Amines, C12-14-tert-alkyl, C14-18 and C18-unsatd.-alkyl phosphates

Endpoint summary

Description of key information

The absorption of the target UVCB substance into the body is expected to be low  via all exposure routes. If absorbed, it is not expected be distributed throughout the body but accumulated to some extent, predominantly in adipose tissues. The substance can be hydroxylated at C atoms of alkyl chains, conjugated with conjugated agens and then excreted via the urine or faeces. 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

General

The toxicokinetic profile of Reaction Products of alcohols, C14-18, C18 unsat., esterified with phosphorus pentoxide and salted with amines, C12-14,-tert-alkyl was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physico-chemical properties of this substance were integrated with the available toxicological data to create a prediction of the toxicokinetic behavior.

Toxicological profile of Reaction Products of alcohols, C14-18, C18 unsat., esterified with phosphorus pentoxide and salted with amines, C12-14,-tert-alkyl

The substance is not acutely toxic via oral and dermal routes of exposure. The oral and dermal LD50 values of greater than 2000 mg/kg bw were established in animal studies with rats (Sanders, 2012a,b). The substance is not irritating to skin or eyes (Sanders, 2012c,d) and not sensitising in guinea pigs in Buehler Test (Smedley, 2012). The substance was not mutagenic in any of the bacterial strains (Ames Test), and in mammalian cells (Mouse Lymphoma Assay conducted with cell line L5178Y) (Bowles, 2012; Brown, 2012). No chromosome aberrations were detected in human lymphocytes (Morris, 2012). In the 28-day study, the effects in 1000 mg/kg bw/day animals and in 300 mg/kg bw/day males were confined to body weight reductions (1000 mg/kg bw/day males only), blood chemical changes (1000 mg/kg bw/day animals only), organ weight changes, microscopic liver and thyroid changes (1000 mg/kg bw/day animals only) and microscopic kidney changes (males only). The microscopic changes are considered to be adaptive in nature or species specific and do not represent “serious damage” to health. The body weight and blood chemical changes are considered to be a consequence of the adaptive microscopic liver changes and also do not represent “serious damage” to health. The effects in the OECD 421 were similar to those in the 28 -day study but they were more pronounced. There were significant clinical findings, decreases in body weight and food consumption (primarily females), as well are organ weight changes and microscopic findings at 500 and 1000 mg/kg/day. Test article-related microscopic findings were present in the ovaries, liver, kidneys, adrenal glands, stomach, and duodenum. Most findings were predominantly observed at 1000 mg/kg/day, but were also noted to some extent in animals at 500 mg/kg/day. Therefore, NOAEL of 150 mg/kg bw was established for general toxicity for males and females. The substance did not affect any of the reproductive parameters and was not developmental toxicant (NOAEL of 1000 mg/kg bw).

Toxicokinetic analysis of Reaction Products of alcohols, C14-18, C18 unsat., esterified with phosphorus pentoxide and salted with amines, C12-14,-tert-alkyl

The substance is a yellow, slightly viscous liquid with MW of 533.82 and 784.29 g/mol for two representative structures: mono- and dialkyl amino salt. The substance is slightly soluble in water (1.64 mg/L at 20°C) and has a LogPow of 8.0. It has a high vapour pressure of 0.0029 Pa at 25°C (Tremain, 2013) and the pour point at -3°C under atmospheric conditions. Hydrolysis rate is expected to be limited due to the low water solubility of the substance (Fox, 2013).

Absorption

Oral absorption is favoured for small water-soluble molecules with MW up to 200 which can pass through aqueous pores or can be carried with the bulk passage of water (TGD, Part I, Appendix IV, 2003). Based on the molecular weight of > 533.82 < 784.29, the low water solubility and the high logPow value, the substance is not expected to be readily absorbed via the gastrointestinal (GI) tract by passive diffusion. This thesis is supported by the fact that the acute toxicity via oral route is low (LD50 >2000 mg/kg bw; Sanders, 2012a). 50% oral absorption for the purposes of DNEL derivation (in case of oral-to-inhalation extrapolation) is considered appropriate based on the low acute toxicity observed in rats and on the physico-chemical properties which are not in the range suggestive of absorption from the gastro-intestinal tract.

Based on the low vapour pressure, exposure by inhalation is not relevant for this substance. It is very unlikely, that considerable amounts of the substance reach the lung and when this occurrs, the substance is expected to be absorbed directly across the respiratory tract epithelium, due to the logPow of 8.0. Absorption through the aqueous pores can be ruled out since water solubility of the substance is very low (1.64 mg/L). For the purposes of derivation of DNEL for inhalation exposure by route-to-route extrapolation, 100% absorption is considered due to the lack of substance specific information on absorption (worst case).

Similarly, based on the physico-chemical properties, the substance is unlikely to penetrate the skin extensevely as the substance is too lipophilic to cross the stratum corneum (logPow of 8.0) and not sufficiently soluble in water to partition from the stratum corneum into the epidermis (water solubility of 1.64 mg/L). Absorption through the skin is anticipated to be low to moderate if water solubility lies between 1- 100 mg/L. In addition, the molecular weight of >533.82<784.29 g/mol indicates a low potential to penetrate the skin as well. This is supported by the findings of the acute dermal toxicity study where LD50>2000 mg/kg bw for both sexes was established (Sanders, 2012b). Due to the physico-chemical properties which are not in the range suggestive of absorption through the skin, according to TGD, Part I (2003), 10% of dermal absorption is considered for the target substance.

 

Distribution and accumulative potential

Due to low absorption rates via all exposure routes, a significant amount of the substance is not expected to be available for distribution. Generally, the smaller is the molecule , the wider is the distribution. The target substance has a large molecule size (MW of > 533.82 <784.29) indicating a limited distribution throughout the body. As the cell membranes require a substance to be soluble in both water and lipids to be taken up, the target substance is not expected to reach the inner cell compartment through the aqueous pores or channels due to its low water solubility (1.64 mg/L) and its large size. There may be specific transport proteins which could contribute to the transport of such kind of substances through the cell membrane. On the other hand, the high LogPow of 8.0 points to a distribution into cells particularly in fatty tissues. Generally, substances with high logPow values have long biological half-lives and are expected to accumulate in individuals that are frequently exposed (TGD, Part I, 2003). It may explain why the oral administration of the target UVCB substance to pregnant rats (the phisiological condition when fat reserves are mobilised more rapidly) resulted in more pronounced effects than those observed in the 28 -day study. The target substance, in case of contact with the skin, can penetrate the stratum corneum to a very limited extent but cannot be absorbed systemically. So, the substance may persist in the stratum corneum until is sloughed off. The substance is not expected to distribute into the intravascular compartment as it is not sufficiently soluble in water. Due to the high logPow value and low absorption rates predicted for the target substance, a low risk for accumulation will be associated with the substance.

 

Metabolism

The target substance consists of mono-, and dialkyl phosphate amino alkyl salts. Alkylamines are known to be oxidized by cytochrome P450 enzymes (Phase I reactions) (Eisenbrand et al., 2005). So, C12 -14 alkyl moiety of the substance is a primary aliphatic amine and therefore is expected to undergo oxidative dealkylation leading to unstable intermediates (i.e N-alkyloles) with subsequent release of either hydroxylated derivatives at any C atom of alkyl chain or aldehyde derivatives. Aldehydes can be involved into intermediary metabolism (β-oxidation). Dealkylated amino derivatives can undergo further oxidation or hydroxylation reactions. Mono-, and dialkyl phosphate moieties of the UVCB substance can undergo hydroxylation at C atoms of the aliphatic chain. Dialkyl phosphate ester moieties can be hydrolysed forming aliphatic alkohol derivatives and phosphoric acid. Hydroxylated derivatives can conjugate with a number of conjugation agents i.e. glucuronic acid, glutathion (GSH), methionin etc (Phase II reactions) and then to be excreted.

 

Excretion

As the UVCB target substance is a stable compound and not sufficiently soluble in water, it can not be extensevely filtered by the kidneys and undergo primarily urinary excretion without metabolic processing to more hydrophilic species. On the other hand, excretion via the urine is a major pathway for the oxidised and/or hydroxylated derivatives of aklyamines. The rate of excretion is, however, unknown for this substance. Metabolites which will re-enter the system are expected to occur in some extent. Entering the body orally, excretion via the faeces is also expected to occur.

Literature: Eisenbrand, G., Metzler M., Hennecke F.J. Toxikologie für Naturwissenschaftler und Mediziner. Willey VCH, ISBN 978 -3-527 -30989 -6