Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
178.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
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:
DNEL (Derived No Effect Level)
Value:
357 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 100 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
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
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

In Appendix R.8-13 of the Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (ECHA, 2008) it is noted that:

‘When an EU IOEL exists the registrant may, under conditions as described below, use the IOEL in place of developing a DNEL. A registrant is allowed to use an IOEL as a DNEL for the same exposure route and duration, unless new scientific information that he has obtained in fulfilling his obligations under REACH does not support the use of the IOEL for this purpose. This could be because the information obtained is more recent than the information that was used to support setting the IOEL at EU level and because it leads to another value being derived which requires different risk management measures (RMMs) and operational conditions (OCs)’.

In the case of MTBE a final SCOEL evaluation is available (SCOEL, 2006). The summary of the SCOEL evaluation is as follows:

Animal studies in mice and rats reveal a spectrum of tumours induced by MTBE in liver, kidney, parathyroid and Leydig-cells that occur only at high doses (> 250 mg/bw after oral administration and > 3000 ppm in inhalation studies). Neither the kidney tumours caused by alpha-2-microglobulin and, consequently, the parathyroid tumours seen in male rats, nor the liver tumours in female mice which were seen also in the control animals seem to be of relevance for human health. The same is true for the Leydig-cell tumours. There are neither epidemiological studies addressing a possible association of MTBE with human cancer, nor grounds for assuming there to be a concern. MTBE is not genotoxic. Therefore, a threshold for the carcinogenic potential of this compound is assumed.

Studies on toxicokinetics concluded that MTBE or its metabolites do not accumulate in humans.

Experimental animal studies involving repeated inhalation exposure indicate no effects of toxicological significance for human health below 1000 ppm, with effects having been reported only at 3000 ppm and above. There are no relevant data for the toxicity of MTBE in man after repeated exposure.

In a human volunteers study (FIOH, 1997), mild symptoms, mainly feeling of "heaviness in the head", and mild mucosal irritation were reported. The frequency of symptoms was related to the exposure level (0, 25, 75 ppm) and reached statistical significance at 75 ppm after 3h of exposure to MTBE. No effects were seen on simple reaction time or body sway posturography. This study suggests a LOAEC of 75 ppm.

In another volunteer study Nihlén et al (1998) found no increased ratings of either irritation, or CNS effects. Further, none of the objective measurements indicated any irritative or inflammatory response (blinking frequency, eye redness score, tear-film break-up time, conjunctival epithelial damage score, inflammatory markers in nasal lavage, nasal acoustic rhinometry, nasal blockage index). This study suggests a NOAEC for short-term exposure of 50 ppm.

Taking into account the low inhalation toxicity in animal studies, the NOAEC of 50 ppm for irritation in humans and the mild effects seen after several hours at 75 ppm, the SCOEL proposed an 8-h TWA of 50 ppm (178.5 mg/m3) and a 15-min STEL of 100 ppm (357 mg/m3).

Kinetics

The oral, inhalation and dermal absorption percentages used for DNEL derivation (in cases of route-to-route extrapolation) are 100%, 40% and 0.2%, respectively.

Acute toxicity

Regarding acute toxicity, the DNELacute needs only be derived if an acute toxicity hazard (leading to classification and labelling) has been identified and peak exposures are likely to occur. The data support classification of MTBE for skin irritation, however, it is not possible to derive a DNEL on the basis of the available data. It is necessary to implement risk management measures that prevent dermal exposure that will cause skin irritation.

Nevertheless, there is a published IOELV STEL (derived by the SCOEL, see above) of 100 ppm for MTBE. This value will used in the risk characterisation as an acute DNEL (workers) or as an starting point to derive an acute DNEL (general population).

Long-term toxicity

The inhalation NOAEC for MTBE is 800 ppm (2856 mg/m3) (6 hours/day, 5 days/week) based on mild liver effects noted in a 90-day inhalation rat study. The oral NOAEL for MTBE is 209 mg/kg bw/day based on increased relative kidney weights in male and female rats in a 13 week drinking water study.

No dermal repeated dose toxicity studies are available. In general, due to the effective lipid extraction properties of MTBE, it can be presumed that repeated skin exposure may result in skin fatigue (and consequent risk of toxic eczema), an effect common to a variety of organic solvents. No quantitative data on this effect are available. Therefore a qualitative risk characterisation will be performed.

MTBE is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

Based on the available data, MTBE is not considered as toxic to fertility in rats and mice. Therefore, no DNEL has to be derived for this endpoint. Developmental effects were only observed at maternally toxic concentrations in rats and mice (from 3000 ppm (10710 mg/m3)) and do not trigger classification for developmental toxicity. The long-term DNEL (repeated dose toxicity) will also prevent the occurrence of developmental toxicity.

Furthermore, there are no indications from the available data that dams are more sensitive regarding systemic effects compared to non-pregnant animals exposed in the repeated dose toxicity studies.

DNEL calculations

Inhalation exposure

After the date of finalisation of the SCOEL evaluation, some new toxicological data was published (which are included in this dossier). These new data are not considered key and do not change the conclusions of the SCOEL. Therefore, the 15-min STEL of 100 ppm (357 mg/m3) and the 8-h TWA of 50 ppm (178.5 mg/m3) as recommended by the SCOEL will be used as DNEL for acute and long-term for inhalation exposure, respectively.These figures will also protect against the occurrence of reproductive toxicity as the SCOEL also considered the available reproductive toxicity data for MTBE.

Dermal exposure

Regarding dermal exposure, no dermal repeated dose toxicity studies are available. To arrive at a long-term value for workers, route to route extrapolation will be applied starting with the inhalation long-term value of the SCOEL:

 178.5 mg/m3* 40/0.2 (a) * 10 m3(b) / 70 kg (c) = 5100 mg/kg bw/day

(a) correction for absorption (40% inhalation and 0.2% dermal absorption)

(b) 8 hour respiratory volume for workers

(c) body weight for workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
53.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1.7
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:
DNEL (Derived No Effect Level)
Value:
214 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
1.7

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 570 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
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
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
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

Background information relevant to the development of DNELs for the general population (including the available key animal data its interpretation by SCOEL (2006)) is discussed above.

 DNEL calculations

Inhalation exposure

Regarding acute exposure, the SCOEL has established a15-min STEL of 100 ppm (357 mg/m3). The SCOEL value is derived for workers. To arrive at a long-term value for the general population, a factor for intraspecies differences will be applied to the 15-min STEL. This factor is derived from the scientifically based assessment factors reported by ECETOC (2010) (see later):

 

100 ppm (357 mg/m3) * 3/5 (a) = 60 ppm (214 mg/m3)

(a) correction for intraspecies differences: workers default factor: 3, general population default factor: 5

No correction for exposure duration isapplied as the STELvalue is largely driven by sensory irritation effects which are influenced by concentration and not time.

No correction for differences in activity levels between workers and the general population is applied. As workers have a higher ventilation rate compared to the general population, the current proposed acute DNEL for the general population is considered a worst-case acute DNEL.

 

Regarding long-term exposure, the SCOEL has established an 8-h TWA of 50 ppm (178.5 mg/m3). The SCOEL value is derived for workers. To arrive at a long-term value for the general population, a factor for exposure modification and intraspecies differences will be applied to the 8-h TWA (assuming ‘recovery’ to ‘no recovery’):

 

50 ppm (178.5 mg/m3) * 10/20 (a) * 3/5 (b) = 15 ppm (53.6 mg/m3)

(a) modification based on differences in exposure duration and activity (10 m3 in 8 h for workers, 20 m3 in 24 h for the general population)

(b) correction for intraspecies differences: workers default factor: 3, general population default factor: 5

NOTE: Using the overall inhalation NOAEC of 800 ppm (2856 mg/m3) as starting point for the DNEL derivation and applying a factor of 6/24 (exposure duration adjustment) and the ECETOC assessment factors for interspecies (1), intraspecies (5) and semichronic to chronic exposure (2) results in DNEL of 20 ppm (71.4 mg/m3). The DNEL derived from the 8-h TWA SCOEL figure is more conservative and hence selected for the risk characterisation.

 

Dermal exposure

The SCOEL has established an 8-h TWA of 50 ppm (178.5 mg/m3). The SCOEL value is derived for workers. To arrive at a long-term value for the dermal route for the general population, route to route extrapolation will be applied starting with the inhalation long-term value calculated for the general population:

 

53.6 mg/m3* 40/0.2 (a) * 20 m3(b) / 60 kg (c) = 3570 mg/kg bw/day

(a) correction for absorption (40% inhalation and 0.2% dermal absorption)

(b) 24 hour respiratory volume for the general population (to calculate the internal dose corresponding to 24 hour exposure)

(c) body weight for the general population

 

Oral exposure

The SCOEL has established an 8-h TWA of 50 ppm (178.5 mg/m3) for workers. To arrive at a long-term value for the oral route for the general population, route to route extrapolation will be applied starting with the inhalation long-term value calculated for the general population:

 

53.6 mg/m3* 40/100 (a) * 20 m3(b) / 60 kg (c) = 7.1 mg/kg bw/day

(a) correction for absorption (40% inhalation and 100% oral absorption)

(b) 24 hour respiratory volume for the general population (to calculate the internal dose corresponding to 24 hour exposure)

(c) body weight for the general population

 

Explanation of ECETOC Assessment Factors

Intraspecies sensitivity extrapolation from rat to man is done by extrapolation from the already interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) to an assumed human EC05 (= NOAEL human). It is assumed, that the rodent EC05 is a NOAEL and is conservatively 3.16 times smaller than the rodent EC50 and 10 times smaller than the rodent EC95. So the ratio between the rat EC95 and EC05 is assumed to be a factor of 10. This is in agreement with the applied dose range in a rodent study being at least a factor of 10.

 

·        The ECETOC intraspecies factor of 3, applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means that the ratio between worker EC95 and EC05 is assumed to be 90.

·        The ECETOC intraspecies factor of 5 applied to the interspecies extrapolated rodent EC05 (= EC05 interspecies adjusted rat to human) means, that the ratio between consumer EC95 and EC05 is assumed to be 250.

 

In the general population the ratio between the EC95 and EC05 is about a factor of 25. That is larger than that in the rat. The intraspecies assessment factors of ECETOC account for this factor of 25 and in addition, for statistical uncertainty in the comparison between human and animal studies on repeated tolerable dose levels. Therefore, the ECETOC intraspecies assessment factors are conservative for deriving a DNEL for workers and for consumers (=general population).