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Registration Dossier
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EC number: 906-265-7 | CAS number: -
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 70 mg/m³
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- skin irritation/corrosion
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 106 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 42
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- low hazard (no threshold derived)
Additional information - workers
The context of this discussion is deriving an appropriate DNEL for the dermal route. A contribution from sodium acetate is discounted because, as an ionic substance, uptake through the skin is likely to be very low compared to the other components. Of the remaining components, monoethylene glycol (MEG, ethan-1,2-diol) is the most toxic and is the one with the most data and the one present in the highest concentration, as a conservative approach, the DNEL calculations are made on the assumption that the substance is 100% MEG.
The critical effects of Mono-ethylene glycol (MEG) after acute exposure are (in 3 subsequent stages) CNS toxicity, metabolic acidosis, and renal toxicity. Lethal effects in human adults (case reports from accidents, misuse, or suicidal attempts) occur from doses of 1600 mg/kg bw onwards, metabolic acidosis being strongly related to glycolic acid (GA) production and renal toxicity to oxalic acid (Hess et al., 2004).
Repeated oral exposure to sub-lethal doses may lead to oxalate nephrosis (renal destruction by Ca-oxalate crystals) and is therefore considered to relevant for a STOT classification.
In terms of renal toxicity, rats appear to be more resistant than rabbits and less resistant than mice (NTP, 2004), however, also different strains of rats may show different sensitivities with more severity and more accumulation of oxalate in the kidneys of Wistar rats than Fischer rats (Cruzan et al., 2004). All subchronic and chronic oral studies in rats appear to converge in a NOAEL around 150 mg/kg bw and day (Corley et al., 2008).
In terms of developmental toxicity, mice (with critical doses from 500 mg/kg bw and day onwards) are more sensitive than rats (1000 mg/kg bw and day onwards) and rats as more sensitive than rabbits. In fact, rabbits appeared to be refractory and showed no developmental toxicity at oral doses of 1000 and 2000 mg/kg and day; these doses, in contrast to rats, led to pronounced maternal toxicity in the rebbits (Tyl et al., 1993). Rabbit pregnancies are not dependent on the inverted yolk sac placenta like rats and mice. There are reasons to assume that also humans, like rabbits, are either refractory or less prone to MEG-related developmental toxicity than rats and mice (Carney et al., 1994; NTP, 2004). For the onset of prenatal toxicity a saturation of glycolic acid oxidation appears to be critical.
A spontaneous formation and renal excretion of the MEG metabolites glycolic acid and oxalic acid has been noted in the human organism. This natural background can be set into perspective with biomonitoring results after occupational exposure. It has been shown that 4 hrs of MEG inhalation exposure to 25 mg/m3 or, equivalently, 6 hrs of dermal exposure to liquid MEG on a 66 cm2 skin surface led to an excretion rate of these metabolites at rates of 15 % and 2.2 %, respectively, above the naturally occuring levels (Upadhyay et al., 2008).
DNEL long term dermal systemic: Explanation and justification for using dermal dog sub-acute study as a starting point: The key study is a set of two subsequent dermal 28 day studies in dogs (BASF, 1991) which were undertaken for the assessment of local and systemic toxicity of undiluted MEG including an ingredient, para-tert.-butylbenzoic acid (PTBBA; 1.42 % as sodium-salt) which is known for a potential of testicular toxicity. The undiluted formulation was spread on 30 % of the body surface. In a first study, dose levels of 0.5, 2 and 8 ml/kg bw and day were administered. In the top dose, severe nephrotoxicity (including lethalities) was observed and also some testicular toxicity. The latter was considered to be more a sequel of PTBBA than of renal toxicity. At 2 ml/kg bw and day (2220 mg/kg bw and day) there was an increase of urinary oxalate crystal formation which was considered as not adverse due to the absence of histological findings. In a second study, 2 and 4 ml/kg bw were employed; with this dose design a NOAEL of 4 ml /kg bw (4440 mg/kg bw) was identified. Again, an increase of urinary oxalate crystal formation could be detected but no adverse histopathological findings. The NOAEL of 4440 mg/kg bw is also supported by the results of a dermal developmental study in mice in which undiluted MEG at a dose level of 3500 mg/kg bw was considered a NOAEL for renal toxicity (Tyl et al., 1995). The large difference between the NOAELs from oral studies in rats and the dermal study in dogs may be explained, first of all, by the fact that the dermal resorption of MEG is much more limited than from oral uptake (Sun et al., 1995). Moreover, dogs and humans have a higher renal clearance rate for oxalic acid than rats (Corley et al., 2008). This may indicate that the allometric factor of 4 (between rats and humans) is well-based for acute toxicity but much less substantiated for (sub)chronic toxicity (oxalate nephrosis).
References
BASF, (1991)
Carney et al., Reprod.Toxicol. 8, 99 -113 (1994).
Corley et al., Toxicol.Appl.Pharmacol. 228, 165 -178 (2008).
Cruzan et al. Toxicol.Sci. 81, 502 -511 (2004).
Frantz et al., Xenobiotica 26, 1195 -1220 (1996).
Hess et al., Arch.Toxicol. 78, 671 -680 (2004).
Loden et al., Acta pharmacol. et toxicol. 58 (1986).
MAK-documentation (1991).
NTP, Reprod.Toxicol. 18, 457 -532 (2004).
Pottenger et al., Toxicol. Sci. 62, 10 -19 (2001).
Sun et al., (1995). - - ten Berge (2009).
Tyl et al., FAT 20, 402 -412 (1993)
Tyl et al., FAT 27, 155 -166 (1995).
Upadhyay et al., Toxicol. Lett. 178, 132 -140 (2008).
Wills et al., Clin.Toxicol. 7, 463 -476 (1974).-
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 35 mg/m³
Acute/short term exposure
- Hazard assessment conclusion:
- low hazard (no threshold derived)
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- skin irritation/corrosion
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 53 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 84
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.25 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 80
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 19 mg/kg bw/day
- Most sensitive endpoint:
- acute toxicity
DNEL related information
- Overall assessment factor (AF):
- 100
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- low hazard (no threshold derived)
Additional information - General Population
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