, glycerol, propylene glycol and Triacetin (CAS 102-76-1) were used as starch substitutes in young and adult rats (Shapira et al., 1975). The experiments were performed in order to evaluate nutritional needs associated with long term space missions. Triacetin was fed at concentrations of 20% and 30% of the starch-deficient diet (approximately 9000 and 15000 mg/kg bw/day) to groups of eight young and adult male Sprague-Dawley rats for a period of 13 weeks. Control animals received a diet containing starch only. Compared to the control animals, animals receiving Triacetin containing diets showed a reduced gain in body weight and increased mean liver weights. No mortalities occurred during the study period. The results are difficult to interpret, as the treated animals received a starch-deficient diet, which is probably a not suitable diet for rats. Therefore, a NOAEL could not be identified since the observed effects could be due to the diet-deficiency rather than the test substance treatment.

A 60 day oral feeding study with Triacetin (CAS 102-76-1) was performed in male and female rats to analyse the ability of fatty components to supply energy and support growth (Cox, 1933). Four rats, two males and two females were fed a diet containing 55% Triacetin (ad libitum) for 60 days. Triacetin at concentrations of 55% in the diet (supply of 77% of the caloric intake) supported normal growth and body weight gain in rats. Since no concurrent control animals fed with a normal rat diet were reported, no further evaluation of the results is possible.

Conclusion for Repeated Dose Toxicity – Oral

A Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted with Triacetin (CAS 102-76-1) did not show effects in rats. Therefore, the NOAEL for repeated oral toxicity was found to be greater than 1000 mg/kg bw/day. In addition, Triacetin studies were available performed with rats to determine the nutritional needs during long-duration space missions. A 90-day feeding study with rats resulted in a well-tolerated amount of 20% Triacetin in diet (~10000 mg/kg bw/day). Overall, a NOAEL exceeding 1000 mg/kg bw for "Reaction mixture of glycerol-1,3-di(acetate), glycerol acetate and triacetin" was deduced.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from the source substance Triacetin following an analogue approach, the available data on repeated dose toxicity of "Reaction mixture of glycerol-1,3-di(acetate), glycerol acetate and triacetin" do not meet the criteria for classification

according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and the data are therefore conclusive but not sufficient for classification.