1-Butanamine, N-[3-(trimethoxysilyl)propyl]-, reaction products with (trimethoxysilyl)-N-[(trimethoxysilyl)propyl]-1-propanamine and 1,6-diisocyanatohexane homopolymer

Endpoint summary

Description of key information

Based on the physicochemical properties systemic availability of the UVCB substance itself
may be limited but cannot be completely excluded following oral intake. Moreover,
hydrolysis may enhance the chemical’s overall absorption properties. Due to hydrolysis of the
alkyloxysilane groups free methanol is formed which will be readily taken up through the
walls of the GI tract. However, the absence of any specific effects in the toxicity studies
indicates that only negligible amounts of methanol emerge from hydrolysis reactions.
Although the physicochemical properties do not favour transdermal absorption, the
immunological response observed in a LLNA provides evidence that at least small amounts of
the UVCB substance itself or its respective hydrolysis products become systemic available
following dermal administration. Considering the low vapour pressure no relevant amounts of
the UVCB substance are expected to be inhalable under normal use conditions. Based on the
physicochemical properties and the calculated BCF values neither the parent molecule nor its
hydrolysis products are considered to be bioaccumulative.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

1 Physicochemical Data on Hexamethylene diisocyanate, oligomers, reaction products with N-(3-trimethoxysilyl)propylbutylamine and Bis-(Trimethoxysilylpropyl)amine

The UVCB substance Hexamethylene diisocyanate, oligomers, reaction products with N-(3-

trimethoxysilyl)propylbutylamine and Bis-(Trimethoxysilylpropyl)amine appears as a viscous,

clear liquid at standard ambient temperature and pressure. The molecular weight of the UVCB

substance will be found in the range of approximately > 500 to 1800 g/mol.

The substance has a very low vapour pressure of 1x 10^-4 Pa at 20°C which can be regarded as

negligible for the present assessment. The UVCB substance has a very low water solubility

and is considered to be practically insoluble in aqueous solutions. Depending on the different

structures the respective logPow values, estimated by Epiwin, are expected to be in the range

of 3 to 10. The BCF values for the UVCB substance, as estimated by scientifically accepted

calculation models (CATALOGIC v5.11.2, and EPI suite v3.20), fall in the range of 2.35 to

60.67. The UVCB substance is reactive with water. More specifically, when placed in an

aqueous solution (e.g. in the body), the isocyanate end groups will readily hydrolyse to yield

carbamic acid, which decarboxylates to produce CO2 and an amine end group. Furthermore

the alkyloxysilane groups will readily become hydroxylated and form free methanol. Due to

the slow reaction, hydrolysis of the urea groups are not considered to play an important role

with regard to this assessment.

2 Toxicokinetic Analysis of Hexamethylene diisocyanate, oligomers, reaction products

with N-(3-trimethoxysilyl)propylbutylamine and Bis-(Trimethoxysilylpropyl)amine

Absorption

Oral route:

In order to be absorbed into the systemic circulation, chemicals have to dissolve into the

gastro-intestinal (GI) fluids and make contact with the mucosal surface. Hence, the poor water

solubility of the UVCB substance may drastically reduce the amount available for uptake into

the systemic circulation.

Moreover, the molecular weight of the reaction products itself (> 500 g/mol) does not favour

absorption into the systemic circulation via the GI tract. However, once the water reactive

chemicals come in contact with the digestive fluids of the stomach, hydrolysis reactions will

enhance the overall absorption properties. In addition, smaller more polar compounds are

formed. More specifically hydrolysis of the alkyloxysilane groups will yield small amounts of

free methanol which are known to be readily absorbed from the GI tract (Barceloux et al.,

2002).

With regards to toxicological data, an acute oral systemic toxicity studies in rats (OECD 423)

conducted with the UVCB substance determined the respective LD50 value to be greater

2000 mg/kg (limit dose). Besides local effects in the GI tract of a single animal, no systemic

effects were observed. Similarly no definite signs of systemic toxicity were observed in a 14

day dose range finding study with rats. Here, slightly lower body weights, protein and

albumin levels at the highest testing dose of 1000 mg/kg bw/day, were regarded as secondary

effects induced by local irritation of the GI system. No further effects were noted.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity

screening test in rats (OECD 422) one female animal died spontaneously due to severe

ulceration of the forestomach after receiving the high dose of 750 mg/kg bw/day. Also a

decreased body weight gain in males was noted which was regarded as a secondary effect

resulting from local irritation of the forestomach. No further effects were observed in the

parental animals. Conclusively, the systemic NOAEL was determined to be 750 mg/kg

bw/day while the NOAEL for local toxicity was set to 75 mg/kg bw/day due to the observed

GI tract irritation. No effects on reproduction and offspring development were noted and the

respective NOAELs were determined to be 750 mg/kg bw/day.

Overall, based on the physicochemical properties and the results obtained in the toxicity

studies, systemic availability of the UVCB substance itself seems to be limited but cannot be

completely excluded following oral intake. Hydrolysis reactions acting on the reaction

products may enhance the overall absorption properties. As indicated above, free methanol is

formed by hydrolysis reactions which in turn is readily absorbed through the walls of the GI

tract. However, the absence of any specific effects in the toxicity studies indicates that only

minor amounts of methanol emerge by hydrolysis.

Inhalation route:

Considering the low vapour pressure and the resulting low volatility, it is unlikely that the

UVCB substance will become bioavailable via inhalation when handled at room temperature.

Furthermore, results obtained from an acute inhalation toxicity study (OECD 403) where rats

were exposed to a liquid aerosol form of the UVCB substance, indicate that even if the

substance becomes inhalable, no adverse systemic effects are to be expected. The respective

LD50 value was estimated to be 5.03 mg/L, a concentration which is above the limit dose.

Dermal route:

The physicochemical properties of the UVCB substance itself such as molecular weight and

water solubility, do not favour dermal absorption. Also the amount of methanol, produced by

hydrolysis reactions with air humidity, is regarded to be negligible for dermal exposure.

However, the immunological response observed in a local lymph node assay (LLNA) with

mice (OECD 429) provides evidence that at least small amounts of the UVCB substance itself

or its respective hydrolysis products become systemic available following dermal

administration.

Distribution

With regards to the physicochemical properties and the results achieved from the

comprehensive toxicity testing, it appears that the bioavailability of the UVCB substance

itself via the main entrance routes (i.e., oral, dermal and through inhalation) is limited but

cannot be excluded. If any amounts of the UVCB substance or its hydrolysis products become

systemically available, they will be most likely transported within the body via the blood

stream. Due to the absence of systemic effects in the oral toxicity studies, there are no hints

with regard to any potential target organ.

Once absorbed, the minor amounts of methanol formed by hydrolysis reactions will be

distributed within the body via the blood stream before being transported to the liver (Wu

Chen et al., 1985).

Metabolism

Because absorption of the UVCB substance itself into the interior part of the body cells is

considered to be limited, considerable contact of the substance with intracellular metabolising

enzymes is unlikely. However, in the event that the UVCB substance or its hydrolysis

products reach the systemic circulation it cannot be ruled out that they are metabolised by

Phase I enzymes while undergoing functionalisation reactions aiming to increase their

hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an

endogenous substrate to the chemicals or its Phase I metabolites in order to ultimately

facilitate excretion.

Following absorption, the hydrolysis product methanol is readily metabolised by alcohol

dehydrogenase to formaldehyde, which is further metabolised to formic acid. Formic acid

dissociates to formate and a hydrogen ion. Formate is metabolised to CO2 and water by a

folate-dependent mechanism.

Excretion

As mentioned before, it is expected that the bioavailability of the UVCB substance itself is

most likely to be limited and distribution into the body will be low. Thus it is expected that

following oral ingestion the vast majority of the chemicals is excreted with the faeces.

However, if a certain amount of the reaction product is absorbed, it will most likely be

excreted via the urine following potential metabolism reactions. Moreover, it is highly

unlikely that bioaccumulation within the body will occur according to the estimated BCF

values. Absorbed amounts of methanol will be either excreted as parent compound in the

urine or via expired air, or as formic acid metabolite in urine (Rowe and McCollister 1981).

3 Summary

Based on the physicochemical properties systemic availability of the UVCB substance itself

may be limited but cannot be completely excluded following oral intake. Moreover,

hydrolysis may enhance the chemical’s overall absorption properties. Due to hydrolysis of the

alkyloxysilane groups free methanol is formed which will be readily taken up through the

walls of the GI tract. However, the absence of any specific effects in the toxicity studies

indicates that only negligible amounts of methanol emerge from hydrolysis reactions.

Although the physicochemical properties do not favour transdermal absorption, the

immunological response observed in a LLNA provides evidence that at least small amounts of

the UVCB substance itself or its respective hydrolysis products become systemic available

following dermal administration. Considering the low vapour pressure no relevant amounts of

the UVCB substance are expected to be inhalable under normal use conditions. Based on the

physicochemical properties and the calculated BCF values neither the parent molecule nor its

hydrolysis products are considered to be bioaccumulative.

4 References

Barceloux D.G., Bond R., Krenzelok E.P., Cooper H,. Vale J.A. (2002) American Academy

of Clinical Toxicology Practice Guidelines on the Treatment of Methanol Poisoning. Ad Hoc

Committee. Journal of Toxicology - Clinical Toxicology; 40(4):415-46.

Bonse G., Metzler M. (1978) Biotransformation organischer Fremdsubstanzen. Thieme

Verlag, Stuttgart.

ECHA (2008) Guidance on information requirements and chemical safety assessment,

Chapter R.7c: Endpoint specific guidance.

Marquardt H., Schäfer S. (2004) Toxicology. Academic Press, San Diego, USA, 2nd Edition

688-689.

Mutschler E., Schäfer-Korting M. (2001) Arzneimittelwirkungen. Lehrbuch der

Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart.

Renwick A.G. (1994) Toxicokinetics - pharmacokinetics in toxicology. In Hayes,A.W. (ed.)

Principles and Methods of Toxicology. Raven Press, New York, p 103.

Rowe V.K., McCollister S.B. (1981) Alcohols. In: Patty's Industrial Hygiene and Toxicology,

3rd ed. Vol. 2C, G.D. Clayton, F.E. Clayton, John Wiley & Sons, New York:4528-4541.

Rozman K.K., Klaassen C.D. (1996) Absorption, Distribution, and Excretion of Toxicants. In

Klaassen C.D. (ed.) Cassarett and Doull's Toxicology: The Basic Science of Poisons.

McGraw-Hill, New York.

Wu Chen N.B., Donoghue E.R., Schaffer M.I. (1985) Methanol intoxication: distribution in

postmortem tissues and fluids including vitreous humor. Journal of Forensic Sciences,

30(1):213-6.