Amines, N-(C16-18 and C18-unsatd. alkyl)trimethylenedi-, N-(hydroxyethyl) derivs.

Endpoint summary

Description of key information

There are no specific studies available that study Absorption, distribution, metabolism or excretion of ethoxylated diamines.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

1. Physical-chemical properties

The test substance, Tris (2-hydroxyethyl) tallow diaminopropane, CAS 90367-27-4 (recently redefined as Amines, N-(C16-18 (even numbered) and C18-unsatd. alkyl) trimethylenedi-, ethoxylated (NLP), CAS 1290049-56-7), also referred to as Tallow-diamine3EO, has a molecular weight range of 426-454 g/mol and is an amber coloured liquid at 23°C. The substance has a measured melting point of 19°C, a measured boiling point of > 300°C at 1013 hPa and a vapour pressure < 0.0015 Pa at 20°C. The octanol-water partition coefficient (log Pow) is2.8 at 25 °C (OECD 123) and as the substance forms micelles in water the water solubility is expressed as the critical micelle concentration (CMC, a solubility limit) at 19 mg/L at pH 7 and 23°C.

In physiological circumstances the nitrogens can become positively charged, resulting to a cationic surfactant structure which leads to high adsorptive properties to negatively charged surfaces as cellular membranes. At pH below 7.2 more than 99.9% of the substance has at least one positively charged nitrogen. The apolar tails easily dissolve in the membranes, whereas the polar head causes disruption and leakage of the membranes leading to cell damage or lysis of the cell content. As a consequence, the whole molecule will not easily pass membrane structures. Cytotoxicity at the local site of contact through disruption of cell membrane will is considered the most prominent mechanism of action for toxic effects.

 

2. Data from acute toxicity studies and irritation studies

Acute toxicity data was evaluated in an Acute Toxic Class (ATC, OECD 423) study on tallow-diamine3EO, indicating a LD50 in the range of50 - 300 mg/kg bw, with a LD50 cut-off of 500 mg/kg bw. A second, older study on Tallow-diamine3EO confirms these results with an LD50 that was calculated to be 770) mg/kg bw.

Tallow-diamine3EO is severely corrosive (Classification Cat. 1B) to the skin and is not expected to easily pass the skin in view of its ionised form at physiological conditions. However, as this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.

 

3. Data from repeated dose toxicity studies

Oral:

Repeated dose toxicity data was evaluated in a Combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) on the comparable substance Oleyl-diamine3EO. The difference between both substances is a slightly lower average alkyl chain for the tallow as it contains some C16-alkyl chains and a higher level of unsaturation of the C18 alkyl chain for the oleyl. For further information use is made of cross-reading to various results obtained on non-ethoxylated alkyl amines.

 

The most significant treatment-related changes in all studies areincreased WBC (neutrophils) at higher dose levels combined with changes in body weight gain. The critical effects are histopathological test item-related effects on the small intestine and mesenteric lymph nodes, which only partially regressed during the recovery period. A relatively strong inflammatory reaction is also observed. These effects have consistently been observed with these sort of substances (Fatty amine derived substances), which support the current approach of grouping of substances and read-across of data. When taking into consideration the relatively strong corrosive effects of these substances and the route of administration, it cannot be excluded that the overall toxicity reflects a point-of-first-contact effect. A mode of action has not been established but it is possible to suspect the known corrosivity to be at least partially involved.

The observed effects of foamy macrophages are local and are by some interpreted as phospholipidosis (PLDsis), something which is commonly observed following treatment with cationic amphiphiolic drugs and considered to be non-adverse.

 

 

When comparing the 28-day results on Oleyl-diamine3EO (OECD 422) with the 28-day study on Oleyl diamine clearly shows a comparable toxicological profile.For both studies the effects observed, as well as the levels of the effects are very similar resulting to the same NOAEL of 1 mg/kg bw for Oleyl-diamine3EO and 1.25 for Oleyl-diamine (differences are related to dose selection per study rather than actual differences in response).

This can be explained on the basis of their comparable structure leading to comparable properties and toxicological behaviour, and the notion that these substances do not undergo important phase-one metabolism leading to different structures and toxicity.

 

Also the further studies on C12-14-diamine show the same toxicological responses.

The results from C12-14-diamine are considered to represent a worst case situation for Oleyl-diamine (and thus also for Oleyl-diamine3EO),as both substances share the same molecular structure, but due to its overall smaller alkyl chain length, its solubility and potential to pass cell-membranes is expected to be possibly somewhat higher than that of Oleyl-diamine3EO. This is expected to lead to the relative highest absorption. Therefore, any inherent hazards for systemic toxicity are more likely to be expressed when testing with C12-14-diamine than with Oleyl-diamine.

 

All findings observed in the 90-day repeated dose toxicity study are comparable with the 28-day repeated dose toxicity study performed with C12-14-diamine, which indicates that duration has no great impact on the NOEAL.

Small intestinal and mesenteric lymph node lesions show only slowly reversible. The effects were not reversible during the 28-day recovery period, but had partially regressed after the 90-day recovery period. Other effects seen at higher dose levels as spleen, bone marrow and tracheal changes had completely regressed after the 28-day and 90-day recovery period.

 

 

Although based on a summary and therefore information of low validity, the reported results from the Tallow-diamine3EO based 90-day dietary study in rats perfectly agrees with the information as presented by the repeated dose studies on Oleyl-diamine3EO, Oleyl-diamine and C12-14-diamine, thus supporting the acceptability of this cross-reading from these substances to Tallow-diamine3EO.

 

An additional observation is that for risk assessment derivation of DNELs from the 90-day study on C12-14-diamine (NOAEL 0.4 mg/kg) and from the 28-day study on Oleyl-diamine3EO (NOAEL 1 mg/kg) leads to the same results. This is base on the considerations for assessment factors used for extrapolation for study duration:

- C12-14-diamine, NOAEL from 90 day: Default assessment factor 2 for sub-chronic to chronic.

- Oleyl-diamine3EO, NOEAL from OECD 422: The guidance indicates that for sub-acute to chronic a factor 6 should be applied. However, we know that the dose levels of the NOAEL for this effect of foamy macrophages in mesenteric lymph nodes is not influenced by the duration of the study. Besides, the females have been dosed for 43-52 days rather than 28 days (Males 29 days). Therefore a factor 5 is considered sufficient.

 

Inhalation:

Tallow-diamine3EO is a viscous liquid/paste with bp > 300°C and has a vapour pressure below 0.0015 Pa at 20°C. Its use is limited to industrial and professional users and does not involve the forming of aerosols, particles or droplets of an inhalable size. So exposure to humans via the inhalation route will be unlikely to occur.

 

Dermal:

There is an illegible copy of an old report of a repeated dose study by dermal route on Tallow-diamine3EO. Rabbits werepercutaneous dosed with 0, 0.77 or 7.7 mg/kg/day for 91 days. Treatment with the test material resulted in slight to moderate skin irritation in both dose groups.

Besides irritation, also foamy macrophages in mesenteric lymph nodes were noted in 2/6 animals treated at 7.7 mg/kg. No other effects other effects were observed. As these effects are local reactions following the route of absorption, it is most likely that this is most likely a consequence following oral uptake from grooming.

Tallow-diamine3EO is severely corrosive to the skin and is not expected to easily pass the skin in view of its ionised form at physiological conditions. The dermal route is therefore not a preferred route for dosing when evaluating repeated dose toxicity. In addition, there is no consumer exposure to Tallow-diamine3EO. Further, manufacture and use are highly controlled. Its use is limited to industrial and professional users where following its severe corrosive properties the applied protection measures will provide for sufficient protection to prevent exposure.

 

4. Absorption, distribution, metabolism, excretion

There are no specific studies available that study Absorption, distribution, metabolism or excretion of ethoxylated diamines.

It is expected that Tallow-diamine3EO when administered orally is not extensively absorbed, due to its low solubility and CMC formation. The effects of the diamines and the ethoxylated diamines on which the NOAEL’s are based in the 28 and 90-day repeated dose toxicity studies, concern effects in the small intestinal and mesenteric lymph node lesions intestines. As these indicate local effects they can probably be considered local NOAEL’s.

 

The available repeated dose studies show that the NOAEL does not change with increasing study duration from 28-day to 90-days. This is an indication for lack of bioaccumulating potential.

 

Dermal absorption:

At this stage no data are available on dermal absorption. Based on the severe corrosive properties of tallow-diamine3EO, dermal absorption as a consequence of facilitated penetration through damaged skin can be anticipated. Dependent on the solvent and concentration, up to 60% dermal absorption may be taken as a worst case for assessment purposes (value taken from the existing EU risk assessment on primary alkylamines).

Due to the lack of quantitative absorption data, 100% absorption is taken as a conservative approach.