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Dean JL II, Weaver JA, Kaiser JP. Provisional Peer-Reviewed Toxicity Values for trans-Crotonaldehyde (CASRN 123-73-9). Cincinnati (OH): U.S. Environmental Protection Agency; 2021 Mar.
Provisional Peer-Reviewed Toxicity Values for trans-Crotonaldehyde (CASRN 123-73-9).
Show detailstrans-Crotonaldehyde, CASRN 123-73-9, is an α,β-unsaturated aldehyde with defined stereochemistry (WHO, 2008). The commercial product crotonaldehyde is represented by CASRN 4170-30-3 and consists of >95% trans-isomer (CASRN 123-73-9). cis-Crotonaldehyde is represented by CASRN 15798-64-8. trans-Crotonaldehyde is primarily used in chemical manufacturing as a precursor, intermediate, or solvent (WHO, 2008; HSDB, 2005). It is synthesized by aldol condensation of acetaldehyde and a dehydration step (HSDB, 2005). Commercial crotonaldehyde and trans-crotonaldehyde are both listed on the U.S. EPA’s Toxic Substances Control Act (TSCA) public inventory (U.S. EPA, 2018b), and crotonaldehyde is registered with Europe’s Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) program (ECHA, 2018).
The empirical formula for trans-crotonaldehyde is C4H6O (see Figure 1). Its physicochemical properties are shown in Table 1. trans-Crotonaldehyde is a reactive, clear liquid, with high water solubility. In the air, it will exist in the vapor phase based on its vapor pressure of 30.0 mm Hg. trans-Crotonaldehyde will be degraded in the atmosphere by reacting with photochemically produced hydroxyl radicals. Direct photolysis of trans-crotonaldehyde in the atmosphere does not occur [BUA (1993) as cited in WHO (2018)]. Volatilization of trans-crotonaldehyde from dry soil surfaces is expected based on the compound’s vapor pressure, and moderate volatilization from water or moist soil surfaces is expected based on its estimated Henry’s law constant of 1.45 × 10−5 atm-m3/mole. The estimated Koc for trans-crotonaldehyde indicates potential for mobility in soil and negligible potential to adsorb to suspended solids and sediment in aquatic environments; however, trans-crotonaldehyde polymerizes readily and may react when released in the environment (HSDB, 2005). Hydrolysis is not expected to be an important fate process under environmental conditions, although trans-crotonaldehyde will undergo hydrolysis in low or high pH conditions (WHO, 2018). In dilute acid aqueous solutions, trans-crotonaldehyde reversibly hydrates to form the aldol, 3-hydroxybutanal (ECHA, 2018).
Figure 1
trans- (CASRN 123-73-9) and cis-Crotonaldehyde (CASRN 15798-64-8) Structures.
Table 1
Physicochemical Properties of trans-Crotonaldehyde (CASRN 123-73-9) and Commercial Crotonaldehyde (>95% trans-; CASRN 4170-30-3).
A summary of available toxicity values for trans-crotonaldehyde from U.S. EPA and other agencies/organizations is provided in Table 2. Toxicity values for commercial crotonaldehyde (>95% trans-isomer) are also included in Table 2. A 2010 PPRTV assessment from the U.S. EPA was previously available for “crotonaldehyde.” The assessment herein provides an updated evaluation of trans-crotonaldehyde based on recent scientific literature and current PPRTV assessment practices. Information pertaining to commercial crotonaldehyde mixtures (CASRN 15798-64-8) was also considered as this mixture is defined as containing at least 95% trans-crotonaldehyde isomer. To promote evaluation of the trans-isomer of crotonaldehyde in the context of human health, studies using unspecified isomers, or other isomers of crotonaldehyde (i.e., cis-) are mentioned only for comparison, where necessary.
Table 2
Summary of Available Toxicity Values for trans-Crotonaldehyde (CASRN 123-73-9) and Commercial Crotonaldehyde (>95% trans-; CASRN 4170-30-3).
METHODS
Literature Search
Four online scientific databases (PubMed, Web of Science [WOS], TOXLINE, and Toxic Substances Control Act Test Submissions [TSCATS] via TOXLINE) were searched by U.S. EPA’s Health and Environmental Research Online (HERO) staff and stored in the HERO database.1 The literature search focused on chemical name and synonyms (identified as “valid/validated” or “good” via the U.S. EPA’s Chemistry Dashboard2 and ChemSpider3) with no limitations on publication type, evidence stream (i.e., human, animal, in vitro, in silico), or health outcomes. Full details of the search strategy for each database are presented in Appendix A. The initial database searches were conducted in May 2019 and updated in July 2020.
Screening Process
Two screeners independently conducted a title and abstract screen of the search results using DistillerSR4 to identify study records that met the Population, Exposure, Comparator, Outcome (PECO) eligibility criteria (see Appendix B for a more detailed summary):
- Population: Humans, laboratory mammals, and other animal models of established relevance to human health (e.g., Xenopus embryos); mammalian organs, tissues, and cell lines; and bacterial and eukaryote models of genetic toxicity.
- Exposure: In vivo (all routes), ex vivo, and in vitro exposure to the chemical of interest, including mixtures to which the chemical of interest may contribute significantly to exposure or observed effects.
- Comparison: Any comparison (across dose, duration, or route) or no comparison (e.g., case reports without controls).
- Outcome: Any endpoint suggestive of a toxic effect on any bodily system or mechanistic change associated with such effects. Any endpoint relating to disposition of the chemical within the body.
Records that were not excluded based on title and abstract screening advanced to full-text review using the same PECO eligibility criteria. Studies that have not undergone peer review were included if the information could be made public and sufficient details of study methods and findings were included in the report. Full-text copies of potentially relevant records identified from title and abstract screening were retrieved, stored in the HERO database, and independently assessed by two screeners using DistillerSR to confirm eligibility. At both title/abstract and full-text review levels, screening conflicts were resolved by discussion between the primary screeners with consultation by a third reviewer to resolve any remaining disagreements. During title/abstract or full-text level screening, studies that were not directly relevant to the PECO, but could provide supplemental information, were categorized (or “tagged”) relative to the type of supplemental information they provided (e.g., review, commentary, or letter with no original data; conference abstract; toxicokinetics and mechanistic information aside from in vitro genotoxicity studies; studies on routes of exposure other than oral and inhalation; acute exposure studies only; etc.). Conflict resolution was not required during the screening process to identify supplemental information (i.e., tagging by a single screener was sufficient to identify the study as potential supplemental information).
LITERATURE SEARCH AND SCREENING RESULTS
The database searches yielded 992 unique records. Of the 992 studies identified, 818 were excluded during title and abstract screening, 174 were reviewed at the full-text level, and 49 were considered relevant to the PECO eligibility criteria (see Figure 2). This included 2 human health effect studies, 22 in vivo animal studies, and 12 in vitro genotoxicity studies. Thirteen additional studies were tagged for inclusion as “supplemental/other.” The detailed search approach, including the query strings and PECO criteria, are provided in Appendix A and Appendix B, respectively.
Figure 2
Literature Search and Screening Flow Diagram for trans-Crotonaldehyde (CASRN 123-73-9).
Footnotes
- 1
U.S. EPA’s HERO database provides access to the scientific literature supporting U.S. EPA science assessments. The database includes more than 2,500,000 scientific references and data from the peer-reviewed literature used by U.S. EPA to develop its regulations.
- 2
U.S. EPA’s Chemistry Dashboard: https://comptox
.epa.gov /dashboard/dsstoxdb /results?search=123-73-9. - 3
- 4
DistillerSR, a web-based systematic review software used to screen studies, is available at https://www
.evidencepartners .com/products /distillersr-systematic-review-software.
- INTRODUCTION - Provisional Peer-Reviewed Toxicity Values for trans-Crotonaldehyd...INTRODUCTION - Provisional Peer-Reviewed Toxicity Values for trans-Crotonaldehyde (CASRN 123-73-9)
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