Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance 1,2-Diethoxypropane is an organic mono-constituent liquid with a purity of ≥99.5% and impurities at ≤0.5%.

A full ADME toxicokinetic study in the rat is not available. The toxicokinetic analysis is based on the physicochemical and in vivo toxicological data. In vivo studies covering the oral route (acute toxicity, 28 day repeated dose toxicity, Chernoff/Kavlock preliminary screening developmental toxicity test) and dermal route (GPMT) are available. No studies via the inhalation route are available. Further details on the endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical data and available in vivo toxicological data, 1,2-Diethoxypropane can be absorbed via the oral, dermal and inhalation routes. 1,2-Diethoxypropane is distributed throughout the body, is metabolised in the liver and is likely to be excreted in the urine.

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

1.Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of 1,2-Diethoxypropane in the body.

Absorption - oral

The molecular weight of 1,2-Diethoxypropane (132.2 g/mol) is in the range for favourable oral absorption (<500 g/mol). The substance is very soluble in water (52 g/L(pH=7) at 25°C) so should readily dissolve in the gastrointestinal fluids. The log Kow of 1,2-Diethoxypropane (1.1 at 22±0.5°C) is in the range favourable for passive diffusion.

Absorption – dermal

The molecular weight and log Kow of 1,2-Diethoxypropane are in the favourable range for dermal absorption.  However, due to the moderate volatility (1915 Pa at 20°C), the amount available for uptake may be reduced.

Absorption – inhalation

1,2-Diethoxypropane is a moderately volatile liquid (1915 Pa at 20°C), so there will be exposure via the inhalation route. 1,2-Diethoxypropane has a moderate log Kow which is favourable for absorption. As a very hydrophilic substance, the rate of systemic uptake may be limited by the rate at which it can partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. It may be transported out of the deposition region with the mucus and swallowed or may pass across the respiratory epithelium via aqueous membrane pores.

Distribution/Metabolism/Excretion

Based on the molecular weight, water solubility and lipophilicity, 1,2-Diethoxypropane is likely to be widely distributed in the body but not accumulate; excretion is expected via the urine.

2. Information from other studies in the dossier

Absorption - oral

In an acute oral toxicity study (equivalent or similar to OECD 401/GLP), the LD50 was > 2000 mg/kg bw with minimal clinical signs up to 4 hrs after dosing.

In a sub-acute toxicity study (equivalent or similar to OECD 407/GLP), 1,2-Diethoxypropane (99.54%) was administered by gavage to Sprague-Dawley rats (5/sex/group) in distilled water with 2% Tween 80 at 0, 10, 100 or 1000 mg/kg bw/day for 28 days. There were no premature deaths. Clinical reaction to treatment which included piloerection and sleepy and/or subdued behaviour was seen in High dose males and females post dose from Day I to Day 9 of the study. There were no notable intergroup differences in either sex in body weights, food consumption, haematological or clinical chemistry parameters. A slight, equivocal increase in kidney weight was seen in High dose males and females; there were no related histological changes. Centrilobular hepatocyte hypertrophy in the liver was increased in incidence but not severity in High dose males, this change may relate to the slight, equivocal increase in liver weight seen in High dose males and females. Since the centrilobular hepatocyte hypertrophy was graded as very mild and seen in males only its reproducibility is considered to be doubtful. The changes noted in the male livers are more than likely adaptive but as the dosing interval was 10-fold, a NOAEL of 100 mg/kg bw/day was selected, as a conservative approach.

In a Chernoff/Kavlock preliminary screening developmental toxicity test (no guideline/GLP), 1,2-Diethoxypropane in distilled water with 2% Tween 80 was administered to 10 female Sprague-Dawley rats/dose by gavage at dose levels of 0, 1000 or 1600 mg/kg bw/day from days 6 through 16 of gestation. Ethylene glycol diethyl ether (EGDE), a known developmental toxin was used as a positive control (1000 mg/kg bw/day). Maternal toxicity was demonstrated at 1600 and 1000 mg/kg bw/day DEP and at 1000 mg/kg bw/day EGDE, by a reduction in body weight and food consumption, and by clinical signs of toxicity. The toxicity observed at 1000 mg/kg bw/day DEP and at 1000 mg/kg bw/day EGDE was of a comparable magnitude. Marked embryotoxicity was demonstrated at 1000 mg/kg bw/day EGDE with the 9 pregnant animals resorbing their litters. At 1000 mg/kg bw/day DEP, however, the offspring were considered to have been unaffected. Effects on the offspring of the DEP treated animals were limited to a slight reduction in pup weight on Day 4 of lactation, at 1600 mg/kg bw/day DEP. The maternal LOAEL was 1000 mg/kg bw/day; the NOAEL (offspring) was 1000 mg/kg bw/day.

Based on the physicochemical data and available in vivo toxicological data, there is systemic absorption after oral administration. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

Absorption – dermal

In a GPMT sensitization study (OECD406/GLP), there were minimal signs of skin irritation and the substance was not a skin sensitiser. Based on the physicochemical data and available in vivo toxicological data, dermal absorption is likely to be low. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption – inhalation

No inhalational toxicity study data is available. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, using a conservative approach.

Distribution/Metabolism/Excretion

Based on the physicochemical data and available in vivo toxicological data, 1,2-Diethoxypropane is distributed throughout the body, is metabolised in the liver and is likely to be excreted in the urine.