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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Data waiving:
other justification
Justification for data waiving:
other:

Description of key information

Results from TK assessment: absorption rates are assumed to be 30%  for oral exposure and less than 10% for dermal exposure. Absorption via inhalation route is not expected due to the low vapour pressure of the constituents.
For its chemical nature, constituents of the substance are likely to be accumulated in fatty tissues.
Substance is expected to be metabolized by hydrolysis on mono/diesters and alcohol further oxidized to carboxylic acid. Finally it is either metabolized to CO2 exhaled or conjugated and excreted as sulphates or glucuronides.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
30
Absorption rate - dermal (%):
10

Additional information

The substance is characterized as UVCB i.e. a complex reaction product, which contains different ratios of reactants and reaction product of stearyl-diethanol-amine, palmitic acid (C16) and stearic acid (C18). The large number of different individual constituents in the UVCB substance makes a comprehensive toxicokinetic testing/assessment technically impossible. However, data on the physicochemical properties as well as toxicity data regarding individual and representative constituents provides the insight that can be used as a basis for the assessment of the toxicokinetics of the complex reaction product.

Absorption 

Basically, humans can be exposed to the substance by inhalation, dermal contact and through ingestion. The substance is in form of wax that does not volatilize in ambient temperature. The vapour pressures calculated based on individual constituents are in the range of0.0074 to 2.01×10-18Pa.For complex substances the vapour pressure is the sum of the partial pressure of the individual constituents (Raoult’s law), based on which the substance is expected to have very low vapour pressure (<<10-2Pa) at ambient temperature. Consequently inhalation exposure will be generally low and dermal exposure is expected to be the most relevant exposure route since the substance is unlikely to be ingested. Nevertheless, the oral absorption is assessed in case incidental poisoning happens.

Oral

In general, a compound needs to be dissolved before it can be taken up from the gastro-intestinal tract after oral administration.The UVCB substance is a reaction product containing multiple constituents with differentiated water solubility. Testing measured by DOC concentration indicated the dependency of solubility on amount of the test item (nominal load), ranging from 6.4-27.1 mg/L solubility at 3000-10001 mg/L nominal concentration (LAUS GmbH, 2015). Consequently the mean value of dissolvable ratio was established as 0.23%,which means the substance is expected to dissolve only to a small extent in the gastrointestinal fluids. In addition, the relatively high value of log P (6.85 to 24.17 based on individual QSAR estimation) makes it more unlikely to penetrate to biological membranes. However,the substance may be readily absorbed into the gastrointestinal tract due to the moderate molecular weight (ca. 250- 350g/mol)as it is generally considered that moderate molecular substances (molecular weights below 500) are well absorbed(ECHA guidance).

An acute oral toxicity study on the substance itself, a 13 weeks (90 days) repeated feeding study and a teratogenicity study on the structural analogues were contributed to the oral absorption evaluation. In acute oral study the test item was administered to 6 females in limit dose 2000 mg/kg did not cause death. No body weight losses were observed between one and two week after administration of the test item. No important signs of toxicity were observed at the dosage of 2000 mg/kg during first 4 hours or in 14 day observation period. During necropsy, no macroscopically changes were noticed (Hamels rds a.s., 2015a).

Two 90-day repeated toxicity studies conducted on polyoxyethylene (1-6) alkylamine (C12-C22) fatty acid (C12-C22) ester and polyoxyethylene stearylamine stearate, as read-across information, were taken in to account. The substances were added to the feed at a concentration of 0.03%~1% for polyoxyethylene (1-6) alkylamine (C12-C22) fatty acid (C12-C22) ester and 0.05% to 0.5% for polyoxyethylene stearylamine stearate, respectively. Rats were fed this diet for 3 months. The results showed differences between control group and testing groups in bodyweight gain, food intake, hematological, biochemistry and urinary parameters as well as organ weights. Based on the results, a non-reactive limiting value in mice and rats after the administration of samples was assumed to be 0.1% (ca. 104 to 132.7 mg/kg/day) for polyoxyethylene (1-6) alkylamine (C12-C22) fatty acid (C12-C22) ester and 0.16% (dose value not verified) for polyoxyethylene stearylamine stearate. (Yanagimoto Y et al., 1976, Yanagimoto Y et al., 1975).

A teratogenicity study was conducted on 2,2'-(Octadec-9-enylimino)bisethanol as an analogue to the representative constituent of the substance.The test item was administered by gavage to three groups each of twenty-four time mated SD rats, between Days 5 and 19 of gestation inclusive at dose levels 15, 50, and 150 mg/kg bw/day. Results showed for maternal toxicity there were no unscheduled deaths during the study. Clinical sign did not indicate any effect of treatment at any dose. Body weight and body weight gain, including adjustment for the contribution of the gravid uterus, was unaffected by treatment, as well as food/water consumption. No macroscopic abnormalities were detected for parental females in any dose group. For offspring developmental toxicity, the number of implantations, subsequent embryo fetal survival and litter size, sex ratio and mean fetal, litter and placental weights on Day 20 of gestation were unaffected by maternal treatment at any dose. There was no effect of maternal treatment on morphological development of the fetuses up to highest dose. Based on the absence of adverse effect the No Observed Effect Level (NOEL) for the pregnant females and the survival, growth and embryo fetal development of the offspring was considered to be 150 mg/kg bw/day. 

None of the acute and repeated dose toxicity studies showed any significant systemic toxicity.The actual NOEL in 90-days toxicity study can only be represented as concentration in the diet due to the deficiency on dose verification. In teratogenicity study the pregnant female rats, which is considered to be more sensitive showed no maternal toxicity up to 150 mg/kg/day in 20-day concessive administration.It can be therefore considered that the absorption of the substance via oral was limited. Consequently,taking into account the poor water solubility, the high log P and the moderate molecular weight of the substance,a default value for oral absorption of the substance is considered to be3 0%.

Dermal

 The relatively high log P value (6.85to24.17)and low water solubility (0.23%) is to limit the rate of transfer between the stratum corneum and the epidermis, therefore a low dermal absorption is expected.On the other hand, the moderate molecular weight may increase the absorption to some extent but not the dominant factor. 

The integrity of the stratum corneum is an important factor affecting dermal absorption, the skin irritation property is taken into account with the human epidermal model testing conducted on the substance. The result indicated the non-irritant property of the substance therefore dermal absorption contributed to impaired skin is not anticipated.

An acute dermal toxicity study was conducted in rats. The test item was applied to 5 females and 5 males in limit dose 2000 mg/kg did not cause death. No body weight losses were observed one and two week after application of the test item. No important symptoms were observed during first 4 hours neither in females nor in males or in 14days observation period. During necropsy, no macroscopically changes were noticed (Hameln rds a.s., 2015b).

Based on the above information, the skin absorption of the substance is considered to be low and a default value of skin absorption is considered to be less than10%.

Distribution, Metabolism and Excretion

After the poor absorption,the distribution sites of the substance are limited in the body due to the physico-chemical properties. According to the results from 90-days study, the analogue substance polyoxyethylene stearylamine stearate caused organ weight changes in liver and kidney but not with histological findings. These organs are therefore considered as most dominant target after distribution.In addition, the substance with lipophilic constituents has a high tendency to distribute to adipose tissues as well.

Metabolism and Excretion

Substance is a reaction product of stearyl-diethanol-amine with C16-C18 saturated fatty acids. The constituents include fatty acids as the reactant and mono/diesters as reaction products. It is expected that the mono/diesters will go through hydrolysis that are metabolized to fatty acids and ethanol. The alcohols are either further oxidized to carboxylic acid, which may be broken down further and finally exhaled as CO2, or conjugated and excreted as sulphates or glucuronides.

Conclusion

In conclusion, the complex nature of the substance makes comprehensive toxicokinetic study and assessment impossible. However, individual and representative constituent can be used to inform the general profile of the UVCB substance while exposed to humans.

It is expected that the substance will be mainly absorbed via oral (assumed to be30%)although less relevant to human exposure,or dermal(assumed to be less than 10%).Absorption via inhalation route is not expected due to the low vapour pressure of the constituents. After absorption the substance would be distributed most likely in the liver and kidney, possibly other fatty tissues. Substance is expected to be metabolized by hydrolysis on mono/diesters and alcohol further oxidized to carboxylic acid. Finally it is either metabolized to CO2exhaled or conjugated and excreted as sulphates or glucuronides.