Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on bioaccumulation potential result: 
The metabolism and toxicokinetics of TS-ED 532 was investigated using 12-[14-C] acetoxy-octadecanoic acid-2,3- diacetoxy-propyl ester (labelled TS-ED 532). Based on the results, metabolism is expected to be rapid with extensive hydrolytic cleavage of the 12-acetyl function from labelled TS-ED 532 and subsequent catabolism of the majority of the released 14-C labelled acetate to 14C-CO2. The recovery of a substantial proportion of the administered radioactivity as 14C-CO2 suggests that deacylation may be initiated in the stomach and that there is no significant absorption of unchanged TS-ED 532.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Absorption and metabolism after oral exposure:

The metabolism and toxicokinetics of TS-ED 532 were investigated according to OECD Guideline 417 (See section 7.1.1) No treatment related clinical signs were observed. Uptake of radioactivity into the systemic circulation was rapid with a peak concentration in blood occurring between 1 and 3 hours post-dosing at 500 mg/kg and at 6 hours post-dosing at 5000 mg/kg. The peak concentration represented approximately 1.2 to 1.3% of the administered dose at 500 mg/kg and approximately 0.56% of the dose at 5000 mg/kg. Elimination of radioactivity from the blood was slow at both doses. The mean plasma elimination half-life time was 55.6 hours at 500 mg/kg and 51.9 hours at 5000 mg/kg. Radioactivity was eliminated from the body as14CO2with 62% accounted for within 12 hours of dosing, 70.8% within 24 hours and 77% after 72 hours. The remaining radioactivity was excreted in urine (6.5%) and faeces (24.6%). Maximum concentrations in the tissues include liver (1.29% of the dose) at 24 hours post-dosing, kidneys (0.23% of the dose) at 6 hours post-dosing, and thymus (0.026% of the dose) at 12 hours post-dosing. Metabolism is expected to be relatively rapid and consist of extensive hydrolytic cleavage of the 12-acetyl function then catabolism of the acetate to CO2. The recovery of a substantial proportion of the administered radioactivity as14CO2 suggests that deacylation may be initiated in the stomach and that there is no significant absorption of unchanged TS-ED 532 across the gastrointestinal epithelium.

The emulsifier is probably extensively but not completely hydrolyzed to glycerol and its constituent acids (J. Phillips, 24 October 2003 – See attached document), mainly as a result of hydrolysis in the intestines (T.F. Jensen, 1 March 2002 – See attached document). The acetoxy-groups are hereby released as acetic acid and subsequently absorbed and may be further degraded and exhaled as CO2. The 12-acetoxy-group is probably the least labile to hydrolysis. Hydrolysis components are excreted in faeces mainly as 12-acetoxy acid (12-acetoxystearic acid, CAS No. 1069-92-7) and 12-hydroxyoctadecanoic acid (12- hydroxystearic acid, CAS No. 106-14-9) and minor amounts of 12-acetoxy-octadecanoic acid 2,3-bis(hydroxy)propyl ester and 12-hydroxy-octadecanoic acid 2,3-bis(hydroxy)propyl ester (T.F. Jensen et al. 25 February 2002 – See attached document). The hydroxylated fatty acid may be further metabolized involving a number of pathways including beta-, alpha- and omega-oxidation, catalysed by enzymes located in mitochondria, peroxisomes and endoplasmatic reticulum (J.Phillips, 24 October 2003 – See attached document).

In a 90-day study, rats were exposed orally to 500, 1600 or 5000 mg TS-ED 532 /kg bw/day. The only effects considered possibly test article-related were minimally higher alkaline phosphatase for males and females given 5000 mg/kg/day. A NOAEL of 5000 mg/kg bw/day was derived. No clear evidence of absorption could be deduced from this study (See section 7.5.1). The oral administration of TS-ED 532 to rats for a period of up to 12 months at dietary concentrations of up to 30000 ppm (equivalent to an overall intake of 1333 mg/kg bw/day) did not result in effects that were considered to represent an adverse effect of treatment. A NOAEL of 1333 mg/kg bw/day could be derived (See section 7.5.1). Evidence of absorption and metabolism could be deduced from body weight and food consumption changes which were comparable to the control group enriched with a comparable amount of arachis oil. The absorption and metabolism are in accordance with exhalation of 14CO2 following oral administration (gavage) of radiolabelled TS-ED 532.

 

Absorption and metabolism after dermal exposure:

There were no evidence of dermal absorption in the acute dermal toxicity test in rats with 2000 mg/kg bw or in the dermal irritation test. TS-ED 532 was not a skin sensitizer in the LLNA test indicating no potential to penetrate the skin. TS-ED 532 is a transparent liquid with a high molecular weight, a low water solubility and a high n-octanol-water partition coefficient indicating a low potential for dermal absorption.

Absorption and metabolism after inhalation:

TS-ED 532 is a transparent liquid with a low vapour pressure of 1.1x10-7 Pa at 25°C and 4.8x10-8 Pa at 20°C. TS-ED 532 is therefore not volatile and absorption via the respiratory system is considered unlikely.

Discussion on bioaccumulation potential result:

The metabolism and toxicokinetics of TS-ED 532 was investigated according to OECD Guideline 417 using dose levels of 500 mg/kg and 5000 mg/kg. No treatment related clinical signs were observed.

Uptake of radioactivity into the systemic circulation was rapid with a peak concentration in blood occurring between 1 and 3 hours post-dosing at 500 mg/kg bw and at 6 hours post-dosing at 5000 mg/kg bw. The peak concentration represented approximately 1.2 to 1.3% of the administered dose at 500 mg/kg and approximately 0.56% of the dose at 5000 mg/kg. Elimination of radioactivity from the blood was slow at both doses.

The mean plasma elimination half-life was 55.6 hours at 500 mg/kg bw and 51.9 hours at 5000 mg/kg. Radioactivity was eliminated from the body as 14CO2with 62% accounted for within 12 hours of dosing, 70.8% within 24 hours and 77% after 72 hours. The remaining radioactivity was excreted in urine (6.5%) and faeces (24.6%). Maximum concentrations in the tissues include liver (1.29% of the dose) at 24 hours post-dosing, kidneys (0.23% of the dose) at 6 hours post-dosing, and thymus (0.026% of the dose) at 12 hours post-dosing.

Based on the data, metabolism is expected to be relatively rapid and consist of extensive hydrolytic cleavage of the 12-acetyl function followed by catabolism of the acetate to CO2. The recovery of a substantial proportion of the administered radioactivity as14CO2 suggests that deacylation may be initiated in the stomach and that there is no significant absorption of unchanged TS-ED 532.

Categories Display