Implementing a globally harmonized risk assessment-based approach for regulatory decision-making of crop protection products.

A global, harmonized evaluation system for crop protection chemicals based on exposure and risk will improve the ability to inform risk management decisions and better support innovation. This would be achieved through harmonized risk assessment-based regulatory decision-making realized through the application of the best available science, via integration of new methods and traditional data to create tailored exposure-driven risk assessments. A requirement to achieve success is a structure that encourages direct communication between the regulatory community and the regulated industry, which would enable a more rapid incorporation of new technologies and advancing science. An approach that emulates the International Conference of Harmonization (ICH) for pharmaceuticals would bring together regulatory authorities and the regulated industry along with relevant experts from academia and Non-Governmental Organizations to discuss scientific and technical advances and their implementation. These discussions would also encourage the elimination of outmoded practices that no longer serve a purpose resulting in more uniform testing requirements and best practices for data evaluation to support safe use and scientifically defensible human health and environmental risk assessments. New and developing technologies offer exciting opportunities to improve the current toxicity testing paradigms to provide better solutions and diminish animal testing. Implementation of a harmonized approach will increase the speed, efficiency and accuracy of regulatory decision-making for human health and environmental protection while increasing the efficiency of providing safe and effective innovative products to the agriculture community. © 2020 Society of Chemical Industry.

Evaluation of the reproductive and developmental toxicity of 6:2 fluorotelomer alcohol in rats.

6:2 Fluorotelomer alcohol (6:2 FTOH) was evaluated for potential developmental and reproductive toxicity. 6:2 FTOH was administered by oral gavage to Sprague-Dawley rats as a suspension in 0.5% aqueous methylcellulose at dosages of 5, 25, 125, or 250 mg/kg/day. The developmental toxicity study was performed in accordance with the Organization for Economic Development (OECD) Test Guideline 414, and the one-generation reproductive toxicity study was performed in accordance with the OECD Test Guideline 415. For the developmental toxicity study, adverse maternal toxicity observed at 250 mg/kg/day included reductions in body weight parameters and food consumption. Evidence of developmental toxicity was limited to increases in skeletal variations (ossification delays in the skull and rib alterations) at 250 mg/kg/day. There were no adverse maternal or developmental effects observed at 5, 25, or 125 mg/kg/day and there were no effects on reproductive outcome or quantitative litter data at any dose level. For the one-generation reproduction toxicity study, systemic parental and developmental toxicity were observed at 125 and 250 mg/kg/day. At 250 mg/kg/day, there was increased mortality among male and female parental rats, effects on body weight parameters, food consumption, and clinical signs, and there were effects on offspring survival indices and body weights. At 125 mg/kg/day, there was an increase in mortality in parental males only, and parental toxicity was limited to effects on body weight gain, food consumption (lactation), and clinical signs. Uterine weights were decreased at 125 and 250 mg/kg/day, although there were no corroborative histopathological changes. At 125 mg/kg/day, pup mortality was increased on lactation day 1, and body weights of the offspring were decreased during the second half of lactation. There was no evidence of either parental or developmental toxicity at 5 or 25mg/kg/day, and there were no effects on reproductive outcome at any dose level. Based on these data, 6:2 FTOH is not a selective reproductive or developmental toxicant at dosages that induce clear maternal/parental toxicity. Therefore, 6:2 FTOH would not be classified for reproductive/developmental toxicity under the United Nations' Globally Harmonized System of Classification and Labeling of Chemicals.

Decision trees for evaluating skin and respiratory sensitizing potential of chemicals in accordance with European regulations.

Guidance for determining the sensitizing potential of chemicals is available in EC Regulation No. 1272/2008 Classification, Labeling, and Packaging of Substances; REACH guidance from the European Chemicals Agency; and the United Nations Globally Harmonized System (GHS). We created decision trees for evaluating potential skin and respiratory sensitizers. Our approach (1) brings all the regulatory information into one brief document, providing a step-by-step method to evaluate evidence that individual chemicals or mixtures have sensitizing potential; (2) provides an efficient, uniform approach that promotes consistency when evaluations are done by different reviewers; (3) provides a standard way to convey the rationale and information used to classify chemicals. We applied this approach to more than 50 chemicals distributed among 11 evaluators with varying expertise. Evaluators found the decision trees easy to use and recipients (product stewards) of the analyses found that the resulting documentation was consistent across users and met their regulatory needs. Our approach allows for transparency, process management (e.g., documentation, change management, version control), as well as consistency in chemical hazard assessment for REACH, EC Regulation No. 1272/2008 Classification, Labeling, and Packaging of Substances and the GHS.

Toxicological assessment of tridecafluorohexylethyl methacrylate (6:2 FTMAC).

The toxicity of tridecafluorohexylethyl methacrylate (6:2 FTMAC), an acrylic monomer used in producing polymeric substances, was evaluated. 6:2 FTMAC has low acute oral and dermal toxicity (LD50>5000 mg/kg), was not a skin or eye irritant, and did not demonstrate skin sensitization potential in a local lymph node assay (LLNA). 6:2 FTMAC was not mutagenic in the bacterial reverse mutation (Ames) test or in the mouse lymphoma assay. 6:2 FTMAC induced structural aberrations in human peripheral blood lymphocytes in vitro in the absence of metabolic activation but not in the presence of S9 metabolic activation. No numerical aberrations were detected under any testing condition. Also, no increase occurred in structural or numerical chromosomal aberrations in an in vivo mouse micronucleus assay in 6:2 FTMAC treated animals compared to controls. 6:2 FTMAC was administered at 0, 100, 500 and 1000 mg/kg/day via gavage to male and female SD rats for 14 days. No test substance-related effects on mortality, clinical signs, body weights, nutritional parameters, or clinical pathology were observed at any dose. Test substance-related increases in liver weights in males and females at all dose levels and thyroid and kidney weights in 500 and 1000 mg/kg/day males were noted. While there was no histopathological correlate for thyroid and kidney weight changes, minimal hypertrophy was noted in liver in males and females at 1000 mg/kg/day group. The changes noted in teeth (altered mineralization; retention of basophilic material) and femur (increased mineralization) in all treated groups were not associated with clinical signs or microscopic changes and were likely related to free fluoride formed from 6:2 FTMAC metabolism. Plasma (3-4-fold) and urine (30-50-fold) fluoride was higher in treated groups versus controls. Therefore, the changes noted in organ weights, teeth, femur, plasma or urine were not considered adverse. In the repeated dose toxicity study, the no-observed-adverse-effect-level (NOAEL) was 1000 mg/kg/day. Based on mean measured concentrations, the 96-h LC50 in fathead minnow was >14.5 mg/L and the 72-h EC50 in Pseudokirchneriella subcapitata was >24.6 mg/L, while the 48-h EC50 in Daphnia magna, based on nominal concentrations, was >120 mg/L. Overall, 6:2 FTMAC is considered to have low toxicity potential based on these studies.

8:2 fluorotelomer alcohol: a one-day nose-only inhalation toxicokinetic study in the Sprague-Dawley rat with application to risk assessment.

8:2 fluorotelomer alcohol (8:2 FTOH) inhalation exposure was investigated to (1) compare plasma metabolites to oral data, (2) conduct a route-to-route extrapolation (oral to inhalation), (3) develop a human equivalent air concentration (HEC) from a 90-day oral sub-chronic study in rats using BMD analysis, and (4) calculate a margin of exposure (MOE) between the HEC and measured air concentrations. Male and female rats were exposed nose-only for 6h at 3 or 30mg/m(3). Blood was collected at 1, 3 and 6h during exposure and 6 and 18h post exposure. Alcohol, perfluorocarboxylic acid and polyfluorinated acid metabolites were determined in plasma by LC-MS/MS. 8:2 FTOH was

Absorption, distribution, metabolism, and excretion of [1-¹4C]-perfluorohexanoate ([¹4C]-PFHx) in rats and mice.

The absorption, tissue distribution, elimination, and metabolism of [1-¹4C]-PFHx in rats and mice dosed orally at 2 or 100 mg/kg was evaluated following a single dose or after 14 consecutive doses. Absorption was rapid in rats as evidenced by a short time to maximum concentration (C(max)) of 30 min in male rats and 15 min in female rats at both the 2 and 100mg/kg dose level. The plasma elimination half-life was somewhat longer in males (1.5-1.7 h) than in females (0.5-0.7 h). Absorption in the mouse was also rapid with the maximum plasma concentration occurring between 15 and 30 min after dosing. The maximum concentration was not appreciably different between male and female mice (8 µg equiv./g at 2 mg/kg; ~350 µg equiv./g at 100 mg/kg). The primary route of elimination was via the urine. PFHx was not metabolized in rat or mouse hepatocytes, nor were any metabolites observed after oral dosing in either rodent species. Essentially 100% of the dose was eliminated in urine within 24 h demonstrating that PFHx is readily absorbed and bioavailability approaches 100%, even at a dose as high as 100 mg/kg. The route and extent of elimination was unchanged after 14 days of daily dosing. Tissues were collected at three time points (rat: 0.5, 2, and 24 h; mice: 0.25, 1, and 24 h) after dosing to investigate the tissue clearance kinetics of PFHx following a single dose at 2 or 100 mg/kg. In all tissues except skin, PFHx was not quantifiable 24 h after dosing in both sexes of the two species.

Absorption of [14C]-tetrabromodiphenyl ether (TeBDE) through human and rat skin in vitro.

The skin is the largest organ in the human body and has the potential to come into contact with a variety of xenobiotics both intentionally (e.g., drugs and cosmetics) or accidentally (e.g., agrochemicals and industrial chemicals). These chemicals may then cross the skin barrier (the stratum corneum) and enter into the systemic circulation where they may produce a desired or an undesired effect, or even no systemic effect at all. Tetrabromodiphenyl ether (TeBDE) is one congener in a mixture of polybrominated diphenyl ethers that makes up a flame-retardant commercial product called pentabromodiphenyl ether (PeBDE). TeBDE was used as a surrogate to assess the potential dermal absorption of this product. The physicochemical properties, including lipophilicity, of TeBDE and PeBDE are similar. Operator exposure of PeBDE product to human skin is possible during production and use. However, during these activities, operators wear protective clothing to protect from or minimize exposure. This study was designed to assess the rate and extent of absorption of [14C]-tetrabromodiphenyl ether ([14C]-TeBDE) through human and rat skin in vitro. [14C]-TeBDE was applied to human and rat split thickness skin membranes in vitro in a single test preparation: [14C]-TeBDE in acetone (ca. 20%, w/v). Dermal delivery and absorbed dose of TeBDE applied to human skin was 3.13% (313 microg equiv/cm(2)) and 1.94% (194 microg equiv/cm(2)) of the applied dose, respectively. Dermal delivery and absorbed dose of TeBDE applied to rat skin was 17.94% (1804 microg equiv/cm(2)) and 14.81% (1489 microg equiv/cm(2)) of the applied dose, respectively. These results confirm that the risk of systemic exposure due to external dermal exposure of the PeBDE product is low in the human. Consequently, based on the toxicological profile of these materials, the potential for undesirable effects is also quite low. The results also confirm that the rat is a conservative model overpredicting human absorption about eight fold.