To:	Maureen Ruskin (OSHA)
From:	Chuck Schwartz, Ph.D., DABT
Principal Consulting Toxicologist - TOXDOC1, LLC
Date:	14 April 2010
RE:  	Assessment of OSHA's Proposed Adoption of GHS Serious Eye Damage /Eye Irritation Criteria; Critique by NIEHS
On 30 September 2009, the Occupational Safety and Health Administration (OSHA) published proposed revisions to their current Hazard Communication Standard (HCS) in the Federal Register.  The effect of this proposal was to modify the HCS to conform with the United Nations' (UN) Globally Harmonized System of Classification and Labelling of Chemicals (GHS).  On 29 December 2009, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) submitted comments stating that if OSHA were to adopt the GHS-based system for Classification and Categorization of Serious Eye Damage /Eye Irritation as part of their revisions to HCS, many substances currently classified as eye irritants under the current OSHA Hazard Communication Standard (HCS) would no longer be classified as such.  TOXDOC1 has been asked to assist in the assessment of these comments submitted to the Docket (No. OSHA - H022K - 2006 - 0062).
Using as its reference a publically-available database of 149 chemicals for which there are detailed data from in vivo Draize eye irritation studies, NICEATM stated that of the 81 chemicals in the ECETOC database now classified as eye irritants under OSHA's current FHSA-based criteria, at least fourteen substances would be "Not Classified" for eye irritation hazards under the proposed GHS-based HCS classification criteria.  Detailed examination of the referenced data in the ECETOC report reveals that while there is some question about the exact numbers to be used if a formal statistical analysis were to be done, the bottom line on NICEATM`s assessment appears to be correct:  12 of the 13 unique chemicals identified by NICEATM as irritants under FHSA but not GHS are confirmed to have been correctly classified.  At least one other in the data set, cellosolve acetate, also appears to be a FHSA irritant but not a GHS irritant.  In one instance, the same chemical (methyl amyl ketone) appears to have been counted twice by NICEATM from the ECETOC database; it was seen to be an FHSA irritant both times but a GHS irritant neither time.  There is also one instance where a chemical (xylene) appears twice in the database but was counted once by NICEATM (it was a FHSA irritant in one set of data but not in the other, and a GHS irritant in neither case).  Another of the 13 (sodium lauryl sulfate) that are FHSA but not GHS irritants appears in the database as a 3% dilution.  Data for higher strength solutions of the same surfactant that also appear in the database (10% and 30%) clearly demonstrate that the material is an irritant at higher concentrations.  As for the single discordant substance, the data cited by NICEATM purporting myristyl myristate to be an FHSA irritant could not be verified.  In the ECETOC database, it appears to be neither a FHSA nor GHS irritant.
Among the 12 (14 including myristyl myristate and cellosolve acetate) chemicals in question, all appear to be of relevance to OSHA's mandate of assuring workplace safety.  They consist of a variety of chemical types (aromatic solvents, surfactants, alcohols, ketones, acetates, esters, heterocyclics, (meth)acrylates, sulfur-containing materials, etc.), all with occupational relevance.
In all cases examined, the irritant effects reported in the in vivo data set were transient; all animals returned to normal (Draize Score "0") within 3 to 10 days.  Indeed, animals usually returned to normal or sub-irritation threshold readings (cornea, iris = 0; conjunctival erythema/edema = 0 or 1) within 72 hours.  (NOTE:  Timing for Onset of Positive Response under FHSA-based criteria and time to display Reversibility (return to "sub-positive response") appear in the attached data spreadsheet.  As the GHS-based criteria are based on an averaging of scores for the 24-, 48- and 72-hr readings, such parameters are not relevant.)  
It appears that the major difference between the FHSA-based classification and the GHS-based classification lies in this transience.  FHSA uses a classification rubric in which any single "positive" reading at 24, 48, or 72 hours for any of the four parameters examined (corneal opacity, iritis, conjunctival erythema, conjunctival edema) causes an animal to be considered "positive" for irritation.  If 4 of 6 animals tested indicate a positive response, the substance is considered to be an irritant.  In contrast, the GHS-based rubric takes the per-animal average irritation score over these same 24-, 48-, and 72-hour readings and compares it to a slightly higher cut-off to determine if the animal had a "positive" reaction.  If the single sentinel animal tested in an abbreviated assay, or 2 of the 3 animals tested in a full assay, indicate a positive response, the substance is again considered to be an irritant.  Obviously, if the scores indicate that the reactions seen are both borderline and transient, this averaging procedure may take the overall response below the criteria threshold resulting in a "non-positive" response for the animal.
In order to compensate for this difference in approaches, OSHA has proposed to also adopt the GHS concept of "pronounced variability".  Under this concept, for those chemicals where there is pronounced variability among animal responses, such information may be taken into account in determining the classification.  As discussed specifically under OSHA's proposed criteria for Classification and Categorization of Skin Corrosion/Irritation, but only mentioned in passing under Serious Eye Damage /Eye Irritation, this notion would allow for classification in cases where there are very definite, positive irritant effects related to chemical exposure in a single animal, but the overall data set does not support classification.  In cases where the response is borderline but persistent or severe but transient, the Assessor would likely classify a substance as irritating.  It is noted that there are at least two chemicals among those under examination where "pronounced variability" would likely cause the Assessor to classify them as irritants (see data for ethyl thioglycolate and glycidyl methacrylate; fomesafen, 2,2-dimethyl-3-pentanol, and cellosolve acetate might also be classified as irritants under this concept).   
Finally, a quick search of secondary and tertiary sources available on-line indicates that 12 of the 14 chemicals in question would be classified as hazardous materials under both the current and proposed classification criteria.  Those that would not be classified are N,N-dimethylguanidine sulfate (sub-EU classification eye and skin irritation responses; not a sensitizer; no other data found); and tetraaminopyrimidine sulfate (not an acute or chronic toxicant; identified as non-irritating by EU Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP))
CSS.
cc:	Arlene Levin (ERG)
