Reaction mass of Octadec-9-en-1-yl ammonium di-n-hexyl phosphorodithioate and Octadec-9-en-1-yl ammonium mono- and di-butylphosphate

Endpoint summary

Description of key information

No toxicokinetic data are available on EC 434-280-4. Dissociation to the starting materials is expected to occur in aqueous media, and therefore, these are evaluated for any TK endpoints related to ingestion. EC 434-280-4 is expected to be stable as the final salt reaction product during use as a lubricant. As such, dermal exposure is likely to be to EC 434-280-4 as the salt and not the starting materials, at least for exposures of short duration. No Kow or water solubility data is available for EC 434-280-4 due to the rapid dissociation in water. However, a valid vapor pressure result for EC 434-280-4 demonstrates low inhalation exposure potential.

The physiochemical properties used in the TK assessment are in the table below (see attached document in Section 13 for Assessment approach that discusses the physiochemical properties and contains references).

 

Physical and Chemical Properties Relevant for the TK Assessment

Parameter	EC 434-280-4	(Z)-octadec-9-enylamine (112-90-3)	Dibutyl hydrogen phosphate (CAS 107-66-4, AKA ‘DHP’)	Butyl dihydrogen phosphate (CAS 1623-15-0)	Di-n-hexyl dithiophosphoric acid (78-64-8, AKA DHDPA)
Kow	NA	7.5 (calculated) (EU RAR)	0.57 (OECD, 1994)	-0.3	4.7
Water solubility	NA	Insoluble at 25 °C 0.07639 mg/L (calculated) (EU RAR)	17 g/L (OECD, 1994)	61 g/L	1.2 mg/L
Molecular weight	Variable	267.5	210.2	154.1	298
Vapor pressure	9.6E-6 Pa @ 25C	0.005 hPa at 20 °C (EU RAR)	<7.4 x 10^-3Pa at 100 °C (OECD, 1994)	<0.000015 Pa @ 20C	3.79 x 10^-5mmHg at 25°C*

*EPI SUITE v. 4.1

 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Absorption

1. Oral

(Z)-octadec-9-enylamine (112-90-3)

The absorption of (Z)-octadec-9-enylamine was assessed by the EU in a Risk Assessment Report (2008). Based on the physical and chemical properties, the oral bioavailability is expected to be low. However, based on animal toxicology studies (acute and repeat dose), where effects were observed, absorption is known to occur through this route. 

 

Dibutyl hydrogen phosphate (107-66-4)

Dibutyl hydrogen phospahte is likely bioavailable through the oral route. Based on the ECHA guidance R.7.C (R.7.12), the physical and chemical parameters are optimal for oral absorption:

- MW <500

- Highly water soluble

- Kow between -1 and 4

- Acute and repeat dose toxicity data indicate oral bioavailability (OECD, 1994)

 

Butyl dihydrogen phosphate (1623-15-0)

Butyl dihydrogen phosphate is likely bioavailable through the oral route. Based on the ECHA guidance R.7.C (R.7.12), the physical and chemical parameters are optimal for oral absorption:

- MW <500

- Highly water soluble

- Kow between -1 and 4

 

Di-n-hexyl dithiophosphoric acid (78-64-8)

Dihexyl dithiophosphate is expected to have limited oral bioavailability. Based on the ECHA guidance R.7.C (R.7.12), the physical and chemical parameters show some aspects that would favor oral absorption while other aspects are expected to limit oral bioavailability:

- Likely ionisable based on acid properties and the presence of a thiol group – this is expected to limit absorption

- MW <500

- Limited water solubility

- Kow greater than 4, which is not optimal for oral absorption

 

2. Dermal

 

(Z)-octadec-9-enylamine (112-90-3)

The TK of (Z)-octadec-9-enylamine was assessed by the EU in a Risk Assessment Report (2008). The dermal absorption is expected to be variable based on concentration (i.e., higher concentrations are corrosive, which will likely result in enhanced penetration through damaged skin) and physical state/presence of solvent. The EU RAR (2008) assumes 60% dermal absorption of primary alkyl amines as a worst-case scenario. 

 

Dibutyl hydrogen phosphate (107-66-4)

Dibutyl hydrogen phosphate is likely bioavailable through the dermal route. Based on the ECHA guidance R.7.C (R.7.12), the physical and chemical parameters are optimal for dermal absorption:

- MW <500

- Water soluble

- Kow between -1 and 4

 

Butyl dihydrogen phosphate (1623-15-0)

Butyl dihydrogen phosphate is likely bioavailable through the dermal route. Based on the ECHA guidance R.7.C (R.7.12), the physical and chemical parameters are optimal for dermal absorption:

- MW <500

- Water soluble

- Kow between -1 and 4

 

Di-n-hexyl dithiophosphoric acid

Dihexyl dithiophosphate is expected to have limited dermal bioavailability. Based on the ECHA guidance R.7.C (R.7.12), the physical and chemical parameters show some aspects that would favor dermal absorption while other aspects are expected to limit dermal absorption:

- MW <500

- Limited water solubility – water solubility is expected to be approximately 1.2 mg/L and materials with water solubility less than 1 mg/L are expected to have low dermal bioavailability

- Kow greater than 4, which is not optimal for dermal absorption

 

3. Inhalation

 

EC 434-280-4 and the starting materials all have low vapor pressure, indicating that inhalation exposure is unlikely. Based on the physical and chemical properties, absorption through the respiratory tract if the material is aerosolized may occur. However, aerosolization is not expected to occur as a relevant exposure route.

 

Distribution

 

There are no to limited data on how the starting materials of EC 434-280-4 will distribute after absorption. (Z)-octadec-9-enylamine is the most relevant starting material as it is the source of the observed target organ toxicity. Based on the EU RAR (ECHA, 2008), primary alkyl amines are distributed into the lungs, brain, heart, spleen, kidney and liver. In addition, the repeat dose data for EC 434-280-4 (OECD 407) resulted in macrophage accumulation in the small intestine and mesenteric lymph nodes, most likely as a result of phagocytosed material.

 

Based on the Ps&Cs, DHP and BAP are likely distributed throughout the body.

 

Metabolism

 

For dibutyl hydrogen phosphate, butyl dihydrogen phosphate, and dihexyl dithiophosphate, metabolism is modeled using LMC OASIS TIMES v2.27.17.6 in vivo rat v.07.07 simulator to support literature information or where there is no existing metabolism information. All modeling reports are attached in separate TK endpoints.

 

(Z)-octadec-9-enylamine (112-90-3)

The metabolism of (Z)-octadec-9-enylamine was assessed by the EU in a Risk Assessment Report (2008). Alkylamines are oxidatively deaminated by monoaminooxidases forming ammonia and the corresponding alkylamine aldehyde. The aldehydes are then oxidised by aldehydedehydrogenases to the corresponding carboxylic acids, which are further metabolised by ß-oxidation.

 

 

Dibutyl hydrogen phosphate and butyl dihydrogen phosphate

A study with tributyl phosphate (CAS 126-73-8), administered a single I.P. dose to rats, found the principle metabolic pathway is a stepwise debutylation to yield predominantly dibutyl hydrogen phosphate and some butyl dihydrogen phosphate (Suzuki et al., 1984; OECD, 2001). This demonstrates that dibutyl phosphate will be metabolized to butyl dihydrogen phosphate, but the amount and rate is uncertain – based on the Suzuki et al (1984) study, only 11-21% was formed.

 

Dibutyl phosphate is metabolized by phosphate ester hydrolysis to the mono substituted alkyl phosphate (i.e., CAS 1623-15-0), which is demonstrated by modeling with OASIS TIMES in vivo rat metabolism simulator (v.07.11). Approximately 40% is predicted to undergo phosphate ester hydrolysis (modeling report attached; 40% is based on adding the mol/mol parent of all transformation products that have undergone phosphate ester hydrolysis). The substance has an observed map in the training set and is 100% in the models parametric and structural domain, demonstrating high confidence in this prediction.

 

For butyl dihydrogen phosphate, OASIS TIMES in vivo rat metabolism simulator (v.07.11) predicts glucuronidation will occur either directly to the free alcohol on the phosphate group or on the alkyl side chain after oxidation (approximately 75%). Approximately 25% will undergo dephosphorylation to butyl alcohol.

  

Di-n-hexyl dithiophosphoric acid (DHDPA)

OASIS TIMES in vivo rat metabolism simulator (v.07.11) predicts two primary routes of metabolism (approximately 50% each): The first is methylation of the sulfhydryl group; the second is oxidative desulfuration, transforming the thio group to an oxo group. After oxidative desulfuration, phosphate ester hydrolysis occurs followed by oxidation and glucuronidation.  

 

 Excretion

 

(Z)-octadec-9-enylamine (112-90-3)

According to the EU Risk Assessment Report (2008), (Z)-octadec-9-enylamine is excreted to a minor extent in the urine. Carbon dioxide, which is a final breakdown product formed, will be exhaled.

 

Dibutyl hydrogen phosphate and butyl dihydrogen phosphate

No information was found on the excretion. However, tributyl phosphate is primarily excreted via the urine (OECD, 2001). Therefore, it is likely that these two constituents of EC 434-280-4 are also excreted primarily through the urine.

 

Di-n-hexyl dithiophosphoric acid

No information is available on the route of excretion.