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EC number: 202-905-8 | CAS number: 100-97-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
Methenamine showed some skin sensitizing potential in humans. Guinea pigs exhibited strong skin sensitization in a maximization test with a 50% aqueous solution of methenamine. In a Local Lymph Node Assay (LLNA) a positive effect concentration (EC3) of 30.6% methenamine was derived. A comparable EC3 for formaldehyde was determined in the same study. Thus, it may be concluded that also for skin sensitization formaldehyde, which may be generated by hydrolysis of methenamine in contact to skin, and not methenamine as such, is the main causative agent of sensitization.
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1984-05-15 to 1985-05-03
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Version / remarks:
- 1981
- Deviations:
- no
- GLP compliance:
- not specified
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- Please refer to the supporting study de Jong, 2005.
- Species:
- guinea pig
- Strain:
- other: Pirbright White (Bor: DHPW)
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: 6-9 weeks
- Weight at study initiation: 344-485 g
- Housing: single housing makrolon cage, type III
- Diet: standard diet ad libitum (ALTROMIN(R) Nr. 3022 from Altromin, Lage, Germany)
- Water: ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2°C
- Humidity (%): 55 +/- 15 %
- Photoperiod (hrs dark / hrs light): 12 hrs / 12 hrs - Route:
- other: Intradermal (Day 1), Epidermal (Day 8)
- Vehicle:
- physiological saline
- Concentration / amount:
- Induction:
Intrademal 30 %
Epidermal: paste (0.5 g test substance with 0.4 ml physiol. saline)
Challenge: 50 % - Route:
- epicutaneous, occlusive
- Vehicle:
- physiological saline
- Concentration / amount:
- Induction:
Intrademal 30 %
Epidermal: paste (0.5 g test substance with 0.4 ml physiol. saline)
Challenge: 50 % - No. of animals per dose:
- control group: 10
test group: 20 - Details on study design:
- MAIN STUDY
A. INDUCTION EXPOSURE
Introdermal
- No. of exposures: 6 (2 x test substance, 2 x test substance / FCA (1:1), 2x FCA)
- Exposure period: Day 1
- Test groups: test group: see above
- Control group: same treatment, but vehicle instead of test substance
- Site: shoulder region
- Frequency of applications: once on day 1
- Duration: single exposure, next exposure on day 8
- Concentrations: 30 %
Epidermal
- No. of exposures: 1
- Exposure period: Day 8
- Test groups: occlusive patch with test substance: paste (0.5 g test substance with 0.4 ml physiol. saline)
- Control group: same treatment, but vehicle instead of test substance
- Site: shoulder region
- Frequency of applications: once on day 8
- Duration: 48 h
- Concentrations: paste (0.5 g test substance with 0.4 ml physiol. saline)
B. CHALLENGE EXPOSURE
- No. of exposures: 2
- Day(s) of challenge: day 22, day 23
- Exposure period: 24 h
- Test groups: right flank (vehicle), left flank (test substance)
- Control group: same as test group
- Site: flank
- Concentrations: 50 %
- Evaluation (hr after challenge): 24 and 48 hrs after last challenge - Challenge controls:
- yes (see details on study design)
- Positive control substance(s):
- no
- Positive control results:
- no positive control
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- not tested
- Clinical observations:
- not tested
- Remarks on result:
- not measured/tested
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- 50 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 50 %
- No. with + reactions:
- 15
- Total no. in group:
- 20
- Clinical observations:
- none
- Remarks on result:
- positive indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- 50 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- none
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 50 %
- No. with + reactions:
- 15
- Total no. in group:
- 20
- Clinical observations:
- none
- Remarks on result:
- positive indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- not tested
- Clinical observations:
- not tested
- Remarks on result:
- not measured/tested
- Interpretation of results:
- Category 1 (skin sensitising) based on GHS criteria
- Conclusions:
- Methenamine is sensitising in the guinea pig maximation test.
- Executive summary:
In a dermal sensitization study (GPMT) with methenamine (> 99 %) in physiological saline 6-9 weeks old female Pirbright White guinea gigs were tested using the method of Magnusson and Kligman.
No clinical signs were noted. After intradermal (30 %) and epidermal induction (paste: 0.5 g test substance in 0.4 ml physiol. saline) and challenge (50 %) 15 out of 20 animals showed etythema and edema 24 and 48 h after the last challenge. In the negative control group none of the 10 animals tested showed signs of sensitisation.
In this study, methenamine is a dermal sensitizer.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (sensitising)
- Additional information:
Key study:
In a dermal sensitization study (GPMT) with methenamine (> 99 %) in physiological saline 6-9 weeks old female Pirbright White guinea gigs were tested using the method of Magnusson and Kligman.
No clinical signs were noted. After intradermal and epidermal induction (30 %) and challenge (50 %) 15 out of 20 animals showed etythema and edema 24 and 48 h after the last challenge. In the negative control group none of the 10 animals tested showed signs of sensitisation.
In this study, methenamine is a dermal sensitizer.
Supporting study:
In a Local Lymph Node Assay (LLNA) similar to OECD Guideline 429 (de Jong, 2005), an EC3 (test concentration, which causes a Stimulation Index (SI) of the auricular lymph nodes of 3.0) of 30.6% was determined for methenamine, while an EC3 as low as 0.96% was determined for formaldehyde in the same study. The test was performed treating young adult (6-8 weeks of age) female BALB/c mice with methenamine dissolved in a acetone-olive oil mixture (4:1). Test concentrations were 2.5, 5, 10 and 20%. In order to enhance possible low responses of weak sensitizers animals were pretreated with sodium dodecyl sulfate 1% (SDS) on the dorsum of the ears one hour before administration. In second test with repeated exposures the fist test was coonfirmed revealing a Stimulation Index of 5.78. Results of the LLNA affirm the classification of methenamine as a skin sensitizer.
Human data:
In 1992/1993 among 2150 patients with dermatitis tested for methenamine sensitivity (1% in petrolatum) 27 (1.3%) showed a positive skin reaction. Out of these, 15 (0.7%) were interpreted as irritant reaction and 12 patients (0.5%) were regarded as sensitized. In 1994/1995, among 3082 persons tested, 38 (1.2%) showed positive skin reactions with methenamine Out of these, 15 (0.5%) were interpreted as irritant reactions and 23 patients (0.8%) were regarded as sensitized (IVDK, 1996).
Within a study related to rubber-related allergic contact dermatitis, patch-testing was performed with a number of rubber-related substances. Out of 309 patients, 1.9% showed positive skin reactions with 2% methenamine (Holness and Nethercott, 1997).
A 54-year-old employee with an itchy eruption on his hands, neck and shoulders was presented in March 1987. He had worked in a foundry for 10 years being engaged in a core molding process and had developed itchy eruptions on the dorsum of his hands, neck and shoulders 3 years ago. The eruptions and itching were aggravated by sweating. His work was making a mixture of sand, phenolic resin, methenamine and lubricant, and he was often covered with the mixture. Offensive stench gas was evaporated from the heated sand core. Open patch testing and closed patch testing with raw materials and chemicals detected within the gas from the heated sand core were performed. The patient reacted positive to 1% methenamine in petrolatum, but did not react positively to formaldehyde. Repeated patch testing in October 1987 confirmed the negative reaction to formaldehyde (Hayakawa et al., 1988).
In one molding resin producing factory, 10% of the workers were affected with dermatitis during a period of one year. Patch tests with various types of resins performed on 10 cases showed that sensitivity to methenamine and to formaldehyde was the cause of 80% of the dermatitis in this plant (Schwartz, 1957).
Methenamine adversely affected 60 employees in a local rubber factory. Acute dermatitis of the exposed surfaces was the principle symptom: Removal of methenamine from the entire rubber stock alone prevented further cases (Cronin, 1924). However, it cannot be concluded from this case study that dermal irritation was caused by sensitization.
The total number of cases observed in a report on the shellac and lacquer industries amounted to 7 patients each, all of whom manifested allergic symptomatology upon separate exposure to ethylenediamine and methenamine. A skin test with 1% dilutions gave severe positive reactions, characterized by immediate wheal formation. The provocative inhalation test with methenamine was positive in 7/7 patients. On exposure to the substance, the patients showed either wheezing and heaviness on the chest or severe asthma, allergic coryza, or skin manifestations of allergy. 14 patients from the beauty industry were also challenged with methenamine and other substances. Of these, 13 showed diverse positive responses. However, since there was exposure to several chemicals, cross-reactivity may have occurred. In a factory where machines for the processing of chemicals are produced, a worker who tested a machine with chemicals used for the preparation of rubber was exposed directly after the chemicals had run through the machine. He suffered from coughing and wheezing resulting in three consecutive severe asthma attacks after repeated exposure (Gelfand, 1963). Due to the study limitations (only a few case reports, no detailed description of the exposure level of the individuals affected, and possible contributions of other substances in addition to methenamine to positive findings) no clear conclusion on respiratory sensitization can be drawn from this study.
A more recent study was designed to assess the health effects of methenamine on the airways and the skin of workers in the chemical industry (Merget et al., 1999). 17 “highly” exposed and 16 “low” exposed employees of a methenamine producing plant were examined (a quantification of high or low exposure is not given). Among the 17 highly exposed persons 8 subjects were baggers, 5 were shift leaders and 4 were executive staff. 11 blue collar and 5 white collar workers with no exposure to known sensitizers were recruited as controls.(n = 16). Four persons, who had left the production department and another 15 who had left the plant for reasons not related to methenamine exposure, were also included (n = 19). Medical history, total and specific IgE to four environmental allergens, lung function and bronchial responsiveness to metacholine were assessed by standard procedures. Lung function was evaluated by measurement of forced expiratory volume in 1s and maximal expiratory flow at 50% of forced vital capacity (pneumotachograph, CustoVit, CustoMed, Munich, Germany). Measuring conditions and reference values were chosen as described recently (Quanjer et al., 1993). Bronchial hyperresponsiveness was assessed as described in Merget et al. (1996) with two modifications: methacholine was used instead of histamine and maximally 31 instead of 63 cumulative breaths of the 8 mg/mL methacholine solution were administered. Skin prick tests were performed with known sensitizers and methenamine. 64.7 % of the exposed subjects and 68.8 % of the controls reported symptoms during the year before the study began, most of them not related to work. Work-related symptoms and objective parameters did not show differences between groups, and skin tests showed no sensitization to methenamine. Among those who had left methenamine production for medical reasons, two former baggers showed sensitization to methenamine by patch test and reported eczema during exposure which disappeared after removal from exposure. Geometric mean methenamine concentrations were 0.3 mg/m3 in shiftleaders and 0.6 mg/m3 in baggers. It was concluded that high exposures to methenamine may cause allergic contact dermatitis. However, there was no evidence of an increased risk for occupational asthma at airborne concentrations in the range of 0.2 - 2.6 mg/m3 (Merget et al., 1999).
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
- Additional information:
Human data:
The total number of cases observed in a report on the shellac and lacquer industries amounted to 7 patients each, all of whom manifested allergic symptomatology upon separate exposure to ethylenediamine and methenamine. A skin test with 1% dilutions gave severe positive reactions, characterized by immediate wheal formation. The provocative inhalation test with methenamine was positive in 7/7 patients. On exposure to the substance, the patients showed either wheezing and heaviness on the chest or severe asthma, allergic coryza, or skin manifestations of allergy. 14 patients from the beauty industry were also challenged with methenamine and other substances. Of these, 13 showed diverse positive responses. However, since there was exposure to several chemicals, cross-reactivity may have occurred. In a factory where machines for the processing of chemicals are produced, a worker who tested a machine with chemicals used for the preparation of rubber was exposed directly after the chemicals had run through the machine. He suffered from coughing and wheezing resulting in three consecutive severe asthma attacks after repeated exposure (Gelfand, 1963). Due to the study limitations (only a few case reports, no detailed description of the exposure level of the individuals affected, and possible contributions of other substances in addition to methenamine to positive findings) no clear conclusion on respiratory sensitization can be drawn from this study.
A more recent study was designed to assess the health effects of methenamine on the airways and the skin of workers in the chemical industry (Merget et al., 1999). 17 “highly” exposed and 16 “low” exposed employees of a methenamine producing plant were examined (a quantification of high or low exposure is not given). Among the 17 highly exposed persons 8 subjects were baggers, 5 were shift leaders and 4 were executive staff. 11 blue collar and 5 white collar workers with no exposure to known sensitizers were recruited as controls.(n = 16). Four persons, who had left the production department and another 15 who had left the plant for reasons not related to methenamine exposure, were also included (n = 19). Medical history, total and specific IgE to four environmental allergens, lung function and bronchial responsiveness to metacholine were assessed by standard procedures. Lung function was evaluated by measurement of forced expiratory volume in 1s and maximal expiratory flow at 50% of forced vital capacity (pneumotachograph, CustoVit, CustoMed, Munich, Germany). Measuring conditions and reference values were chosen as described recently (Quanjer et al., 1993). Bronchial hyperresponsiveness was assessed as described in Merget et al. (1996) with two modifications: methacholine was used instead of histamine and maximally 31 instead of 63 cumulative breaths of the 8 mg/mL methacholine solution were administered. Skin prick tests were performed with known sensitizers and methenamine. 64.7 % of the exposed subjects and 68.8 % of the controls reported symptoms during the year before the study began, most of them not related to work. Work-related symptoms and objective parameters did not show differences between groups, and skin tests showed no sensitization to methenamine. Among those who had left methenamine production for medical reasons, two former baggers showed sensitization to methenamine by patch test and reported eczema during exposure which disappeared after removal from exposure. Geometric mean methenamine concentrations were 0.3 mg/m3 in shiftleaders and 0.6 mg/m3 in baggers. It was concluded that high exposures to methenamine may cause allergic contact dermatitis. However, there was no evidence of an increased risk for occupational asthma at airborne concentrations in the range of 0.2 - 2.6 mg/m3 (Merget et al., 1999).
Justification for classification or non-classification
Guinea pigs exhibited strong skin sensitization in a maximization test with a 50% aqueous substance solution. In a Local Lymph Node Assay (LLNA) a positive effect concentration (EC3) of 30.6% methenamine was derived. A comparable EC3 for formaldehyde was determined in the same study. Thus, it may be concluded that also for skin sensitization formaldehyde, which may be generated by hydrolysis of methenamine in contact to skin, and not methenamine, is the main causative agent of sensitization. Nevertheless, taken all data together, the existing classification with R 43 "May cause sensitization by skin contact" according to 67/548/EEC and skin sens. cat.1B (H317) according to CLP (GHS) is warranted and justified. This C+L proposal is in line with occupational findings as Methenamine has demonstrated some skin sensitizing potential in humans.
From earlier studies a number of cases of allergic symptoms such as wheezing and asthma were reported upon inhalation exposure to methenamine (Gelfand, 1963). Some other occupational reports of a potental respiratory sensitisation potential were not confirmed in well documented newer studies. In consequence, there is not clear evidence of a respiratory sensitization potential of methenamine at airborne levels present at workplaces. Classification with R 42 „May cause sensitization by inhalation“ according to 67/548/EEC and resp. sens. cat.1 (H334) according to CLP (GHS) is therefore not justified.
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