Original language | English (US) |
---|---|
Article number | 113516 |
Journal | Food and Chemical Toxicology |
Volume | 173 |
DOIs | |
State | Published - Mar 2023 |
ASJC Scopus subject areas
- Food Science
- Toxicology
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In: Food and Chemical Toxicology, Vol. 173, 113516, 03.2023.
Research output: Contribution to journal › Short survey › peer-review
}
TY - JOUR
T1 - Update to RIFM fragrance ingredient safety assessment, 3-methylbutyl 2-methylpropanoate, CAS Registry Number 2050-01-3
AU - Api, A. M.
AU - Belsito, D.
AU - Botelho, D.
AU - Bruze, M.
AU - Burton, G. A.
AU - Cancellieri, M. A.
AU - Chon, H.
AU - Dagli, M. L.
AU - Date, M.
AU - Dekant, W.
AU - Deodhar, C.
AU - Fryer, A. D.
AU - Jones, L.
AU - Joshi, K.
AU - Kumar, M.
AU - Lapczynski, A.
AU - Lavelle, M.
AU - Lee, I.
AU - Liebler, D. C.
AU - Moustakas, H.
AU - Na, M.
AU - Penning, T. M.
AU - Ritacco, G.
AU - Romine, J.
AU - Sadekar, N.
AU - Schultz, T. W.
AU - Selechnik, D.
AU - Siddiqi, F.
AU - Sipes, I. G.
AU - Sullivan, G.
AU - Thakkar, Y.
AU - Tokura, Y.
N1 - Funding Information: There are no repeated dose toxicity data on 3-methylbutyl 2-methylpropanoate. The read-across material, isoamyl isovalerate (CAS # 659-70-1; see Section VI), has sufficient repeated dose toxicity data to support the repeated dose toxicity endpoint. A 90-day dietary study was conducted in CRL:COBS CD (SD) BR rats. Groups of 10–16 rats/sex/dose were fed diets containing the test material, isoamyl isovalerate, at doses of 0, 21.9, 69.2, or 219 mg/kg/day for 90 days. There were no treatment-related adverse effects observed up to the highest dose tested. Thus, the NOAEL was considered to be 219 mg/kg/day (RIFM, 1980). In another study, an OECD/GLP 422 combined repeated dose toxicity with a reproduction/developmental toxicity screening test was conducted in Sprague Dawley rats. Groups of 12 rats/sex/dose were administered via gavage the test material, isoamyl isovalerate, at doses of 0, 75, 250, or 800 mg/kg/day. Males were dosed for 2 weeks prior to mating and continued through the day before euthanasia (total of 50 days), while females were dosed for 2 weeks prior to mating and continued through to lactation day 13. Additional groups of 6 rats/sex/dose were assigned to the control and high-dose group (but were not mated) to serve as the 14-day treatment-free recovery groups. One high-dose dam was euthanized on GD 24 because all pups were found dead. Prolonged parturition, irregular respiration, and skin paleness were observed during GD 23 to 24 for this dam. Macroscopic examination revealed greenish-black luminal contents in the stomach and colon and pinkish, transparent thoracic fluid. The relationship between the treatment and these findings was unclear since it was only observed in 1 high-dose female. However, this death was not considered to have toxicological relevance since no treatment-related adverse effects in other parameters at 800 mg/kg/day were observed during the study. At 800 mg/kg/day, salivation was observed among both males and females, but this finding was considered to be attributed to the palatability and not the systemic toxicity of the test material. Significant increases in T4 thyroid hormone levels were observed in high-dose adult males (1.24-fold of the control) and mid- and high-dose pups (up to 1.22-fold of the control). However, this was not considered to be toxicologically significant since there were no correlated microscopic findings in the thyroid (with parathyroids). There were no treatment-related adverse effects in any of the systemic toxicity parameters evaluated (body weight, food consumption, functional behavior and motor activity examination, hematology, clinical chemistry, organ weights, and macroscopic and microscopic findings). Thus, the NOAEL for systemic toxicity was considered to be 800 mg/kg/day, the highest dose tested (RIFM, 2017). Since both studies determined the NOAEL to be the highest dose tested, a NOAEL of 800 mg/kg/day from the OECD 422 was selected for this safety assessment.There are no reproductive toxicity data on 3-methylbutyl 2-methylpropanoate. The read-across material, isoamyl isovalerate (CAS # 659-70-1; see Section VI), has sufficient reproductive toxicity data to support the reproductive toxicity endpoint. An OECD/GLP 422 combined repeated dose toxicity with a reproduction/developmental toxicity screening test was conducted in Sprague Dawley rats. Groups of 12 rats/sex/dose were administered via gavage the test material, isoamyl isovalerate, at doses of 0, 75, 250, or 800 mg/kg/day. Males were dosed for 2 weeks prior to mating and continued through the day before euthanasia (a total of 50 days), while females were dosed for 2 weeks prior to mating and continued through to lactation day 13. Additional groups of 6 rats/sex/dose were assigned to the control and high-dose groups (but were not mated) to serve as the 14-day treatment-free recovery groups. In addition to the systemic toxicity parameters, the fertility and developmental toxicity parameters were also evaluated. Estrus cycle, precoital time, fertility data, reproductive and littering findings, F1 pup clinical signs, body weight, anogenital distance, nipple retention, and external examination were measured. Thyroid hormone (T4) level in the blood was also analyzed for adult males and F1 pups. One high-dose dam was euthanized on GD 24 because all pups were found dead. Prolonged parturition, irregular respiration, and skin paleness were observed during GDs 23 to 24 for this dam. Macroscopic examination revealed greenish-black luminal contents in the stomach and colon and pinkish, transparent thoracic fluid. The relationship between the treatment and these findings was unclear since it was only observed in 1 high-dose female. However, this death was not considered to have toxicological relevance since no treatment-related adverse effects in other parameters at 800 mg/kg/day were observed during the study. Significant increases in T4 were observed in high-dose adult males (1.24-fold of the control) and mid and high-dose pups (up to 1.22-fold of the control). However, this was not considered to be toxicologically significant since there were no correlated microscopic findings in the thyroid (with parathyroids). There were no treatment-related adverse effects in any of the fertility and developmental toxicity parameters evaluated. Thus, the NOAEL for fertility and developmental toxicity was considered to be 800 mg/kg/day, the highest dose tested (RIFM, 2017). Therefore, the 3-methylbutyl 2-methylpropanoate MOE for the reproductive toxicity can be calculated by dividing the isoamyl isovalerate NOAEL in mg/kg/day by the total systemic exposure to 3-methylbutyl 2-methylpropanoate, 800/0.00065, or 1230769.
PY - 2023/3
Y1 - 2023/3
UR - http://www.scopus.com/inward/record.url?scp=85146222548&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85146222548&partnerID=8YFLogxK
U2 - 10.1016/j.fct.2022.113516
DO - 10.1016/j.fct.2022.113516
M3 - Short survey
C2 - 36410625
AN - SCOPUS:85146222548
SN - 0278-6915
VL - 173
JO - Food and Chemical Toxicology
JF - Food and Chemical Toxicology
M1 - 113516
ER -