Chapter 6 and Chapter 8 section only from “Criteria for a Recommended Standard: Occupational Exposures to Diacetyl and 2, 3-pentanedione”

The National Institute for Occupational Safety and Health (NIOSH) of the Centers for Disease Control and Prevention (CDC) published a final document, Criteria for a Recommended Standard: Occupational Exposure to Diacetyl and 2,3-Pentanedione, in October 2016. The links to the final document and the NIOSH responses to the peer and stakeholder and public review comments are provided below.

The entire criteria document had initially undergone external peer review and public comment from August 2011– May 2012. Information on this initial review can be found here. Subsequently, NIOSH conducted an additional peer and public review process for two revised chapters of the draft document from December 2013 – February 2014. Specifically, NIOSH sought external review and public comment on a revised Chapter 6 and a new section of Chapter 8. Descriptions of the new content for these chapters are provided below. This new content supports the conclusions in the draft criteria document so it was reviewed independently of the entire document.

For Chapter 6 – Quantitative Risk Assessment Based on Animal Data:

Overview of changes: After the previous peer review and public comment process was initiated, the National Toxicology Program released a new dataset on diacetyl and 2,3-pentanedione. Chapter 6, titled Quantitative Risk Assessment Based on Animal Data, was updated to accommodate this new dataset. The new dataset and associated quantitative risk assessment of these animal data support the previous conclusions of the human risk assessment in the original draft document.

For Chapter 8 – GHS section:

Overview of changes: After the previous peer review and public comment process was initiated, the Occupational Safety and Health Administration (OSHA) promulgated a revised Hazard Communication Standard aligned with the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). The new section of Chapter 8 includes classifications of these chemicals based on the OSHA GHS criteria. These classifications were added in response to comments received during the public and peer review comment period for the draft criteria document. It is of note that this is the first time that a NIOSH document has provided GHS classifications that were derived by NIOSH. Though other NIOSH documents have previously published GHS classifications (e.g. NIOSH Skin Notations), those GHS classifications were derived by and cited from another authoritative body.

NIOSH considers this Criteria Document to be a highly influential scientific assessment (HISA) containing significant guidance as defined by the Office of Management and Budget Peer Review Bulletin and Good Guidance Practices Bulletin. The overall goal of the peer review and public comment process is to enhance the quality and credibility of NIOSH recommendations by ensuring that the scientific and technical work underlying these recommendations receives appropriate review by independent scientific and technical experts as well as public review. A listing of the external peer reviewers as well as the charge to peer reviewers can be found on the peer review agenda website.

To view the notice and related material visit http://www.regulations.gov, enter CDC-2013-0021 in the search field, then click “Search”.

Peer Review

Cross-Clearance Agencies: None

Date of Dissemination: December 26, 2013

Subject of planned Report: Diacetyl and 2,3-pentanedione

Purpose of Planned Report: The Criteria document provides a forum to review new scientific information in regards to diacetyl and 2,3-pentanedione, and provide guidance to stakeholders, public health agencies and regulatory agencies. The entire criteria document has previously undergone external peer review and public comment from August 2011– May 2012. Peer and public review is now being completed on a revised Chapter 6 and a new section of Chapter 8 only. This new content supports the conclusions in the draft criteria document so can be reviewed independently of the entire document.

Type of Dissemination: Highly Influential

Timing of Review: Federal Register Notice posted on December 26, 2013 through February 10, 2014.

Primary Disciplines or Expertise: 1) Toxicology, 2) Risk assessment, 3) Hazard Communication

Type of Review: Third Party Review

Number of Reviewers: 4

Reviewers Selected by: Oak Ridge Institute for Science and Education (ORISE) will coordinate peer review.

Peer Reviewers

1. Dale Hattis, Ph.D.
   Academic and Professional Credentials: Research Professor, George Perkins Marsh Institute, Clark University
   Organization Affiliation: Clark University
   Area of Expertise, Discipline, or Relevant Experience: Methodology for quantitative health risk assessment for cancer and non-cancer health effects; Human inter-individual variability in susceptibility to toxic effects; Pharmacokinetic and Monte Carlo simulation modeling; Implications of inter-individual variability for population risk for both carcinogens and other toxic substances
2. Sam Kacew, Ph.D., ATS
   Academic and Professional Credentials: Associate Director of Toxicology, McLaughlin Centre for Population Health Risk Assessment; Professor, Department of Cellular & Molecular Medicine, University of Ottawa
   Organization Affiliation: University of Ottawa
   Area of Expertise, Discipline, or Relevant Experience: General toxicology and human health risk assessment, particularly renal, hepatic, and pulmonary toxicology
3. David Halton, Ph.D., CIH; CRSP
   Academic and Professional Credentials: Ph.D. in Toxicology, University of Windsor (1978); Certified Industrial Hygienist (1988); Canadian Registered Safety Professional (1991)
   Organization Affiliation: Private Consultant
   Area of Expertise, Discipline, or Relevant Experience: Toxicology and chemical hazard communication, including Globally Harmonized System (GHS); hazardous material reviews, toxicological risk assessments, industrial hygiene surveys, and safety audits
4. John Howell, Ph.D.
   Academic and Professional Credentials: Ph.D. in Inorganic Chemistry, Drexel University
   Organization Affiliation: Private Consultant
   Area of Expertise, Discipline, or Relevant Experience: Chemical hazard communication; GHS-compliant safety data sheet authoring

For Chapter 6 – Quantitative Risk Assessment Based on Animal Data

Overview of changes: After the previous peer review and public comment process was initiated, the National Toxicology Program released a new dataset on diacetyl and 2,3-pentanedione. Chapter 6, titled Quantitative Risk Assessment Based on Animal Data, has been updated to accommodate this new dataset. The new dataset and associated quantitative risk assessment of these animal data support the previous conclusions of the human risk assessment in the original draft document.

Peer review questions:

1. Is the risk estimation for diacetyl and 2,3-pentanedione presented in Chapter 6 a reasonable reflection of the current understanding of the scientific literature?
2. The new NIOSH risk assessment estimates BMC(L)10 for more than 20 respiratory tract response endpoints in rats and mice. Which of these should be regarded as most relevant for estimating worker risk to diacetyl/2,3- pentanedione and for deriving a REL? Should the most sensitive endpoint (i.e., lowest BMC(L)10) in the most sensitive sex/species be given greatest preference? Are there other features to consider such as site of injury (e.g., bronchus vs. nose) or type of lesion? Please explain the rationale for your response.
3. The new NIOSH risk assessment relies on a computational fluid dynamics/physiologically-based pharmacokinetic (CFD/PBPK) model to determine the human equivalent concentrations (HEC) that correspond to equivalent diacetyl concentrations in the nose and tracheobronchial regions of rodent and lightly exercising workers (see tables 6-4 through 6-9). Please describe the advantages and disadvantages of using these regional rodent-to-human respiratory tissue concentration ratios as dose metrics and describe any viable alternatives.
4. The CFD/PBPK model is also able to predict exposure levels corresponding to diacetyl concentrations in human bronchiolar tissue. How much value would be realized by adding HECs that correspond to the human bronchiolar region to the analysis (based on the assumption that bronchiolar tissue is a target for flavoring-related constrictive bronchiolitis reported in workers)?
5. The animal-to-human dose adjustment factors used in the assessment are based on modeling at a single diacetyl exposure level (1 ppm) under one condition of nasal/mouth breathing. Are there other dose adjustment factors that would provide useful information on human risks based on modeling different diacetyl exposures or greater rates of mouth breathing? What value would those analyses add to the current risk assessment?
6. The new NIOSH risk assessment uses a mouse-to-human dose adjustment factor that assumes a mouse minute volume (VE) based on allometric scaling instead of the 2- to 4-fold higher VE values previously measured in diacetyl-exposed male mice (see 8/2011 external review draft, Appendix 6-A Table 8). Would an extension of the analysis to include basing the dose adjustment factors on the measured mouse minute volume estimates contribute significant value to the present risk assessment? Please explain any additional insight these analyses might offer?
7. The new NIOSH risk assessment applies a series of UFs to the calculated HEC that account for rodent-to-human differences in target tissue sensitivity (UF = 2.5), variability in diacetyl-induced respiratory toxicity in the worker population (UF = 3.2), and extrapolation from a 13-week subchronic exposure study to chronic 45-year working lifetime (UF = 3). The resulting aggregate UF of 24 was used to estimate animal-based candidate RELs. Have the selection and magnitude of the various UFs been adequately described based on best available scientific evidence and/or accepted scientific practice? What other factors for intraspecies variability could be considered to account for the variable susceptibility in impaired pulmonary function among exposed microwave popcorn workers discussed in Chapter 5 (Quantitative Risk Assessment Based on Worker Data)?
8. While the new NIOSH risk assessment uses the deterministic UF approach to derive candidate RELs, the previous risk assessment presented in the 2011 NIOSH external review draft (/niosh/docket/archive/pdfs/NIOSH-245/DraftDiacetylCriteriaDocument081211.pdfpdf icon) used best-fitting probabilistic models to derive risk–specific exposure levels, such as the projected REL corresponding to a 1 in 1000 risk. Is there significant value to adding a quantitative model-derived risk assessment of rodent respiratory tract toxicity as a complement to the primary exposure –response assessment derived from occupational epidemiology investigations?
9. The relative potency of 2,3- pentanedione from a two week inhalation study in mice and diacetyl from the 13-week inhalation study in mice were jointly analyzed across multiple common respiratory tract endpoints using cumulative logistic models. NIOSH concludes that the modeling results suggest that “it would be prudent to treat 2,3- pentanedione as at least as toxic as diacetyl.” Please comment on the validity and utility of the methods used to support this interpretation.

For Chapter 8 – GHS section

Overview of changes:

After the previous peer review and public comment process was initiated, the Occupational Safety and Health Administration (OSHA) promulgated a revised Hazard Communication Standard aligned with the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). The new section of Chapter 8 includes classifications of these chemicals based on the OSHA GHS criteria. These classifications were added in response to some of the comments received during the public and peer review comment period for the draft criteria document. It is of note that this is the first time that a NIOSH document has provided GHS classifications that were derived by NIOSH. Though other NIOSH documents have previously published GHS classifications (e.g. NIOSH Skin Notations), those GHS classifications were derived by and cited from another authoritative body. Peer review questions:

1. In the updated hazard communication chapter of the diacetyl/2,3- pentanedione Criteria Document, NIOSH has provided Globally Harmonized System of Classification and Labeling (GHS) classifications based on the revised Occupational Safety and Health Administration (OSHA) Hazard Communication (HazCom) Standard (29 CFR 1910.1200). Do these classifications reflect a reasonable interpretation of the peer-reviewed data that are presented? Is this section a reasonable reflection of the current understanding of the scientific literature?
2. As part of the OSHA HazCom Standard, labeling of chemicals that are part of mixtures is only required if the hazardous chemicals in the mixture are present in bulk concentrations above specific “cut-off” values outlined in Appendix A of the OSHA HazCom Standard. These cut-off values vary by health endpoint. In the case of diacetyl, it has been observed on several occasions (outlined in the document) that air concentrations of diacetyl exceeded the proposed NIOSH REL, when bulk concentrations of diacetyl in the source mixtures were below the cut-off values prescribed in the OSHA HazCom Standard. NIOSH has described why following these cut-off values for mixtures containing diacetyl will sometimes not alert workers to potential exposures to diacetyl above the proposed REL. Please comment on the rationale NIOSH described. Has NIOSH provided adequate information to support why these cut-off values should be lowered in the specific case of diacetyl? NIOSH has extended this approach to 2,3-pentanedione. Please comment on the rationale NIOSH used to justify this approach. What additional data are available that would inform NIOSH’s reasoning on this issue?
3. Is the current level of detail and explanation for how GHS hazard classifications were derived in the HazCom section of the criteria document sufficient? If not, what additional information would be useful?