RIFM fragrance ingredient safety assessment, 2-methylbutyl 3-methylbutanoate, CAS Registry Number 2445-77-4

A. M. Api; D. Belsito; D. Botelho; M. Bruze; G. A. Burton; M. A. Cancellieri; H. Chon; M. L. Dagli; M. Date; W. Dekant; C. Deodhar; A. D. Fryer; L. Jones; K. Joshi; M. Kumar; A. Lapczynski; M. Lavelle; I. Lee; D. C. Liebler; H. Moustakas; M. Na; T. M. Penning; G. Ritacco; J. Romine; N. Sadekar; T. W. Schultz; D. Selechnik; F. Siddiqi; I. G. Sipes; G. Sullivan; Y. Thakkar; Y. Tokura

doi:10.1016/j.fct.2022.113460

RIFM fragrance ingredient safety assessment, 2-methylbutyl 3-methylbutanoate, CAS Registry Number 2445-77-4

A. M. Api, D. Belsito, D. Botelho, M. Bruze, G. A. Burton, M. A. Cancellieri, H. Chon, M. L. Dagli, M. Date, W. Dekant, C. Deodhar, A. D. Fryer, L. Jones, K. Joshi, M. Kumar, A. Lapczynski, M. Lavelle, I. Lee, D. C. Liebler, H. MoustakasM. Na, T. M. Penning, G. Ritacco, J. Romine, N. Sadekar, T. W. Schultz, D. Selechnik, F. Siddiqi, I. G. Sipes, G. Sullivan, Y. Thakkar, Y. Tokura

Pulmonary & Critical Care Medicine

Research output: Contribution to journal › Short survey › peer-review

Original language	English (US)
Article number	113460
Journal	Food and Chemical Toxicology
Volume	169
DOIs	https://doi.org/10.1016/j.fct.2022.113460
State	Published - Dec 2022

ASJC Scopus subject areas

Food Science
Toxicology

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10.1016/j.fct.2022.113460

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Api, A. M., Belsito, D., Botelho, D., Bruze, M., Burton, G. A., Cancellieri, M. A., Chon, H., Dagli, M. L., Date, M., Dekant, W., Deodhar, C., Fryer, A. D., Jones, L., Joshi, K., Kumar, M., Lapczynski, A., Lavelle, M., Lee, I., Liebler, D. C., ... Tokura, Y. (2022). RIFM fragrance ingredient safety assessment, 2-methylbutyl 3-methylbutanoate, CAS Registry Number 2445-77-4. Food and Chemical Toxicology, 169, [113460]. https://doi.org/10.1016/j.fct.2022.113460

Api, AM, Belsito, D, Botelho, D, Bruze, M, Burton, GA, Cancellieri, MA, Chon, H, Dagli, ML, Date, M, Dekant, W, Deodhar, C, Fryer, AD, Jones, L, Joshi, K, Kumar, M, Lapczynski, A, Lavelle, M, Lee, I, Liebler, DC, Moustakas, H, Na, M, Penning, TM, Ritacco, G, Romine, J, Sadekar, N, Schultz, TW, Selechnik, D, Siddiqi, F, Sipes, IG, Sullivan, G, Thakkar, Y & Tokura, Y 2022, 'RIFM fragrance ingredient safety assessment, 2-methylbutyl 3-methylbutanoate, CAS Registry Number 2445-77-4', Food and Chemical Toxicology, vol. 169, 113460. https://doi.org/10.1016/j.fct.2022.113460

@article{296aff7be5af4377ada298f7df710bc0,

title = "RIFM fragrance ingredient safety assessment, 2-methylbutyl 3-methylbutanoate, CAS Registry Number 2445-77-4",

author = "Api, {A. M.} and D. Belsito and D. Botelho and M. Bruze and Burton, {G. A.} and Cancellieri, {M. A.} and H. Chon and Dagli, {M. L.} and M. Date and W. Dekant and C. Deodhar and Fryer, {A. D.} and L. Jones and K. Joshi and M. Kumar and A. Lapczynski and M. Lavelle and I. Lee and Liebler, {D. C.} and H. Moustakas and M. Na and Penning, {T. M.} and G. Ritacco and J. Romine and N. Sadekar and Schultz, {T. W.} and D. Selechnik and F. Siddiqi and Sipes, {I. G.} and G. Sullivan and Y. Thakkar and Y. Tokura",

note = "Funding Information: There are insufficient reproductive toxicity data on 2-methylbutyl 3-methylbutanoate. 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. 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 2-methylbutyl 3-methylbutanoate MOE for the reproductive toxicity can be calculated by dividing the isoamyl isovalerate NOAEL in mg/kg/day by the total systemic exposure to 2-methylbutyl 3-methylbutanoate, 800/0.0031, or 258064.",

year = "2022",

month = dec,

doi = "10.1016/j.fct.2022.113460",

language = "English (US)",

volume = "169",

journal = "Food and Chemical Toxicology",

issn = "0278-6915",

publisher = "Elsevier Limited",

}

TY - JOUR

T1 - RIFM fragrance ingredient safety assessment, 2-methylbutyl 3-methylbutanoate, CAS Registry Number 2445-77-4

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 insufficient reproductive toxicity data on 2-methylbutyl 3-methylbutanoate. 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. 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 2-methylbutyl 3-methylbutanoate MOE for the reproductive toxicity can be calculated by dividing the isoamyl isovalerate NOAEL in mg/kg/day by the total systemic exposure to 2-methylbutyl 3-methylbutanoate, 800/0.0031, or 258064.

PY - 2022/12

Y1 - 2022/12

UR - http://www.scopus.com/inward/record.url?scp=85139722720&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85139722720&partnerID=8YFLogxK

U2 - 10.1016/j.fct.2022.113460

DO - 10.1016/j.fct.2022.113460

M3 - Short survey

C2 - 36220616

AN - SCOPUS:85139722720

SN - 0278-6915

VL - 169

JO - Food and Chemical Toxicology

JF - Food and Chemical Toxicology

M1 - 113460

ER -

RIFM fragrance ingredient safety assessment, 2-methylbutyl 3-methylbutanoate, CAS Registry Number 2445-77-4

ASJC Scopus subject areas

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