Amines, N-C10–C16-alkyltrimethylenedi-, reaction products with chloroacetic acid

Endpoint summary

Description of key information

Based on physicochemical properties and identified uses, the potential for inhalation of components of DOPA-Glycinate either as vapour or dust appears marginal.
The oral bioavailability was determined to be 34% (OECD guideline 417, GLP; rat).
The systemically available dose after dermal administration was determined to be 0.6±0.6% for the high exposure scenario (20% a.i.), and 5.0±2.5% for the low exposure scenario (0.2% a.i.), respectively (OECD guideline 428, GLP; human skin).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

5

Absorption rate - inhalation (%):

100

Additional information

Inhalative absorption

The substance is a 20% aqueous solution of the active matter DOPA-Glycinate (“product by process”), which is not volatile (vapour pressure < 1.9 × 10^–4 Pa). The active substance is neither a powder nor is it to be included in powdery preparations. Furthermore, the substance is not intended to be applied in a manner leading to generation of aerosols, particles or droplets in the inhalable size range (MMAD < 50 µm). Therefore, the potential for inhalation of components of DOPA-Glycinate either as vapour or dust appears marginal.

However, for chemical safety assessment by default 100% absorption will be assumed in accordance with REACH TGD as no experimental data concerning absorption after inhalative exposure are available.

 

Oral absorption

Absorption of [¹⁴C]- DOPA-Glycinate (20% a.i.) was investigated in the rat (OECD guideline 417). The test substance was administered orally by gavage at two single dose levels of 30 and 100 mg/kg bw, singly intravenous and orally at one repeated low dose level.

The systemic bioavailability, assessed by comparison of plasma radioactivity after oral and intravenous administration, was 34%.

This finding is also supported by the physicochemical properties: DOPA-Glycinate is freely miscible with water (>200 g/L, according to the product being a 20% aqueous solution). In view of the amphoteric properties, the log Dow has been estimated by QSAR at 2.33. Consequently, DOPA-Glycinate may be assumed to be readily dissolved in gastrointestinal fluids and subsequently available for passage through the epithelial barrier of the GI tract by passive diffusion.

Also the toxicological signs observed in the 90-d studies in rats at relatively low doses (approx. 3.0–20 mg a.i./kg bw/d) suggest high oral absorption. 

The Guidance on Information requirements and Chemical Safety Assessment, R.7c (Nov. 2012) states: “In practice, an adjustment in oral toxicity factor (to account for absorbed dose in the dermal exposure pathway) is recommended when the following conditions are met: (1) the toxicity value derived from the critical study is based on an administered dose (e.g., delivery in diet or by gavage) in its study design; (2) a scientifically defensible database demonstrates that the GI absorption of the chemical in question, from a medium (e.g., water, feed) similar to the one employed in the critical study, is significantly less than 100% (e.g., <50%). A cut-off of 50% GI absorption is recommended to reflect the intrinsic variability in the analysis of absorption studies. Thus, this cut-off level obviates the need to make comparatively small adjustments in the toxicity value that would otherwise impart on the process a level of accuracy that is not supported by the scientific literature.”

Thus an oral absorption of 50% will be used for chemical safety assessment.

 

Dermal absorption

The percutaneous absorption of [¹⁴C]-DOPA-Glycinate was tested according to OECD guideline 428 (A6.2/03) in an in vitro study at two different concentrations. It could be shown for a 20% test preparation(aqueous solution) that99.76 % of the applied dose was removed from the skin by washing at 6 h post application. With a mass balance of 101.7% it was concluded that the absorbed dose, dermal delivery and potentially absorbable dose were 0.01 % (0.18 ng equivalent/cm²), 0.62 % (13.17 ng equivalent /cm²) and 0.97 % (20.53 ng equivalent /cm²), respectively. The second test preparation, 0.2% [¹⁴C]-DOPA-Glycinate as aqueous solution, resulted in 73.66 % removable dose by washing at 6 h post application and 0.11 % (0.02 ng equivalent /cm²), 5.04 % (1.01 ng equivalent /cm²) and 11.42 % (2.28 ng equivalent /cm²) of the applied dose, absorbed dose, dermal delivery and potentially absorbable dose, respectively (97.1 % mass balance).

 

According to the Guidance on Information requirements and chemical safety assessment, R.7c: "Dermal absorption represents the amount of topically applied test substance that is found in the epidermis (stratum corneum excluded) and in the dermis, and this quantity is therefore taken as systemically available. Dermal absorption is influenced by many factors, e.g. physico-chemical properties of the substance, its vehicle and concentration, and the exposure pattern (e.g. occlusion of the application site) as well as the skin site of the body […]. The term percutaneous penetration refers to in vitro experiments and represents the amount of topically applied test substance that is found in the receptor fluid – this quantity is taken as systemically available."

 

Thus, the systemically available dose of DOPA-Glycinate (= dermal delivery: exposed skin + absorbed dose) was 0.6±0.6% for the high exposure scenario (20% a.i.), and 5.0±2.5% for the low exposure scenario (0.2% a.i.), respectively. The high exposure scenario (20% a.i.) is relevant for chemical safety assessment of worker uses. A dermal absorption of 1% will be applied for those assessments.

The low exposure scenario (0.2% a.i.) is relevant for the chemical safety assessment of consumer uses. For those assessments, a dermal absorption of 5% will be applied.

Distribution, metabolism and excretion

Distribution, metabolism and excretion of [¹⁴C]- DOPA-Glycinate (20% a.i.) were investigated in the rat according to the OECD test guideline 417. The test substance was administered orally by gavage at two single dose levels of 30 and 100 mg/kg bw, singly intravenous and orally at one repeated low dose level.

Upon oral administration, radioacitivity was predominantly eliminated via faeces (approx. 60 %) and via expired air (approx. 18 %). A lower proportion was excreted via urine (approx. 9 %) and less than 20 % of the administered dose was found in the carcass. No significant differences of absorption and elimination of test substance regarding high or low dose, repeated administration or sex could be identified. The recovery of radioactivity was greatest in the residual carcass (12–19 %), followed by the liver (approx 4 %). In all other tissues the radioactive recovery was low (≤ 1.00 %) and quite uniformly distributed, with no tissue storage in brain, heart, ovaries and spinal cord. There was no relevant difference in the tissue distribution of radioactivity between animals treated orally or intravenously with a single or repeated dose of the test substance. The elimination half-life was approx. 74 hours both in the p.o. and i.v. group.

In plasma, only parent substances but no transformation products could be identified. A first-pass effect following intestinal absorption is therefore unlikely. In urine and faeces, parent substances as well as transformation products were detected. Metabolites in both urine and faeces were characterised by oxidation (hydroxylation) of the parent and some other metabolites like dehydrogenated and acetylated compounds. The most abundant compounds in urine were the oxidation products.