Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
35 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and expert judgement
Overall assessment factor (AF):
2
Dose descriptor:
NOAEC
DNEL value:
67 mg/m³
AF for intraspecies differences:
2
Justification:
Expert judgement for potential intraspecies variation concerning MEG aerosol sensitivity in order to avoid unspecific sensitivities towards MEG aerosoles in workers during spraying.
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:
ECHA REACH Guidance
Overall assessment factor (AF):
42
Dose descriptor starting point:
NOAEL
DNEL value:
4 440 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: starting point - subacute (NOAEL dermal derived from an OECD 410 study) to chronic (end point).
AF for interspecies differences (allometric scaling):
1.4
Justification:
The default allometric scaling factor for the differences between dogs and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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 critical effects of Mono-ethylene glycol (MEG) after acute ingestion 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 sublethal doses may lead to oxalate nephrosis (renal destruction by Ca-oxalate crystals) and is therefore considered to be 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 rabbits (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 GA 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).

 

The following DNELs were not derived:

- acute dermal and acute inhalation exposure (systemic and local): MEG needs no classification for dermal and inhalation toxicity nor for sensitisation or irritancy.

- chronic dermal exposure (local effects): No significant local effects have been observed in a repeated dose study (BASF, 1991). The systemic chronic dermal DNEL (see below) therefore should protect also from local effects.

- chronic inhalation (systemic): the local DNEL is considered to be protective also from systemic effects (MAK-doc., 1991; see also below).

 

DNEL- long term, inhalation, local:

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 in 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.

 

DNEL- long-term, dermal, systemic:

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).

 

The NOAEL from the dermal dog study is taken as the point of departure for the calculation of the dermal DNEL. The following assessment factors are proposed: 1.4 for allometric extrapolation from dog to man, 6 for time extrapolation and 5 for intraspecies variation. The resulting overall assessment factor is 42 and generates from a NOAEL of 4440 mg/kg bw a systemic chronic dermal DNEL of 106 mg/kg bw and day. This value is still lower than the NOAELs from the existing oral studies in rats (150 mg/kg bw and day).

 

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:
no hazard identified
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:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
DNEL value:
67 mg/m³
AF for intraspecies differences:
10
Justification:
Default factor for potental intraspecies variation concerning MEG aerosol sensitivityn in order to avoid unspecific sensitivities towards MEG aerosoles in the general population / among customers during spraying.
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:
ECHA REACH Guidance
Overall assessment factor (AF):
84
Dose descriptor starting point:
NOAEL
DNEL value:
4 440 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor for exposure duration is used: starting point - subacute (NOAEL dermal derived from an OECD 410 study) to chronic (end point).
AF for interspecies differences (allometric scaling):
1.4
Justification:
The default allometric scaling factor for the differences between dogs and humans is used.
AF for other interspecies differences:
1
Justification:
Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "consumer" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

No oral DNELs are proposed since there is no designed oral exposure towards MEG.

For occasional dermal and inhalative exposure from consumer products such as antifreeze agents a chronic systemic DNEL for dermal exposure is proposed which is derived like the dermal DNEL for the workplace but employes a higher intraspecies assessment factor of 10 instead of 5.

This DNEL is assumed to be also protective from local effects on the skin. Furthermore, a chronic inhalation DNEL (local) is proposed for local irritation from aerosol spraying. A default factor for potental intraspecies variation concerning MEG aerosol sensitivity of 10 is proposed (instead of 2 in case on the work-place DNEL) in order to avoid unspecific sensitivities towards MEG aerosoles in the general population / among customers during spraying.