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Toxicological information

Respiratory sensitisation

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Administrative data

Endpoint:
respiratory sensitisation: in vivo
Type of information:
other: Workplace data
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Structural similarities of the target substance to the source substances include the (bi)cyclic ring structure with a carboxylic acid anhydride group as the single reactive moiety. For the target substance the bicyclic ring structures contains a double bond at a specific location within the ring and also contains a substituted methyl group at a specific location on the ring structure whereas for the source substance neither the position of the double bond nor the methyl group are specified.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance is a specific isomer of the source substance, tetrahydromethylphthalic anhydride (MTHPA), in which neither the location of the double bond nor the methyl substitution are defined. MTHPA, has a stated composition comprising the target substance 1,2,3,6-tetrahydro-3-methylphthalic anhydride (CAS No. 5333-84-6, EC No. 226-247-6) together with tetrahydro-4-methylphthalic anhydride (CAS No. 34090-76-1, EC No. 251-823-9), 1,2,3,6-tetrahydro-4-methylphthalic anhydride (CAS No. 3425-89-6, CAS No. 222-323-8) and 3-cyclohexene-1,2-dicarboxylic anhydride, 4-methyl- (CAS No. 19438-64-3).


3. ANALOGUE APPROACH JUSTIFICATION
Generally, the physical and chemical properties do not show major differences. All the above mentioned cyclic anhydrides have comparable boiling temperatures, low vapour pressure and, from a physiological point of view, similar partition coefficients. Differences in melting point may be explained by the fact that the substances are representing multi-constituent or mono-constituent substances.
The cyclic anhydrides rapidly hydrolyse in contact with water and the methyl substituted cyclic anhydrides appear to show a low potential for biodegradation. Based on their physico-chemical properties the substances are expected to have low bioaccumulation potentials and comparable adsorption/desorption properties. The dicarboxylic acid degradation product arising from hydrolysis is the moiety of concern with respect to effects in the aquatic environment. The substances have a rather a low potential to cause toxicity to water based species including fish, daphnia, algae and microorganisms.
Acute toxicity is low. All of the substances are expected to be highly irritant to the eye and be both skin and respiratory sensitisers and a harmonised classification is in place for these properties (Index No. 607-240-000). The absence of a mutagenic potential has been demonstrated in various guideline in-vitro tests. The outcome of the available mammalian studies conducted by the oral route suggest local effects (irritation of the stomach mucosa) probably arising from pH effects of the di-acid degradation product to be significant.
Due to structural similarities, comparable physical/chemical properties such as the molecular weight, partition coefficient and vapour pressure, the toxicokinetic profile of the registered substance and the potential structural analogue substances are also expected to be comparable in terms of physiological absorption, distribution, metabolism and excretion processes. The carboxylic acid anhydride group which rapidly hydrolyses to form the di-acid once in contact with physiological liquid, mainly determine the fate of the substance within the body. Available toxicokinetic data demonstrate that cyclic anhydrides are commonly metabolised to the corresponding di-carboxylic acids within the body and are finally excreted in urine.

Data source

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
List of MAK and BAT values 2000, Maximum concentrations and Biological Tolerance Values at the Workplace
Author:
Commission for the investigation of health hazards of chemical compounds in the work area
Year:
2000
Bibliographic source:
published by Willey-Vch, Deutsche Forschungsgemeinschaft
Reference Type:
review article or handbook
Title:
Guide to occupational exposure values 2002
Author:
ACGIH
Year:
2002
Bibliographic source:
ed by ACGIH ISBN: 1-882417-47-X

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
not applicable
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Tetrahydromethylphthalic anhydride
EC Number:
234-290-7
EC Name:
Tetrahydromethylphthalic anhydride
Cas Number:
11070-44-3
IUPAC Name:
3a-methyl-3a,4,5,6-tetrahydro-2-benzofuran-1,3-dione
Constituent 2
Reference substance name:
Methyltetrahydrophthalic anhydride
IUPAC Name:
Methyltetrahydrophthalic anhydride
Details on test material:
no details given
- Molecular formula (if other than submission substance): C9 H10 O3
- Molecular weight (if other than submission substance): 166.18
- Smiles notation (if other than submission substance): O=C(OC(=O)C1CC=C(C2)C)C12
- InChl (if other than submission substance): 1/C9H10O3/c1-5-2-3-6-7(4-5)9(11)12-8(6)10/h2,6-7H,3-4H2,1H3
- Structural formula attached as image file (if other than submission substance): see Fig. (11070-44-3 structure.jpg)

Test animals

Species:
human
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
no details given

Test system

Route of induction exposure:
inhalation
Route of challenge exposure:
inhalation
Vehicle:
not specified
Concentration:
no details given
No. of animals per dose:
no details given
Details on study design:
no details given
Challenge controls:
no details given

Results and discussion

Results:
MTHPA was classified as "Sa", danger of sensitization of airways by the German MAK commission (Commission for the investigation of health hazards of chemical compounds in the work area).
Substances classified as "Sa" can cause symptoms of the airways and also of the conjunctiva (substances causing airway sensitization).
Positive control results:
no details given
Negative control results:
no details given

Any other information on results incl. tables

no details given

Applicant's summary and conclusion

Interpretation of results:
sensitising
Conclusions:
Tetrahydromethylphthalic anhydride (MTHPA) classified as sensitising to the respiratory tract.
Executive summary:

Tetrahydromethylphthalic anhydride (MTHPA) was classified as "Sa", danger of sensitization of airways by the German MAK commission (Commission for the investigation of health hazards of chemical compounds in the work area). Substances classified as "Sa" can cause symptoms of the airways and also of the conjunctiva (substances causing airway sensitization).