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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA guidance with modification to interspecies factor
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Value:
700 mg/m³
Explanation for the modification of the dose descriptor starting point:
There is no inhalation study, so the NOAEL for oral dosing is used as a starting point with route to route extrapolation. The starting point is a NOAEL of 100mg/kgbw/day from a sub-chronic study in rats. Assuming a 70kg person and a inhaled volume of 10m3/8hr working day and 100% absorption, this equates to a NOAEC of 700mg/m3 (theoretical concentration).
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
default for inhalation study
AF for other interspecies differences:
1
Justification:
no additional factor is required.
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
33.5 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
other: data from human volunteer studies
Overall assessment factor (AF):
2
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
1
Justification:
no additional factor required
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable, human data
AF for other interspecies differences:
1
Justification:
not applicable, human data
AF for intraspecies differences:
2
Justification:
factor considered adequate based on experimental data
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
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
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECHA guidance with modification to interspecies factor
Overall assessment factor (AF):
42
Modified dose descriptor starting point:
NOAEL
Value:
4 440 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic factor
AF for interspecies differences (allometric scaling):
1.4
Justification:
dog to human factor
AF for other interspecies differences:
1
Justification:
no additional factor considered necessary
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
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:
no hazard identified

Additional information - workers

The context of this discussion is deriving an appropriate DNEL for the dermal route. Of the three 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 systemic inhalation: This is derived using route to route extrapolation to provide a starting point then appropriate assessment factors to produce the resultant DNEL. Note that this DNEL will be relevant when there is exposure to vapours.

DNEL acute inhalation: Inhalation exposure to MEG aerosols was shown to cause sensory irritation at concentrations higher than 140 mg/m3 in a human volunteer study. A concentration of 75 mg/m3 was well tolerated in a pilot experiment in four men. In a subsequent experiment with 20 volunteers 67 mg/m³ were confirmed as a NOAEC for a daily working-shift exposure over 1 week (Wills et al., 1974). Combined with a general assessment factor of 2 this NOAEC would result a DNEL of 35 mg/m3 for chronic local irritation. The internal dose obtained from an inhalation exposure under the conditions of the DNEL would be equivalent to an internal dose of 5 mg/kg bw which is approximatedly 30-fold below the oral NOAEL in rodents and, hence, the local DNEL should protect also from systemic toxicity. A more recent investigation (Upadhyay et al., loc. cit.) shows that under conditions of the German MAK value (25 mg/m3) the excretion of oxalic acid and glycolic acid is in the range of the natural background. Note that this DNEL is relevant when there is potential for exposure to aerosols.

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
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA guidance with modification to interspecies factor
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
Value:
700 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no known uses of this multi-component substance in aerosol form, therefore only a DNEL for vapour inhalation is considered relevant. There is no inhalation study, so the NOAEL for oral dosing is used as a starting point with route to route extrapolation. The starting point is a NOAEL of 100mg/kgbw/day from a sub-chronic study in rats. Assuming a 70kg person and a inhaled volume of 10m3/8hr working day and 100% absorption, this equates to a NOAEC of 700mg/m3 (theoretical concentration).
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default for sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
default for inhalation study
AF for other interspecies differences:
1
Justification:
no additional factor is required.
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
other: data from human volunteer studies
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
1
Justification:
no additional factor required
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable, human data
AF for other interspecies differences:
1
Justification:
not applicable, human data
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
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
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECHA guidance with modification to interspecies factor
Overall assessment factor (AF):
84
Modified dose descriptor starting point:
NOAEL
Value:
4 440 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic factor
AF for interspecies differences (allometric scaling):
1.4
Justification:
dog to human factor
AF for other interspecies differences:
1
Justification:
no additional factor considered necessary
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
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
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA guidance with modification to interspecies factor
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
2
Justification:
default, sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
default, rat to human
AF for other interspecies differences:
1
Justification:
no additional factor considered necessary
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
default
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
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
LOAEL
AF for dose response relationship:
5
Justification:
end point is lethality - other effects may occur at lower doses
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable, human data
AF for other interspecies differences:
1
Justification:
not applicable, human data
AF for intraspecies differences:
10
Justification:
default
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
2
Justification:
overall additional factors for quality and accuracy of data used.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

See discussion for workers. All DNELs for consumers are based on derivations as for workers with additional factors as shown.