Update to RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7

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.2022.113031

Update to RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7

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	113031
Journal	Food and Chemical Toxicology
Volume	163
DOIs	https://doi.org/10.1016/j.fct.2022.113031
State	Published - May 2022

ASJC Scopus subject areas

Food Science
Toxicology

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10.1016/j.fct.2022.113031

Cite this

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). Update to RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7. Food and Chemical Toxicology, 163, [113031]. https://doi.org/10.1016/j.fct.2022.113031

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, 'Update to RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7', Food and Chemical Toxicology, vol. 163, 113031. https://doi.org/10.1016/j.fct.2022.113031

@article{5a662a29d21147dea21bd9cc970aff49,

title = "Update to RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7",

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 repeated dose toxicity data on benzyl butyrate. Read-across material benzyl acetate (CAS # 140-11-4; see Section VI) has sufficient data to support the repeated dose toxicity endpoint. Groups of 10 F344/N rats/sex were fed diets containing benzyl acetate at doses of 0, 3130, 6250, 12500, 25000, or 50000 ppm equivalent to 0, 230, 460, 900, 1750, or 3900 mg/kg/day for males and 0, 240, 480, 930, 1870, or 4500 mg/kg/day for females for 13 weeks. Mortality was reported among high-dose group animals. Bodyweight gain and final body weights for the animals of the 25000 ppm dose-group males were significantly lower than the control. There was a reduction in food consumption reported among 25000 ppm and 50000 ppm males and the 50000 ppm females; this was attributed to the palatability of the test material and not considered an adverse effect. Tremors and ataxia were reported among the high-dose group animals. Test material-related lesions were reported in the brain, kidney, tongue, and skeletal muscles of the thigh. Necrosis of the brain involving the cerebellum and/or the hippocampus, degeneration and regeneration of the renal tubule epithelium, and degeneration and sarcolemma nuclear hyperplasia of the tongue and skeletal muscles were reported in most of the high-dose animals. There were no alterations reported among the animals treated with 12500 ppm or lower dose groups. Thus, the NOAEL was considered to be 12500 ppm or 900 mg/kg/day for the males and 930 mg/kg/day for the females (NTP, 1993). In another study, groups of 10 B6C3F1 mice/sex were fed diets containing benzyl acetate at doses of 0, 3,130, 6250, 12500, 25000, or 50000 ppm equivalent to 0, 425, 1000, 2000, 3700, or 7900 mg/kg/day for the males and 0, 650, 1280, 2980, 4300, or 9400 mg/kg/day for the females for 13 weeks. Mortality was reported among the high-dose group animals. Bodyweight gains and final body weights (8%?31% lower among males and 12%?33% lower among females) among the treated animals were significantly lower than the control. Feed consumption among the males of the 3100 ppm males and all treated females was lower than the control. Alterations in organ weights were reported among treated animals; however, this was attributed to lower body weight in relation to lower food consumption, and therefore it was difficult to make comparisons. Tremors were reported among the females of the 12500 ppm and higher dose groups. Necrosis of the brain involving the hippocampus was reported among the animals of the high-dose groups. Hepatocellular necrosis was reported among 1 high-dose male and was characterized as moderate severity necrosis of the hepatocytes randomly distributed throughout the hepatic lobules. No other treatment-related alterations were reported among the animals of the 6250 ppm or lower dose groups. Due to a reduction in body weights and bodyweight gains among all of the treated animals in conjunction with reduced food consumption, a NOAEL could not be derived from the study conducted on mice (NTP, 1993). Later, a dietary 2-year chronic toxicity study was conducted in F344/N rats. Groups of 60 rats/sex/dose were fed diets containing 0, 3000, 6000, or 12000 ppm benzyl acetate (average daily consumption level of 0, 130, 260, or 510 mg/kg/day for males and 0, 145, 290, or 575 mg/kg/day for females) for 2 years. The high-dose males and all exposed females had lower mean body weights than the controls. Feed consumption was slightly reduced in the high-dose males; there were no differences in feed consumption in the females. Food consumption among the high-dose males was lower than in the control. There were no clinical findings reported among the treated animals. Thus, the NOAEL for males and females was considered to be 6000 ppm based on lower body weight at higher doses (NTP, 1993). In another study, groups of 60 male and female B6C3F1 mice were fed benzyl acetate in the diet at concentrations of 0, 330, 1000, or 3000 ppm equivalent to 0, 35, 110, or 345 mg/kg/day for the males and 0, 40, 130, or 375 for the females. The high-dose female mice showed a statistically significant increase in survival. The mean body weights of treated mice were significantly lower (2?14%) than the controls except for the 330 ppm groups. There was no significant difference in terms of food consumption among the treated and control group mice. In the 2-year NTP study with mice (NTP, 1993), benzyl acetate administration in the food of the female and male mice was associated with a dose-related increase in the incidence or severity of non-neoplastic nasal lesions (i.e., mucosal atrophy and degeneration, cystic hyperplasia of the submucosal gland, and luminal exudates and pigmentation of the mucosal epithelium). The study stated that although the nose was not the deposition site for benzyl acetate, nasal tissue could have been exposed directly to high concentrations of the chemical or its degradation products (NTP, 1993). Thus, it was concluded that there was no evidence of carcinogenic activity among the animals treated with benzyl acetate via diet. Overall, the most conservative NOAEL of 6000 ppm or 260 mg/kg/day derived from the 2-year chronic study conducted on rats was considered.There are no reproductive toxicity data on benzyl butyrate. Read-across material benzyl acetate (CAS # 140-11-4; see Section VI) has sufficient data to support the developmental and reproductive endpoints.",

year = "2022",

month = may,

doi = "10.1016/j.fct.2022.113031",

language = "English (US)",

volume = "163",

journal = "Food and Chemical Toxicology",

issn = "0278-6915",

publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Update to RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7

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 repeated dose toxicity data on benzyl butyrate. Read-across material benzyl acetate (CAS # 140-11-4; see Section VI) has sufficient data to support the repeated dose toxicity endpoint. Groups of 10 F344/N rats/sex were fed diets containing benzyl acetate at doses of 0, 3130, 6250, 12500, 25000, or 50000 ppm equivalent to 0, 230, 460, 900, 1750, or 3900 mg/kg/day for males and 0, 240, 480, 930, 1870, or 4500 mg/kg/day for females for 13 weeks. Mortality was reported among high-dose group animals. Bodyweight gain and final body weights for the animals of the 25000 ppm dose-group males were significantly lower than the control. There was a reduction in food consumption reported among 25000 ppm and 50000 ppm males and the 50000 ppm females; this was attributed to the palatability of the test material and not considered an adverse effect. Tremors and ataxia were reported among the high-dose group animals. Test material-related lesions were reported in the brain, kidney, tongue, and skeletal muscles of the thigh. Necrosis of the brain involving the cerebellum and/or the hippocampus, degeneration and regeneration of the renal tubule epithelium, and degeneration and sarcolemma nuclear hyperplasia of the tongue and skeletal muscles were reported in most of the high-dose animals. There were no alterations reported among the animals treated with 12500 ppm or lower dose groups. Thus, the NOAEL was considered to be 12500 ppm or 900 mg/kg/day for the males and 930 mg/kg/day for the females (NTP, 1993). In another study, groups of 10 B6C3F1 mice/sex were fed diets containing benzyl acetate at doses of 0, 3,130, 6250, 12500, 25000, or 50000 ppm equivalent to 0, 425, 1000, 2000, 3700, or 7900 mg/kg/day for the males and 0, 650, 1280, 2980, 4300, or 9400 mg/kg/day for the females for 13 weeks. Mortality was reported among the high-dose group animals. Bodyweight gains and final body weights (8%?31% lower among males and 12%?33% lower among females) among the treated animals were significantly lower than the control. Feed consumption among the males of the 3100 ppm males and all treated females was lower than the control. Alterations in organ weights were reported among treated animals; however, this was attributed to lower body weight in relation to lower food consumption, and therefore it was difficult to make comparisons. Tremors were reported among the females of the 12500 ppm and higher dose groups. Necrosis of the brain involving the hippocampus was reported among the animals of the high-dose groups. Hepatocellular necrosis was reported among 1 high-dose male and was characterized as moderate severity necrosis of the hepatocytes randomly distributed throughout the hepatic lobules. No other treatment-related alterations were reported among the animals of the 6250 ppm or lower dose groups. Due to a reduction in body weights and bodyweight gains among all of the treated animals in conjunction with reduced food consumption, a NOAEL could not be derived from the study conducted on mice (NTP, 1993). Later, a dietary 2-year chronic toxicity study was conducted in F344/N rats. Groups of 60 rats/sex/dose were fed diets containing 0, 3000, 6000, or 12000 ppm benzyl acetate (average daily consumption level of 0, 130, 260, or 510 mg/kg/day for males and 0, 145, 290, or 575 mg/kg/day for females) for 2 years. The high-dose males and all exposed females had lower mean body weights than the controls. Feed consumption was slightly reduced in the high-dose males; there were no differences in feed consumption in the females. Food consumption among the high-dose males was lower than in the control. There were no clinical findings reported among the treated animals. Thus, the NOAEL for males and females was considered to be 6000 ppm based on lower body weight at higher doses (NTP, 1993). In another study, groups of 60 male and female B6C3F1 mice were fed benzyl acetate in the diet at concentrations of 0, 330, 1000, or 3000 ppm equivalent to 0, 35, 110, or 345 mg/kg/day for the males and 0, 40, 130, or 375 for the females. The high-dose female mice showed a statistically significant increase in survival. The mean body weights of treated mice were significantly lower (2?14%) than the controls except for the 330 ppm groups. There was no significant difference in terms of food consumption among the treated and control group mice. In the 2-year NTP study with mice (NTP, 1993), benzyl acetate administration in the food of the female and male mice was associated with a dose-related increase in the incidence or severity of non-neoplastic nasal lesions (i.e., mucosal atrophy and degeneration, cystic hyperplasia of the submucosal gland, and luminal exudates and pigmentation of the mucosal epithelium). The study stated that although the nose was not the deposition site for benzyl acetate, nasal tissue could have been exposed directly to high concentrations of the chemical or its degradation products (NTP, 1993). Thus, it was concluded that there was no evidence of carcinogenic activity among the animals treated with benzyl acetate via diet. Overall, the most conservative NOAEL of 6000 ppm or 260 mg/kg/day derived from the 2-year chronic study conducted on rats was considered.There are no reproductive toxicity data on benzyl butyrate. Read-across material benzyl acetate (CAS # 140-11-4; see Section VI) has sufficient data to support the developmental and reproductive endpoints.

PY - 2022/5

Y1 - 2022/5

UR - http://www.scopus.com/inward/record.url?scp=85128893788&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85128893788&partnerID=8YFLogxK

U2 - 10.1016/j.fct.2022.113031

DO - 10.1016/j.fct.2022.113031

M3 - Short survey

C2 - 35447288

AN - SCOPUS:85128893788

SN - 0278-6915

VL - 163

JO - Food and Chemical Toxicology

JF - Food and Chemical Toxicology

M1 - 113031

ER -

Update to RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7

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