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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.081 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: German MAK
Dose descriptor starting point:
LOAEC
Value:
1.1 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
0.36 mg/m³
AF for dose response relationship:
3
Justification:
LOAEC - NOAEC
AF for interspecies differences (allometric scaling):
1
AF for intraspecies differences:
3
Justification:
Following the method of Brüning et al (2014) and cited in German MAK report (2018) for the transmission of local irritant effects to human the default factor to be used is 1:3
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: German MAK

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.081 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: German MAK
Dose descriptor:
LOAEC
Value:
1.1 mg/m³
AF for dose response relationship:
3
Justification:
LOAEC-NOAEC
AF for interspecies differences (allometric scaling):
1
AF for intraspecies differences:
3
Justification:
Following the method of Brüning et al (2014) and cited in German MAK report (2018) for the transmission of local irritant effects to human the default factor to be used is 1:3.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: German MAK

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information
Explanation for the modification of the dose descriptor starting point:

A quantitative DNEL as not been derived, since such a value does not aid in a relevant risk assessment for dermal exposure. A qualitative asssessment has been performed, using the experience of control measures in practice and no cases of sensitization among the employees.

No difference will be made between short term and long term exposure as sensitization may also develop after severeal short term exposures as well.

Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

DNEL

Inhalation Worker systemic- long term

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

 

 

The German MAK has established an inhalative occupational TLV which can be used as DNEL. This value is in line with the lower other established EU occupational threshold limits.

 

The MAK value first was established in 1991and is based on the 6 months inhalation study with rats, hamsters and monkeys of Short, 1988. This study demonstrated that concentrations as low as 1.1 mg/m³ (0.27 ml/m³) cause irritation of the mucosa of the eyes and upper airways in the obligatory nose breathers, rat and hamster; in primates, inflammation develops in the mucosa of nose and eyes but histological examination reveals minimal focal lesions. The minimal findings in primates indicate that a MAK value of 0.1 ml/m3 (0.4 mg/m3) can provide sufficient protection. Systemic toxic effects are not seen at such concentrations.

 

Due to new information (case report) on respiratory sensitization MAK reviewed their evaluation in 1995. This case study described a worker who was exposed to maleic anhydride and phthalicanhydride and afterwards suffered an acute attack of asthma. In a bronchial provocationtest he reacted to phthalic anhydride and developed asthma of immediate and delayed type eaused by maleic anhydride. For maleic anhydride the inhalable particle mass was 0.83 mg/m³ and the respirable particle mass 0.09 mg/m³ (Lee et al. 1991). It must be noted that the worker was also exposed to Phthalic anhydride. In another publications it was concluded that there is a cross reactivity between Maleic anhydride and Phthalic anhydride (Gannon et. al 1992). There was no change of the MAK value by the MAK commission based on this information.

The German MAK has re-evaluated maleic anhydride [108 -31 -6] in 2017, considering all toxicological endpoints. Maleic anhydride is an irritant to the upper respiratory tract. A LOAEC of 0.27 ml/m³ (equivalent to 1.1 mg/m³) for nasal and ocular irritation was obtained from a 6-month inhalation study in rats, hamsters and monkeys. Since 2014 the Commission uses an empirical approach (method according to Brüning et al., 2014) to set the maximum concentration at the workplace (MAK value) for substances with critical effects on the upper respiratory tract or the eyes. Based on this, the MAK value for maleic anhydride changed and is set at 0.02 ml/m³ (0.081 mg/m³).

 

Therefore, this Occupational threshold limit can be used as DNEL for long-term systemic and local effects via inhalative route.

 

Gannon PFG, Sherwood Burge P, Hewlett C, Tee RD (1992) Haemolytic anaemia in a case of occupational asthma due to maleic anhydride.Br J Ind Med49: 142-143

 

Lee HS, Wang YT, Cheong TH, Tan KT, Chee BE, Narendran K (1991) Occupational asthma due to maleic anhydride.Br J Ind Med48: 283-285

 

Dermal

The result of the local lymph node assay of Dearman et al. (2000) the EC3 value (0.16% w/v) indicates that Maleic anhydride is a strong skin sensitizer. Dermal contact therefore has to be excluded completely. Beyond this, dermal contact may facilitate or even induce the development of a respiratory sensitization.

A quantitative dermal DNEL has not been derived, since such a value does not aid in a relevant risk assessment for dermal exposure. A qualitative assessment has been performed, using the experience of control measures in practice and no cases of sensitization among the employees.

No difference will be made between short term and long term exposure as sensitization may also develop after several short term exposures as well.

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:
no hazard identified
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:
no hazard identified
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

Consumer (local and systemic inhal; dermal; oral)

There is no consumer exposure to maleic anhydride. Reaction of maleic anhydrate in polymers is complete. Beyond this if there were any residual monomeric maleic anhydride it would hydrolize to form to maleic acid. Therefore no DNEL is derived for consumers.