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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
Quality of whole database:
The available information comprises a reliable study (Klimisch score 1) as well as unassigned studies with Klimisch score 4, which are considered to be adequate for hazard assesssment in a weight of evidence approach and are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, 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 (further information necessary)

Additional information

Repeated dose oral (subacute and subchronic):

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 (MHLW, 1998). Groups of twelve CD rats received oral gavage doses of 40, 200 and 1000 mg/kg bw/day of the substance (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, corresponding to dietary doses of approximately 8000 and 15000 mg/kg bw/day, respectively. Groups of 8 male weanling Sprague-Dawley rats were fed the diet ad libitum for a period of up to 90 days. 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 8000 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% in the starch-deficient diet (corresponding to approximately 12200 mg/kg bw/day for 20% in the diet and 15600 to 19200 mg/kg bw/day for 30% in the diet) 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 not a suitable diet for rats. Based on a reduced body weight gain compared to controls, the observed LOAEL for effects on the body weight after receiving diets containing Triacetin was considered to be 12200 mg/kg bw/day, corresponding to 20% Triacetin in the diet. However, it has to be mentioned that 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, this study was not further taken into account for hazard assessment.

Based on a weight of evidence approach of all available subacute and subchronic studies showing NOAEL values that are well above the currently applied limit dose of 1000 mg/kg bw/day, the test substance is not considered to exert toxicity after repeated exposure via the oral route.

Repeated dose intravenous (subacute):

Triacetin was tested as a possible lipid component of parenteral nutrition in the rat (Karlstad, 1992). The goal of this study was to determine if the partial replacement of long-chain triglyceride (LCT) calories with Triacetin in a parenteral-nutrition regimen would be beneficial with respect to improving kinetics and energy metabolism and small and large bowel integrity after burn injury. The effect of total parenteral nutrition with combinations of LCTs and Triacetin, the water-soluble triglyceride of acetate, on structural components of the gastrointestinal tract and protein metabolism was assessed in burned (30% body surface area) rats. Parenteral nutrition with 50% Triacetin and 50% LCTs promoted a positive nitrogen balance similar to that of 100% LCTs, increased protein in rectus muscle and liver, smaller and more numerous mucosal cells in jejunum and colon, and increased colonic mucosal weight compared with the other groups. Triacetin did not appreciably affect whole-body and tissue leucine kinetics. The equicaloric provision of Triacetin and LCTs improved protein utilization and structural components of the small and large bowel and reduced the development of intestinal mucosal atrophy associated with conventional parenteral nutrition in burn injury. Thus, Triacetin might be of benefit as a replacement of long-chain triglycerides in parenteral nutrition after burn injuries. However, as the route of exposure is not relevant, this study was not taken into account for hazard assessment of the substance.

Additional toxicological information (see IUCLID chapter 7.12):

Triacetin is a food additive (E1518) and a component of cosmetic and pharmaceutical products. Further it is used as a plasticizer in filter cigarettes. An estimate of additive intake in the UK suggests that an adult might ingest 7.8 mg triacetin per day as part of a total daily additive intake of 8.0 g (MAFF, 1993).

Triacetin was affirmed as a generally recognized as safe (GRAS) human food ingredient by the Food and Drug Administration (FDA, 1975). The European Scientific Committee on Food (SCF) confirmed Triacetin as a food additive with a "not specified" acceptable daily intake (EU Food Additive Report, 2001). This term is used when, on the basis of the available toxicological, biochemical and clinical data, the total intake of the substance, arising from its natural occurrence and/or its present use or uses in food at the levels necessary to achieve the desired technological effect, will not represent a hazard to health. For this reason, the establishment of a numerical limit for the ADI is not considered necessary for the substance.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is based on the weight of evidence from all available studies.

Justification for classification or non-classification

The available data on repeated dose toxicity of the substance via the oral route do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

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