Reaction product of propylidynetrimethanol, propoxylated, reaction products with ammonia and 2,2-Dimethyl-3-(4-morpholinyl)propanal

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2015-06-09

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement

GLP compliance:

yes

Details on test animals or test system and environmental conditions:

not applicable

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Remarks:

Doses / Concentrations:
not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Details on absorption:

Generally, oral absorption is limited for molecular weights above 500 g/mol. In addition, based on the log Pow of 2.12 SIKA Hardener MTJ can be regarded as moderately lipophilic substance. This characteristic combined with slightly soluble water characteristics may limit oral absorption by the inability of the substance to dissolve in the gastro-intestinal fluids, which in turn hinders contact with the mucosal surface.

However, SIKA Hardener MTJ will be hydrolysed after being in contact with an aqueous solution and degradation products are assumed to have physicochemical properties (lower log Pow, higher water solubility) facilitating oral absorption. Administered without a vehicle in an acute oral toxicity study performed on rats, SIKA Hardener MTJ lead to a LD50 of > 2000 mg/kg bw. Clinical signs on the central nervous system were observed between the treatment day and Day 1. No pathological changes could be observed after the observation period of 14 days.
The test item showed in a combined repeated dose subacute toxicity study on rats at 1000 mg/kg bw/day toxic effects. SIKA Hardener MTJ was administered orally (by gavage) and caused premature death and hyaline droplet nephropathy and tubular necrosis in the kidneys in male (3/12) and female (4/12) Hsd.Brl.Han: Wistar rats. These findings indicate either that the compound or its hydrolysis products might become bioavailable and are of low toxicity caused by the presence of the substance in the stomach.

Due to the low vapour pressure of 0.00109 Pa at 20 °C it is unlikely that the substance will be available as a vapour, but if it is the case absorption via inhalation route is possible due to the water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Similarly, based on physicochemical properties penetration through the skin is assumed to be low. It is general accepted that if a compound’s water solubility falls between 1-100 mg/L, absorption can be anticipated to be low to moderate. This assumption based on the physicochemical properties of SIKA Hardener MTJ is further supported by the results achieved from the LLNA showing skin sensitising properties. Thus, a small amount of the compound or its hydrolysis products might penetrate the skin. No increased penetration is expected after long-term application as the chemical does not induce dermal irritation. (LD50 >2000 mg/kg bw).

Taken together, physicochemical properties and experimental data indicate bioavailability of SIKA Hardener MTJ via oral and dermal route albeit to a small amount.

Details on distribution in tissues:

Assuming that SIKA Hardener MTJ is absorbed into the body following oral, dermal or inhalation intake, it may be distributed into the interior part of cells due to its slightly lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. However it is expected that SIKA Hardener MTJ does not reach the blood without starting to hydrolyse into its hydrolysis products. As mentioned above, the physicochemical properties of the hydrolysis products favour systemic absorption. The results from the combined repeated dose toxicity study indicate that the kidneys are the primary target organs affected by the chemicals. Due to the fast occurring hydrolysis reaction in the body, it is unlikely that the test item can bioaccumulate. Moreover, both hydrolysis products are highly water soluble and have a low log Pow value.

Details on excretion:

As discussed above, SIKA Hardener MTJ will be hydrolysed after being in contact with an aqueous solution and will probably not be excreted in its unhydrolysed form. Dependent on their molecular weight and water solubility hydrolysis products might either be excreted via urine or feaces. Generally, in the rat renal excretion is facilitated for water-soluble molecules with a molecular weight below 300 g/mol.

Details on metabolites:

Based on the structure of the molecule, SIKA Hardener MTJ and its hydrolysis products may be metabolized by Phase I enzymes while undergoing functionalization reactions aiming to increase the compound’s hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the parent compound or the Phase I metabolite in order to ultimately facilitate excretion. Metabolism to more toxic metabolites is not expected based on the results obtained in the in vitro bacterial reverse mutation test (Ames test) as well as the HPRT and in the chromosome aberration test in the presence of a metabolic activation system.

Bioaccessibility (or Bioavailability) testing results:

Physicochemical properties and experimental data indicate bioavailability of SIKA Hardener MTJ via oral and dermal route albeit to a small amount.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
Based on physicochemical characteristics, particularly water solubility and log Pow absorption via oral, inhalation and dermal route is expected to be low. Due to the fast occurring hydrolysis reaction in the body, it is unlikely that the test item can bioaccumulate. Moreover, both hydrolysis products are highly water soluble and have a low log Pow value.
Hydrolytic and metabolic conversion is expected and conjugation of Phase I-metabolites may further increase hydrophilicity. Excretion via urine is assumed to be the main excretion pathway of degradation products and metabolites formed due to their expected lower molecular weight and higher water solubility.

Description of key information

Based on physicochemical characteristics, particularly water solubility and log Pow absorption via oral, inhalation and dermal route is expected to be low. Due to the fast occurring hydrolysis reaction in the body, it is unlikely that the test item can bioaccumulate. Moreover, both hydrolysis products are highly water soluble and have a low log Pow value.
Hydrolytic and metabolic conversion is expected and conjugation of Phase I-metabolites may further increase hydrophilicity. Excretion via urine is assumed to be the main excretion pathway of degradation products and metabolites formed due to their expected lower molecular weight and higher water solubility.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic Assessment of Reaction product of propylidynetrimethanol, propoxylated, reaction products with ammonia and 2,2-Dimethyl-3-(4-morpholinyl)propanal (SIKA Hardener MTJ)

 

Toxicological profile of SIKA Hardener MTJ

An acute oral toxicity study conducted with SIKA Hardener MTJ using rats revealed a LD50 value of > 2000 mg/kg bw. No acute inhalation toxicity study was conducted with SIKA Hardener MTJ since the vapour pressure of the substance is low and inhalation exposure is considered unlikely. An acute dermal toxicity study with the test substance revealed also a LD50 value of >2000 mg/kg bw. In an in vitro skin irritation study conducted with SIKA Hardener MTJ no skin irritation was observed when applied on a human skin model. An isolated chicken eye test revealed that SIKA Hardener MTJ does not induce severe eye damage. In the in vivo Acute Eye Irritation Test the test item MTJ applied to the rabbits eye mucosa, caused slight to severe conjunctivae and slight cornea irritant effects, fully reversible within 1 week. In a LLNA test a skin sensitising potential of SIKA Hardener MTJ was observed when applied on the ear of mice. SIKA Hardener MTJ did not induce reverse mutations in a bacterial reverse mutation test (Ames test) with five Salmonella typhimurium strains in the absence and presence of a metabolic activation system. It did also neither induce increases in mutant frequency over the background in the in vitro HPRT test in Chinese hamster ovary cells, nor induce structural chromosome aberrations in Chinese hamster lung cells. Both test systems were tested with and without metabolic activation.

In a combined repeated dose toxicity study with a reproduction/developmental toxicity screening test Sika Hardener MTJ was administered orally (by gavage). At 1000 mg/kg bw/day caused premature death and hyaline droplet nephropathy and tubular necrosis in the kidneys in male (3/12) and female (4/12) Hsd.Brl.Han: Wistar rats. Slightly reduced body weight development, food consumption, increases in the kidneys weights (males and females) and hyaline droplet nephropathy (males) were observed in surviving animals at 1000 mg/kg bw/day. There was no adverse influence on the reproductive performance (gonad function, mating behavior, conception, pregnancy, parturition) in parental male and female Hsd.Brl.Han: Wistar rats at 1000 mg/kg bw/day. At 300 and 100 mg/kg bw/day, there were no test item related adverse alterations or impairment of the reproductive performance (gonad function, mating behavior, conception, pregnancy, parturition) in parental male and female animals. The offspring’s body weight development was slightly depressed at 1000 mg/kg bw/day between postnatal days 0 and 4. Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:

NOAEL for systemic toxicity of male/female rats: 300 mg/kg bw/day

NOAEL for reproductive performance of male/female rats: 1000 mg/kg bw/day

NOAEL for F1 Offspring: 300 mg/kg bw/day

2 Toxicokinetics of SIKA Hardener MTJ

SIKA Hardener MTJ is a faint yellowish liquid at room temperature and consists of several oligomers with a various number of subunits between 2 and 10. It is therefore registered as an UVCB substance. The main component are the oligomers of tri-imine consisting of n=5 and n=6 oligomers as the main components with a molecular weight of 881.3 and 1171.7 g/mol, respectively. A water solubility of ca. 29.9 mg/L at 25 °C was estimated for the n=5 oligomer and of 10.9 mg/L for the n=6 oligomer. The log Pow was determined to be 2.12 at 20 °C (hydrolysed form, most likely Aldehyd M). The vapour pressure of SIKA Hardener MTJ is 0.00109 Pa at 20 °C. In an aqueous solution, SIKA Hardener MTJ is degraded quickly hydrolytically into 2,2-dimethyl-3-(morpholin-4-yl)propanal (Aldehyde M) and a reaction product of propylidynetrimethanol, propylene oxide and ammonia (Jeffamine T). Both substances have a higher water solubility (> 500 g/L) and a lower log Pow value (1.7 and -1.13, respectively) than SIKA Hardener MTJ itself.

2.1 Absorption

Generally, oral absorption is limited for molecular weights above 500 g/mol. In addition, based on the log Pow of 2.12 SIKA Hardener MTJ can be regarded as moderately lipophilic substance. This characteristic combined with slightly soluble water characteristics may limit oral absorption by the inability of the substance to dissolve in the gastro-intestinal fluids, which in turn hinders contact with the mucosal surface.

However, SIKA Hardener MTJ will be hydrolysed after being in contact with an aqueous solution and degradation products are assumed to have physicochemical properties (lower log Pow, higher water solubility) facilitating oral absorption. Administered without a vehicle in an acute oral toxicity study performed on rats, SIKA Hardener MTJ lead to a LD50 of > 2000 mg/kg bw. Clinical signs on the central nervous system were observed between the treatment day and Day 1. No pathological changes could be observed after the observation period of 14 days.

The test item showed in a combined repeated dose subacute toxicity study on rats at 1000 mg/kg bw/day toxic effects. SIKA Hardener MTJ was administered orally (by gavage) and caused premature death and hyaline droplet nephropathy and tubular necrosis in the kidneys in male (3/12) and female (4/12) Hsd.Brl.Han: Wistar rats. These findings indicate either that the compound or its hydrolysis products might become bioavailable and are of low toxicity caused by the presence of the substance in the stomach.

Due to the low vapour pressure of 0.00109 Pa at 20 °C it is unlikely that the substance will be available as a vapour, but if it is the case absorption via inhalation route is possible due to the water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion.

Similarly, based on physicochemical properties penetration through the skin is assumed to be low. It is general accepted that if a compound’s water solubility falls between 1-100 mg/L, absorption can be anticipated to be low to moderate. This assumption based on the physicochemical properties of SIKA Hardener MTJ is further supported by the results achieved from the LLNA showing skin sensitising properties. Thus, a small amount of the compound or its hydrolysis products might penetrate the skin. No increased penetration is expected after long-term application as the chemical does not induce dermal irritation. (LD50 >2000 mg/kg bw).

Taken together, physicochemical properties and experimental data indicate bioavailability of SIKA Hardener MTJ via oral and dermal route albeit to a small amount.

2.2 Distribution

Assuming that SIKA Hardener MTJ is absorbed into the body following oral, dermal or inhalation intake, it may be distributed into the interior part of cells due to its slightly lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. However it is expected that SIKA Hardener MTJ does not reach the blood without starting to hydrolyse into its hydrolysis products. As mentioned above, the physicochemical properties of the hydrolysis products favour systemic absorption. The results from the combined repeated dose toxicity study indicate that the kidneys are the primary target organs affected by the chemicals. Due to the fast occurring hydrolysis reaction in the body, it is unlikely that the test item can bioaccumulate. Moreover, both hydrolysis products are highly water soluble and have a low log Pow value.

2.3 Metabolism

Based on the structure of the molecule, SIKA Hardener MTJ and its hydrolysis products may be metabolized by Phase I enzymes while undergoing functionalization reactions aiming to increase the compound’s hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the parent compound or the Phase I metabolite in order to ultimately facilitate excretion. Metabolism to more toxic metabolites is not expected based on the results obtained in the in vitro bacterial reverse mutation test (Ames test) as well as the HPRT and in the chromosome aberration test in the presence of a metabolic activation system.

2.4 Excretion

As discussed above, SIKA Hardener MTJ will be hydrolysed after being in contact with an aqueous solution and will probably not be excreted in its unhydrolysed form. Dependent on their molecular weight and water solubility hydrolysis products might either be excreted via urine or feaces. Generally, in the rat renal excretion is facilitated for water-soluble molecules with a molecular weight below 300 g/mol.

3 Summary

Based on physicochemical characteristics, particularly water solubility and log Pow absorption via oral, inhalation and dermal route is expected to be low. Due to the fast occurring hydrolysis reaction in the body, it is unlikely that the test item can bioaccumulate. Moreover, both hydrolysis products are highly water soluble and have a low log Pow value.

Hydrolytic and metabolic conversion is expected and conjugation of Phase I-metabolites may further increase hydrophilicity. Excretion via urine is assumed to be the main excretion pathway of degradation products and metabolites formed due to their expected lower molecular weight and higher water solubility.

4 References

ECHA (2012), 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.