Pyridine

Endpoint summary

Description of key information

This substance is considered to be irritating to the skin and eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Pyridine (and methyl-pyridine derivatives) exhibit skin and eye irritation properties. Pyridine, as listed in Annex VI of Regulation (EC) No.1272/2008, Index No. 613-002-00-7, is not classified on irritation endpoints.  Classification according to the requirements of the CLP Regulation is difficult, because the available studies on pyridine do not follow the recommended guidelines. A comparison of the skin irritation method (OECD 404 Guideline, also Regulation EC No. 440/2008, in which 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) with methods used in the past (occlusive patches and limited follow-up) shows that the criteria for classification is currently less stringent.  Similarly for eye irritation studies, the OECD 405 method recommends a 21-day recovery period during which reversibility is assessed, whereas older studies rarely include this recovery period. Furthermore, for pyridine, only one study (of 7) provides the individual and/or group data which may allow evaluation of any excessive reactions by individual animals. It is probable, therefore, that the older data overestimates the irritation potential of pyridine. A weight of evidence approach is used to evaluate and classify pyridine for irritation endpoints.

The highest weighted dermal study is the study of ACS grade (99% pure) pyridine by Costello, 1983 (Klimisch 1), using a U.S.-compliant GLP corrosion protocol with 6 rabbits. Data on the individual animals is provided, with erythema and edema observed in all animals after 4 hours, and only very slight erythema remaining at 48 hours after patching. No skin corrosion was evident at any time point.

 

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 (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, which is a deviation from current standard guidelines. No individual animal data is provided. Pyridine was concluded to be a skin irritant, based on the group score of 6 rabbits (Primary Irritation Index between 2 and 5 (of 8, total)). It was initially evaluated to be an eye irritant (using a group score of 43 at one hour (of 110, total)), but was upgraded to “severely irritating” 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 a reliable industry laboratory (Dow Chemical Company, 1984) but not using standard test protocols, pyridine (96% pure) was found to be irritating to skin on the ears and bellies of rabbits, with reversibility demonstrated at 14 days. The report does not include information on: the dose administered, the type of “bandage” used (occlusive or semi-occlusive), the sites which were bandaged, the duration of the exposure other than “prolonged”, or the evaluation criteria employed. The skin was described as “denatured”, after which scab formation occurred with accompanying animal body weight gain. The conclusion was that pyridine was a mild irritant.

 

In a reliable industry laboratory (Eastman Kodak Company, Rochester, NY, USA, 1978) prior to the establishment of standard protocols, pyridine was found to be moderately irritating to the skin of guinea pigs and the eyes of rabbits.  The data are available only in summary form (Klimisch 2) and it is clear that the scientists evaluated the severity of irritation in both skin and eye to be “moderate” rather than “severe”. Corneal damage was noted in the eye irritation study of pyridine without notation of the time point(s) of the observation. 

In very early chemical toxicity studies (Mellon Institute, University of Pittsburgh, Pittsburgh, PA, USA), Smyth, et al, (1951) found pyridine to be a skin irritant and to cause severe damage to the eye. The skin irritation protocol is not clearly presented, but references the Draize method, suggesting occlusive exposure for 4 hours in 6 rabbits. Patch testing of pyridine resulted in a grade of 3 (of 10), characterized by strong capillary injection of the skin, and no necrosis. The eye irritation study (based on the 1949 method published by Carpenter and Smyth) employed a smaller than usual volume of pyridine into the eyes of 5 rabbits (compared to that in the current OECD 405 guideline), but used only one time point (24 hours after administration) and a non-standard scale heavily weighted on immediate corneal evaluation. They observed corneal damage of a grade 7 (of 10, with a 40% solution of pyridine resulting in some degree of necrosis). This qualified as a severe eye irritant. The authors noted that the “rabbit-eye-injury test is unrealistic in that it exaggerates the hazard from certain materials. It is desirable to add to the present test, which determines the least amount of chemical causing corneal injury of an arbitrary severity, some expression for the rate of healing of the injury.” 

In another study at the Mellon Institute (Carnegie-Mellon University, Pittsburgh, PA, USA, 1974), a U.S. DOT skin irritation study in two rabbits was performed on pyridine produced by a small chemical company with “refined pyridine”. The method involved a 4-hour exposure to the nonabraded skin of rabbits. Dermal necrosis was described in both rabbits, and so pyridine was evaluated as “corrosive”. There is no information on the purity of the test material.

Pullin, et al., (1973, Klimisch 2), in an acute dermal toxicity study, found that pyridine caused "severe chemical burns" to the skin. The exposure duration in this lethality study was 24 hours under occlusive conditions. This study carries a low weight of evidence for the skin irritation endpoint.

 

Handbooks, textbooks and reviews of toxicology (Reinhardt and Britelli, 1981; SCOEL, 2004) classify pyridine as a skin and eye irritant, quoting the conclusions of the above studies. These are secondary sources, yet the experts were consistent in interpreting the data on pyridine as "irritating". 

In other components of a weight of evidence approach, pyridine does not have physico-chemical attributes which are informative in evaluation of skin and eye irritation. (Q)SAR modeling of related compounds is not applicable, as pyridine itself represents the basic building block structure for the analogues. The methyl derivatives of pyridine (picolines) are corrosive to the eye and skin. It is also possible that, in older studies, pyridine sample material may have had impurities which were responsible for corrosion and irritation (specifically 3-methyl pyridine, CAS 108-99-6). Current manufacturing processes produce a pyridine product with few impurities.

The highest weighted study in this collection is the Department of Transportation study by Costello, 1983, as this is performed in rabbits according to current guideline methodology, audited for quality and uses a defined contemporary pyridine which is ACS grade (99%) pure. The conclusion based on six animals was “not corrosive” and mild irritation. Duterte-Catella, et al., 1989 used a guideline protocol but not one common in the chemical industry. The score indicated that pyridine was an irritant, though evidence of reversibility was not observed. Smyth, et al., 1951, also observed pyridine “irritation” and not “corrosion” in rabbits using a method and evaluation scale developed before the establishment of OECD test guidelines. Older studies by Dow Chemical Company and Eastman Kodak Company used a non-standard animal species, and so these studies carry less weight. Similarly, the occlusive exposure duration in the Pullin, et al.,1973 study, at 24 hours, overestimates the effect and thus carries less weight. Pyridine is unlikely to be as irritating as the older data suggest, because the current material is purer and the criteria for demonstrating irritation is less stringent. The most studies are consistent in finding pyridine to be irritating to the skin, and evaluating the data in this way is appropriate in light of the current guidelines.

Among the original studies on eye irritation, Duterte-Catella, et al. 1989, found persistent corneal opacity qualifying as “severely irritating”, though these observations extended to only 7 days. The Eastman-Kodak Company data of 1978 describes moderate eye irritation with corneal damage. The study of Smyth, et al., 1951, uses a method and evaluation scale which is not comparable to current methods, and finds that pyridine is a severe eye irritant. The recovery periods, to assess healing, in all three studies were significantly less than the current guideline allows. Insufficient data is provided on individual animal responses to justify classifying the chemical as corrosive. The conclusions of these three studies are consistent as a strong eye irritant.

In summary, the weight of evidence suggests that pyridine displays irritation to the skin and severe irritation to the eye. We conclude that the appropriate classification for both skin and eye is “Irritant”, Category 2, H315 and H319, with associated precautionary phrases. This classification is adequately protective of the health of workers.

Justification for selection of skin irritation / corrosion endpoint:
experimental result by guideline method

Justification for selection of eye irritation endpoint:
experimental result

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

This substance is listed in Annex VI of Regulation (EC) No.1272/2008, Index No. 613-002-00-7, does not classify on irritation endpoints. Based on the data provided, pyridine is self-classified as a skin irritant (Category 2) and an eye irritant (Category 2).