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Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

In conclusion if systemic absorption occurs, there is a low potential for bioaccumulation, as the ricinoleate will enter common distribution and metabolic pathways of fats, which are considered similar among mammals. 

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

No experimental data on toxicokinetics are available for ZINN(II)RICINOLEAT.

Assessment is based on available toxicity data, physicochemical properties and literature data and is developed with the aid of ECHA guidance on information requirements and chemical safety assessment chapter R7c.

Toxicity profile and physico-chemical characteristics:

·       Acute oral toxicity : LD50 >2000 mg/kg bodyweight

·       Acute dermal toxicity : LD50 >2000 mg/kg bodyweight

·       Sub-acute toxicity: NOAEL 1000 mg/kg bw/day, NOEL 330 mg/kg bw/day

·       Skin irritation test : slight irritation observed, not classified  according to CLP, EU GHS (Regulation (EC) No 1272/2008)

·       Eye irritation test: slight irritation observed, not classified  according to CLP, EU GHS (Regulation (EC) No 1272/2008)

·       Sensitisation: strong skin sensitizer (according to CLP, EU GHS (Regulation (EC) No 1272/2008, 4thATP):

Skin sensitization Cat. 1A, H 317 (may cause an allergic skin reaction)

·       Full set of in-vitro genotoxicity tests required by REACH regulation is negative

(Ames Test, Chromosome aberration study, Gene mutation in mammalian cells (HPRT))

·       Readily biodegradable, 86 % biodegradation in a Manometric Respirometry Test (OECD 301 F)

·       Appearance: liquid under standard conditions

·       Water solubility: 12 mg/L

·       Log Kow: 4.8 at 25 °C

·       Molecular weight: 714 g/mol

·       Vapour pressure: 0.58 Pa at 20 °C

 

The acute oral and dermal toxicity of ZINN(II)-RICINOLEAT is low, with the LD50 being higher than 2000 mg/kg body in both cases. The low toxicity profile is proven in the 28 – day oral study in rats. The NOAEL was determined to be the high dose of 1000 mg/kg bw/day. However, there are some minor findings noted for blood parameters (increased white blood cell (WBC), increased ALAT and decreased Calcium values), whereas effects were without any corroborative functional or morphological findings.

 

There are some indications for an only low dissociation rate of ZINN(II)-RICINOLEAT under acidic conditions in the stomach to form Sn2+ and ricinoleate.

If dissociation occurs under acidic conditions in the stomach,the tin moiety will only be poorly absorbed from the gastrointestinal tract. The following is cited from the WHO evaluation report (WHO 2005, Tin and inorganic tin compounds): 1

In humans and laboratory mammals, absorption of inorganic tin from the gastrointestinal tract is low (generally less than 5%), but is influenced by dose, anion (compound solubility), and the presence of other substances. Unabsorbed ingested tin is mostly (95–99%) excreted in the faeces within 48 h. Absorbed tin distributes mainly to the bone, but also to the lungs, liver, and kidneys. Limited evidence suggests that inorganic tin does not readily cross the blood–brain barrier. Absorbed tin is mainly excreted in the urine, with some additional biliary excretion occurring. In mice, the biological half-life of absorbed inorganic tin was approximately 30 days.

 

The primary constituent ofZINN(II)-RICINOLEAT isRicinoleic Acid the oil derived from the seed of the Ricinus communis plant (Castor oil). For evaluation of metabolism the following is cited from WHO evaluation of castor oil: 2

About 7% of the ricinoleic acid present in a 1 ml oral dose of castor oil given by stomach tube to fasted Sprague-Dawley rats was absorbed into the chyle within a 24-hour period. About 24% of the ricinoleic acid was absorbed if the substance was given to fed rats.

Seven weanling rats were given a diet containing 20% castor oil, the animals gained weight on the diet, although at a lower rate than animals fed an olive oil supplemented diet. After eight weeks on the castor oil diet, the amount of ricinoleic acid in the animals' fat pads was about 9.7%. When animals were fed the castor oil diet for four weeks then switched to an olive oil diet for 14 days, the amount of ricinoleic acid in the fat pads decreased to about 2%.

Studies in humans indicated that the percentage absorption of castor oil is inversely proportional to the dose given. A dose of 4 g of castor oil was almost completely absorbed; whereas, 64% of a dose of 50 g appeared in the faeces within 24 hours, and almost 90% of 60 g dose was excreted in the faeces. Doses of 10 g or more of castor oil produced either mild laxation of purgation.”

 

From physico-chemical data the following toxicokinetic behaviour can be expected for ZINN(II)-RICINOLEAT.

Absorption

Considering the water solubility of 12 mg/L, the molecular weight of approximately 700 g/mol and the log Kow of 4.8, uptake by micellular solubilisation may be of particular importance for the substance. Absorption from the gastrointestinal tract has to be expected and is supported by minor findings in the sub-acute toxicity study.

The potential of generation of inhalable particles is negligible due to the low vapour pressure of 0.58 Pa at 20°C. In general, in humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract.

However, if respirable particles are generated, absorption from the respiratory tract has to be expected, as absorption after inhalation has to be assumed as a basic principle, for substances absorbed after ingestion.Due to the high lipophilicity uptake by micellular solubilisation has to be expected. Due to the absence of route specific information for chemical safety assessment a default factor of 2 is included by assuming 50 % for oral absorption and 100 % absorption after inhalation as a worst case default assumption for route to route extrapolation within DNEL derivation.

Considering the molecular mass and lipophilicity, a default value of 10 % skin absorption could be chosen according to the Guidance on information requirements and chemical safety assessment, Chapter R.7c. No significant effects were observed in an acute dermal toxicity study in rats. The observed hunched posture is considered a sign of discomfort caused by irritation.

However, in the skin sensitization study in guinea pigs ZINN(II)-RICINOLEAT was shown to be a strong sensitizer. The elicitation of sensitizing properties were regarded as prove of dermal absorption. As effects were severe, a 100 % dermal absorption is assumed for chemical safety assessment as a precautionary principle.

 

Distribution

No information on potential target organs are available. However, as the molecule is lipophilic,it is likely to distribute into cells, and the intracellular concentration may be higher than extracellular concentration.

Metabolism

It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone.

However, based on the structure, it may be expected that the ricinoleate moiety of the substance undergoes mitochondrial beta-oxidation, or omega-oxidation in the endoplasmic reticulum.

Elimination

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces.

The fatty acid moiety as one expected metabolite would enter the regular fatty acid metabolism and be indistinguishable from fatty acids from other sources, including diet. Thus, further considerations are not considered necessary.

Conclusion

In conclusion if systemic absorption occurs, there is a low potential for bioaccumulation, as the ricinoleate will enter common distribution and metabolic pathways of fats, which are considered similar among mammals.

References:

1.WHO: Environmental Health Criteria15. Tin and organotin compounds: A preliminary review. Geneva: World Health Organisation, 1980.
2.WHO Food Additives Series 14, Toxicological Evaluation of Certain Food Additives, April 1979, „Castor oil“