3-methylpyridine

Endpoint summary

Description of key information

Corrosive to the skin and causing severe damage to the eye  

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study

Qualifier:

according to guideline

Guideline:

other: US. 52 FR 42964, 49 CFR 173.136(a)

Principles of method if other than guideline:

Test material is applied to the shaved skin of rabbits for 3 min, 60 min and 4 hr, and then removed and the site is rinsed. Evaluations of the site are made at 30-60 min and 48 h after exposure. Skin erythema, edema and corrosion are assessed.

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5 ml/site, undiluted

Duration of treatment / exposure:

3 min, 60 min and 4 h.

Observation period:

30-60 min, and 48 h.

Number of animals:

6 rabbits per group

Details on study design:

Corrosion is defined as irreversible alteration or destruction to the tissue in at least 3 of the animals. Necrosis is defined as ulceration or necrosis of the skin.

Irritation parameter:

other: necrosis

Basis:

mean

Time point:

other: 3 min

Score:

0

Max. score:

6

Reversibility:

other: not applicable

Remarks on result:

other: no indication of corrosion

Remarks:

Corrosion study at 3 min, 60 min, 4 h

Irritation parameter:

other: necrosis

Basis:

mean

Time point:

other: 60 min

Score:

1

Max. score:

6

Reversibility:

not reversible

Remarks on result:

other: in 1 of 6 animals in this group

Remarks:

Qualitative scoring: presence/absence of ulceration/necrosis. Corrosion study at 3 m, 60 min and 4 h

Irritation parameter:

other: necrosis

Basis:

mean

Time point:

other: 4 h

Score:

4

Max. score:

6

Reversibility:

not reversible

Remarks on result:

other: in 3 of 6 animals

Remarks:

Qualitative scoring: presence/absence of ulceration/necrosis. Corrosion study at 3 m, 60 m and 4 h

No effects after a 3 minute exposure.

Interpretation of results:

corrosive

Remarks:

Migrated information Criteria used for interpretation of results: other: U.S. Department of Transportation

Conclusions:

3-Methylpyridine was tested for skin corrosion using U.S. Department of Transportation guidelines. The substance was corrosive to the skin of rabbits after a 4 h occlusive exposure.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study, where conduct according to GLP is not noted.

Qualifier:

according to guideline

Guideline:

other: Primary Eye Irritation, 16 CFR 1500.42

Principles of method if other than guideline:

One eye of each of 6 rabbits was tested for eye irritation according to the Draize scale.

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

1 second duration in the eye

Observation period (in vivo):

24, 48 and 72 h

Number of animals or in vitro replicates:

6

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

24 h

Score:

65

Max. score:

110

Reversibility:

not reversible

Remarks on result:

other: interpreted as Extremely irritating

Irritant / corrosive response data:

Corneal damage was observed in all 6 animals. The condition persisted throughout the entire observation period. Hyperemia, chemosis and conjunctival discharge were observed in all rabbits.

Other effects:

Iridial damage was observed in 3 of 6 animals.

The average test scores of the six animals were: 74, 52, 56, 63, 57 and 88. Two of the animals had at least 1 test score over 80.1 (out of a maximum of 110. The average score of 65 falls between 50.1 and 80 (severely irritating), but is raised to the next highest score based on the severity of reaction of individual animals.

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

3-Methylpyridine is severely irritating to the eye, according to a guideline study (U.S. Department of Transportation) on eye irritation. The Maximal Mean Test Score was 65/110, with one animal exibiting scores of over 80.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

3 -Methyl pyridine and pyridine compounds exhibit skin and eye irritation properties.  Classification according to the requirements of the CLP Regulation is not straightforward, as not all studies follow the recommended test guidelines currently in effect. The current guideline for skin irritation is compared with older methods, with a conclusion that the current method is less stringent. The OECD 404 Guideline for skin irritation and corrosion, also Regulation EC No. 440/2008, uses a semi-occlusive exposure of intact skin occurs for 4 hours, with evaluation at 1, 24, 48 and 72 hours after patch removal and extended evaluation of observation-based reversibility up to 14 days), whereas older methods commonly used occlusive patches and had limited follow-up assessment for reversibility. Similarly for eye irritation studies, the current OECD 405 method recommends a 21-day recovery period during which reversibility is assessed, whereas older studies rarely include a recovery period of this length. Furthermore, studies which do not provide the individual and/or group data cannot allow evaluation of any excessive reactions by individual animals.

A weight of evidence approach is used for evaluation of irritation and corrosion. The highest-weighted dermal study for 3-methylpyridine is by Fitzgerald, 1991 (Klimisch 1), using a U.S.-compliant GLP corrosion protocol with occlusive exposure 6 rabbits. Data on the individual animals is summarized, with necrosis observed in 1 animal after 60 minutes, and in 3 animals after 4 hours, irreversible at 48 hours after patching. The substance is evaluated as corrosive. 

 

The published study of Duterte-Catella, et al. (1989, Klimisch 2) provides summary data on skin and eye irritation in a study based on the French guidelines of 1982 and 1984 (used for evaluation of cosmetic products and similar to standard Draize irritation protocols, employing occlusive patching of intact and abraded skin). It is possible that eye and skin testing was performed in the same 6 animals, which could contribute to artificially enhanced reactions due to excessive stress. In addition, information was used from histopathology investigations which occurred at 7 and 14 days after dosing. No individual animal data is provided. The authors use terminology which is inconsistent with the guideline, when assigning irritation classes.  3-Methylpyridine was concluded to be severely irritating to skin with a score of 6.8 (of 8, total) in 6 rabbits (Primary Irritation Index between 5 and 8. This corresponds to an expression of irritation per the guideline as “highly irritating”. In an eye irritation protocol, the substance was initially evaluated to be an irritant (using a group score of 45 at one hour/one day (of 110, total)), but was upgraded to “severely irritating” (“very irritating” according to the guideline’s recommended expression of results) based on histopathology findings at day 7 (abrasion of the cornea and fibrillary edema in the lamellae with thickness and cellular inflammatory infiltrate). Note that macroscopic assessment of recovery was not carried out to day 21, according to current guidelines.

In another test for skin corrosion according to United States Department of Transportation (U.S. DOT) guidelines, (Spear, 1984), 3-methylpyridine was found at 48 hours to be corrosive to the skin of all six rabbits tested.  In an eye irritation study according to U.S. DOT requirements (based on the Draize method), all six animals showed scores between 50 and 80 (of 110), initially corresponding to “severely irritating”. But with individual animals showing scores over 80, the next highest category of corrosion was selected. 

Handbooks, textbooks and reviews of toxicology (Trochimowitz, 1994; WEEL, 1988) classify 3-methylpyridine as a skin corrosive “with necrosis and burns”, and either moderately to severely irritating to the eye, or causing irreversible “corneal cloudiness”. 

In other components of a weight of evidence approach, 3-methylpyridine does not have physico-chemical attributes which are informative in evaluation of skin and eye irritation. 2-Methylpyridine, a structural analogue of 3-methylpyridine, has a harmonized classification of eye irritation Category 2, according to Annex VI, Regulation EC No. 1272/2008, Index 613-036-00-2. Another analogue, 4-methylpyridine is harmonized as both an eye and skin irritant, category 2, in Index 613-037-00-8.

In consulting the 2013 Guidance on the Application of the CLP Criteria, version 4.0, Section 3.3, if a substance is classified as skin corrosive category 1, then serious damage to eye is implicit and there is no need to proceed with classification for eye effects. As 3-methylpyridine is a skin corrosive, serious damage to eye is expected.

The criteria for subcategorization of skin corrosive Category 1 into A, B, and C refer to the potency or strength of the effect, with variable durations of exposure. Occlusive dermal exposure to 3-Methylpyridine for 60 minutes resulted in 1 of 6 animals showing necrosis; three animals showed necrosis after 4 hours. Considering that now only 3 animals are used, and a semi-occlusive patch and a 14 day recovery period are used in tests to address this endpoint, the most appropriate subcategory is “C”.

For substances whose mechanism of action is corrosion, the CLP regulation requires classification of the substance as EUH071, “Corrosive to the respiratory tract”. While there is no specific data on respiratory corrosion, this default classification is accepted.

In conclusion, the weight of evidence shows that 3-methylpyridine displays severe skin with necrosis and significant eye irritation, in all studies.

Irritation with necrosis qualifies as “corrosion, Category 1C, with associated precautionary phrases. For the eye, a classification of Category 1, “Causes serious eye damage”. These are combined in the H314 phrase, “Category 1, Causes severe skin burns and eye damage.” The substance also requires EUH071, “Corrosive to the respiratory tract”.

Justification for selection of skin irritation / corrosion endpoint:
experimental result according to a guideline method

Justification for selection of eye irritation endpoint:
experimental result according to a guideline method

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: highly irritating

Justification for classification or non-classification

The weight of evidence shows that 3-methylpyridine displays severe skin and eye irritation with necrosis. This qualifies as “corrosion, Category 1C, with associated precautionary phrases. For the eye, a classification of Category 1, “Causes serious eye damage”. These are combined in the H314 phrase, “Category 1, Causes severe skin burns and eye damage.” It also requires EUH071, “Corrosive to the respiratory tract”