A Chronic Aquatic Hazard Assessment for the Perfume Raw Material Octahydro-tetramethyl-naphthalenyl-ethanone.

Octahydro-tetramethyl-naphthalenyl-ethanone (OTNE) is a high-production volume fragrance material used in various down-the-drain consumer products. To assess aquatic risk, the Research Institute for Fragrance Materials (RIFM) uses a tiered data-driven framework to determine a risk characterization ratio, where the ratio of the predicted-environmental concentration to the predicted-no-effect concentration (PNEC) of <1 indicates an acceptable level of risk. Owing to its high production volume and the conservative nature of the RIFM framework, RIFM identified the need to utilize a species sensitivity distribution (SSD) approach to reduce the PNEC uncertainty for OTNE. Adding to the existing Daphnia magna, Danio rerio, and Desmodesmus subspicatus chronic studies, eight new chronic toxicity studies were conducted on the following species: Navicula pelliculosa, Chironomus riparius, Lemna gibba, Ceriodaphnia dubia, Hyalella azteca, Pimephales promelas, Anabaena flos-aquae, and Daphnia pulex. All toxicity data were summarized as chronic 10% effect concentration estimates using the most sensitive biological response. Daphnia magna was the most sensitive (0.032 mg/L), and D. subspicatus was the least sensitive (>2.6 mg/L, the OTNE solubility limit). The 5th percentile hazardous concentration (HC5) derived from the cumulative probability distribution of the chronic toxicity values for the 11 species was determined to be 0.0498 mg/L (95% confidence interval 0.0097-0.1159 mg/L). A series of "leave-one-out" and "add-one-in" simulations indicated the SSD was stable and robust. Add-one-in simulations determined that the probability of finding a species sensitive enough to lower the HC5 two- or threefold was 1/504 and 1/15,300, respectively. Given the high statistical confidence in this robust SSD, an additional application factor protection is likely not necessary. Nevertheless, to further ensure the protection of the environment, an application factor of 2 to the HC5, resulting in a PNEC of 0.0249 mg/L, is recommended. When combined with environmental exposure information, the overall hazard assessment is suitable for a probabilistic environmental risk assessment. Environ Toxicol Chem 2024;43:1378-1389. © 2024 SETAC.

Ninety-day toxicity study of alpha-iso-methylionone in rats.

Alpha-iso-methylionone (AIM), a fragrance ingredient, was evaluated for systemic toxicity in rats. Male and female Sprague Dawley rats were administered 0, 5, 30, or 500 mg/kg/d AIM via gavage for 90 days. Statistically significant changes in blood chemistry parameters (reduced aspartate aminotransferase [AST], and increased cholesterol, creatinine, and total protein) were observed in both sexes at 500 mg/kg/d. There were statistically significant increases in liver and kidney weights in both sexes and in spleen weights in males at 500 mg/kg/d. Adaptive hepatocyte enlargement was observed in both sexes at 500 mg/kg/d. Globular accumulations of eosinophilic material were observed in the renal tubular epithelium in males at ≥30 mg/kg/d. Thyroid and bone marrow histopathological changes were observed in males at 500 mg/kg/d. The no-observed-effect level was 5 mg/kg/d for males and 30 mg/kg/d for females. Based on histopathological changes in the kidney in males, the no-observed-adverse-effect level was 30 mg/kg/d.

Macrocyclic fragrance materials--a screening-level environmental assessment using chemical categorization.

A screening-level aquatic environmental risk assessment for macrocyclic fragrance materials using a "group approach" is presented using data for 30 macrocyclic fragrance ingredients. In this group approach, conservative estimates of environmental exposure and ecotoxicological effects thresholds for compounds within two subgroups (15 macrocyclic ketones and 15 macrocyclic lactones/lactides) were used to estimate the aquatic ecological risk potential for these subgroups. It is reasonable to separate these fragrance materials into the two subgroups based on the likely metabolic pathway required for biodegradation and on expected different ecotoxicological modes of action. The current volumes of use for the macrocyclic ketones in both Europe and North America ranges from <1 (low kg quantities) to no greater than 50 metric tonnes in either region and for macrocyclic lactones/lactides the volume of use range for both regions is <1 to no greater than 1000 metric tonnes in any one region. Based on these regional tonnages, biodegradability of these two subgroups of materials, and minimal in stream dilution (3:1), the conservatively predicted exposure concentrations for macrocyclic ketones would range from <0.01 to 0.05 µg/L in Europe and from <0.01 to 0.03 µg/L in North America. For macrocyclic lactones/lactides, the concentration within the mixing zone would range from <0.01 to 0.7 µg/L in Europe and from <0.01 to 1.0 µg/L in North America. The PNECs derived for the macrocyclic ketones is 0.22 µg/L and for macrocyclic lactones/lactides is 2.7 µg/L. The results of this screening-level aquatic ecological risk assessment indicate that at their current tonnage, often referred to as volumes of use, macrocyclic fragrance materials in Europe and North America, pose a negligible risk to aquatic biota; with no PEC/PNEC ratio exceeding 1 for any material in any subgroup.

In vitro penetration and subchronic toxicity of alpha-methyl-1,3-benzodioxole-5-propionaldehyde.

alpha-Methyl-1,3-benzodioxole-5-propionaldehyde (methyl-3,4-methylene-dioxy-hydrocinnamic Aldehyde, MMDHCA) is a widely used commercially available fragrance material. Because of the wide range of product availability, there is dermal exposure associated with its use. The objective of this study was to determine the in vitro human skin absorption of (14)C MMDHCA and subchronic toxicity of the material. Twenty mL of a 1% solution of radiolabeled MMDHCA in ethanol was applied to the surface of epidermal membranes isolated from full thickness human skin samples and placed in diffusion cells. Samples of the receptor fluid (50% ethanol/water) were harvested at 2, 8, 24, and 48 h and analyzed by liquid scintillation chromatography to assess dermal absorption. At 24 and 48 h, respectively, 42% and 50% of the applied dose of MMDHCA had permeated the human skin in vitro. Only 67% of the applied dose was recovered by 48 h. For the subchronic toxicity, MMDHCA was applied dermally once daily to male and female Sprague-Dawley rats (15/sex/group) at 50, 150, or 300 mg/kg/day (0.043, 0.129, or 0.259 mL/kg/day applied neat to 5 cm(2) dorsal skin) for at least 90 consecutive days. A control group (15/sex) was given vehicle (reverse osmosis water) at 0.259 mL/kg/day for a similar duration. Rats were necropsied at the end of treatment (10/sex/group) or following a 4-week recovery period (5/sex/group). The following parameters were evaluated: dermal irritation, estrous cycle, ophthalmologic examinations, body weight, feed consumption, hematology, blood coagulation, serum chemistry, organ weights, macroscopic and histopathologic examinations, and male reproductive assessment. No test article-related mortalities or effects on, estrous cycles, ophthalmic exams, mean body weights, mean body weight change, feed consumption, absolute or relative organ weights, macroscopic observations, or male reproductive morphology/function were observed. MMDHCA-related dermal irritation was observed across all dose levels with increased incidence and severity at 300 mg/kg/day. Dermal irritation that initially ranged from slight to marked improved to slight or resolved completely during the recovery phase. Based on the findings in this study, it can be concluded that (1) MMDHCA exhibits moderately high human skin permeation; (2) the NOEL for dermal irritation is below 50mg/kg/day when applied undiluted to 5 cm(2) dorsal skin and (3) the NOEL for systemic toxicity is greater than 300 mg/kg/day. During the 4-week recovery period of the 90-day study, the animals had largely recovered from MMDHCA induced dermal irritation and the associated microscopic findings.

Evaluation of the developmental toxicity of acetyl cedrene.

The developmental toxicity of acetyl cedrene (AC), a widely used fragrance ingredient, was evaluated in pregnant Sprague-Dawley rats (25/group). Gavaged dosages of 0 (corn oil), 25, 50, or 100 mg/kg/day were administered on days 7 through 17 of gestation (GDs 7 to 17). First and last day dosing suspensions were analyzed for AC content. All rats were observed daily for viability, clinical signs, abortions, and premature deliveries. Body weights were recorded at frequent intervals. Cesarean-sectioning and necropsy examinations were performed on GD 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. The number of corpora lutea in each ovary was also recorded. Fetuses were weighed and examined for gender and gross external changes and soft tissue or skeletal alterations. Totals of 25, 23, 21, and 24 rats became pregnant in the 0 (control), 25, 50 and 100 mg/kg/day groups, respectively, and analysis of dosage preparations verified that administered dosages reflected calculated dosages +/-10%. No deaths or premature deliveries occurred in the study. Clinical signs included excessive salivation, which was attributed to the administration of AC. When compared to controls, significant reductions in feed consumption and body weight gains occurred only at 100 mg/kg/day. Both absolute (g/day) and relative (g/kg/day) feed consumption values were significantly decreased on GDs 7 to 12. Relative values were decreased significantly on GDs 15 to 18. Body weight gains were significantly reduced on GDs 7 to 10. Mean maternal body weights remained significantly lower than controls on GDs 9 to 14, but a marked compensatory increase in feed consumption on GDs 15 to 18 prevented further deterioration in body weight gains. No cesarean-sectioning or litter parameters were affected by dosages of AC and necropsy of the dams after cesarean section did not reveal any gross changes attributable to AC. No gross external, soft tissue, or skeletal fetal alterations (malformations or variations) were attributed by dosages AC. The average number of ossifications sites per fetus per litter did not differ among the groups. Based on these data, maternal and developmental no-observable-adverse-effect levels (NOAELs) of 50 and 100 mg/kg/day, respectively, were established for AC.