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Diisobutyl adipate
Fragrance raw materials monographs
S53
DIISOBUTYL ADIPATE
Synonyms: Adipic acid bis(2-methylpropyl) ester; adipic acid, diisobutyl ester; adipic acid di-iso-butyl ester; DIBA. CAS Registry Number: 141-04-8 CAS Registry Name: Hexanedioic acid, bis(2-methylpropyl) ester Structure:
~ o
Natural occurrence: Reported to occur in French-fried potatoes and licorice (Glycyrrhiza glabra L.) (TNO, 1994) and in the distilled water extract of Hamamelis virginiana L. (Martelli et al., 1978). Volume of use: The worldwide volume of use (1996) as a fragrance ingredient is between I and 10 metric tons.
Biological data
Acute toxicity Oral studies: The acute oral LD so in rats exceeded 5.0 g/kg based on no deaths in 10 animals tested at that dose. 10 healthy, male Wistar rats with initial body weights of 204-268 g were dosed orally at a dose level of 5.0 g/kg/body weight. Observations for mortality and/or systemic effects were made 3-4 hr post dose and once daily thereafter for 14 days. Gross necropsy was carried out on all animals. Clinical signs observed during the study included lethargy, diarrhea and isolated instances of chromorhinorrhea. All animals appeared normal by day 12. Necropsy revealed consolidated lungs in one animal. Gross observations at necropsy were normal for all other animals (RIFM, 1980a). Dermal studies: The dermal LD so in rabbits exceeded 5.0 g/kg based on no deaths in 10 animals tested at that dose. Male and female (seven male/three female) healthy, New Zealand White rabbits with initial body weights of 1.9-2.8 kg received one dermal application of diisobutyl adipate at a dose of 5.0 g/kg. The test material was applied to clipped, intact or abraded abdominal skin under occluded patches for 24 hr of contact. Observations for mortality and/or systemic effects were made daily for 14 days. Dermal reactions were scored on days I, 7 and 14 by the Draize scoring system. Gross necropsy was conducted on all animals. Clinical signs observed during the study included alopecia, diarrhea, yellow nasal discharge and mucus in feces, all of which were observed in one or two animals; lethargy was also observed in four animals. Necropsy revealed liver abnormalities in one male and reduced body weight in one female. Gross observations at necropsy were normal for all other animals (RIFM, 1980a). Intraperitoneal studies: In a preliminary screen done prior to a reproductive study, female Sprague-Dawley rats (five/dose) with initial body weights of 175-225 g received graded doses of diisobutyl adipate by ip injection. Observations for mortality were made over a 7-day period. The calculated LD so was reported to be 5.95 ml/kg (95% CI 4.69-7.54 ml/kg) (no further details given) (Singh, 1973). Skin irritation Human studies: No irritation was observed after a 48-hr closed patch test with 20% in petrolatum on the backs of29 healthy, male and female volunteers (RIFM, 1980b). Animal studies: As part of the acute dermal LD so study in rabbits described above, the dermal reactions on day I consisted of very slight (six rabbits) to well defined erythema (four rabbits) and very slight (four rabbits) to slight edema (one rabbit) (RIFM, 1980a). Skin sensitization Human studies: A maximization test (Kligman, 1966; Kligman and Epstein, 1975) was carried out with 20% diisobutyl adipate in petrolatum on 29 healthy, male and female volunteers. The test concentration of 20% was based on a reported maximum use concentration of 2% in consumer products. Application was under occlusion to the same site on the forearms of all subjects for five alternate-day 48-hr periods. Patch sites were pretreated for 24 hr with 5% aqueous sodium lauryl sulfate (SLS) under occlusion for the initial patch only. Following a 1O-14-day rest period, challenge patches were applied under occlusion to fresh sites for 48 hr. Challenge applications were preceded by 30-min applications of 5% aqueous SLS under occlusion on the
c. S. Letizia et al.
S54
left side whereas the test material was applied without SLS treatment on the right side. A fifth site challenged with petrolatum served as control. No reactions were observed that were considered significantly irritant or allergic (RIFM, 1980b). Reproductive studies Animal studies: Diisobutyl adipate was evaluated for its embryonic-fetal toxicity and teratogeniceffects in female Sprague-Dawley rats with initial body weights of 175-225 g. Groups of five female rats (five/dose) were housed with one male in a large cage with food and water ad lib. The onset of gestation was established by the presence of sperm in the vaginal smear and was designated at day 0 with the following day being day I of the gestation period. The female rats were then moved to individual cages. On days 5, 10 and 15 of gestation the rats were administered undiluted diisobutyl adipate by ip injection at dose levels of 0.1983, 0.595, 1.19 and 1.9833 ml/kg which were one-thirtieth, one-tenth, one-fifth and one-third of the previously determined LD so (see ip LD so study described above). Three control groups received injections with either 10 ml/ kg distilled water, or 10 ml/kg normal saline or 10 ml/kg cottonseed oil. In addition, a "blunt needle injection" control group was also included in which a dull needle was inserted in the same manner as used for the other ip injections but no substance was actually injected. The rats were sacrificed on day 20 of gestation. The following parameters were investigated: number of corpora lutea, resorption sites, viable and dead fetuses, fetal weight, gross abnormalities, skeletal malformations and visceral abnormalities. Results from the "blunt needle injected" control rats were used as the baseline. Data from the other three control groups were combined to calculate a 95% CI for a "pooled volume control" in regard to resorptions and gross and skeletal abnormalities. The two highest dose levels produced one fetal death at each dose level. Fetal weight was reduced at all dose levels, but this was only considered to be statistically significant at the two highest dose levels. One visceral abnormality, an imperforate anus, was observed at the highest dose level. Gross abnormalities were observed at the three highest dose levels but were only considered to be significantly increased over the "pooled control" at dose levels of 0.595 and 1.9833 ml/kg, A significant increase in resorption sites or in skeletal malformations was not observed at any dose level as compared to the "pooled control". There were no gross, skeletal or visceral abnormalities observed at the lowest dose level (Singh et al., 1973). Genotoxicity Bacterial studies: In an Ames test (Ames et al., 1975) using Salmonella typhimurium strains TA97, TA98, TAIOO and TAI02 and Escherichia coli strain WP2/pKMI01 with and without rat liver S-9 metabolic activation, doses of 200-10,000 Ilg/plate in dimethyl sulfoxide were not mutagenic (Hachiya and Takizawa, 1994). Cytotoxicity Human studies: Cultured epithelial cells derived from human skin (lTC-17) were exposed to diisobutyl adipate which had been dispersed in cultured medium using an ultrasonic emulsion method. The cells were incubated for 24 hr with 1% diisobutyl adipate. Cell viability was then estimated by the Neutral Red dye uptake test. Controls were untreated. Results were given as a cytotoxic index and a cytotoxic score. The control cytotoxic index was 100 and the control cytotoxic score was O. Diisobutyl adipate was found to be toxic to the cultured cells with a cytotoxic index of 17 and a cytotoxic score of 4 (Chiba et al., 1989).
Status
Canadian Domestic Substances List European Inventory of Existing Commercial Chemical Substances Indicative Non-Exhaustive List TSCA Inventory List
Registered Registered 205-450-3 Listed Registered
References Ames B.N., McCann J. and Yamaskai E. (1975) Methods for detecting carcinogens and mutagens with the Salmonella! mammalian-microsome mutagenicity test. Mutation Research 31, 347-363. [Submitted only for the methodology] Chiba K. and Tohyama K. (1989) Safety evaluation of oil ingredients for cosmetic using cell culture system. Journal of the Japanese Cosmetic Science Society 13, 194-202. Hachiya N. and Takizawa Y. (1994) Mutagenicity of plastics additives. Japanese Journal of Mutagenicity Tests on Chemicals 3, 147-154.
Fra grance raw materi als monograph s
S55
Kligman A.M. (1966) The identification of contact allergens by hum an assay. III . The maximizat ion test. A procedure for screening and rating contact sensitizers. Journal oj In vestigative Dermatology 47, 393-409 . [Submitted onl y for the methodolog y] Kligman A.M. and Epstein W. (1975) Upda ting the maximiz ation test for ident ifying contact allergens. Contact Derma titis 1, 231-23 9. [Submitted only for the methodology ] Martelli A., Bicchi C. and Fr attini C. (1978) Hamamelis water (distilled water of Ham amelis virginiana Linnaeus). Pa rt 2. Identification of the essent ial oil components by GLC and GLC -MS. Rlvista ltaliana di Essenze , Profumi , Pia/lie Off. , Aromat .. Syndets , Sap oni , Cosmet ., Aerosols 60, 261-264. Research Institute for Fragran ce Materials, Inc. (1980a) Acute toxicity study in rat s and rabbits. RIFM report number 1774, June 25. Research Institute for Fragrance Mate rials, Inc. (I980b) Hum an maximizati on studies. RIFM report numbe r 1790, Jun e 2. Singh A.R., Lawrence W.H . and Autian J. (1973) Embryonic-fetal toxicity and terat ogenic effects of adipic acid esters in rat s. Journal of Pharmaceuti cal Sciences 62,1 596-1600. TNO (1994) Volatile Compounds in Food, 6th edn, Suppl , 5, cd. H. Maarsc, C.A. Visscher , LiC. Willemsens, L.M . Nijssen and M.H . Boelens. TNO Nut rition a nd Food Research, Zeist, Th e Netherl and s.
S53
DIISOBUTYL ADIPATE
Synonyms: Adipic acid bis(2-methylpropyl) ester; adipic acid, diisobutyl ester; adipic acid di-iso-butyl ester; DIBA. CAS Registry Number: 141-04-8 CAS Registry Name: Hexanedioic acid, bis(2-methylpropyl) ester Structure:
~ o
Natural occurrence: Reported to occur in French-fried potatoes and licorice (Glycyrrhiza glabra L.) (TNO, 1994) and in the distilled water extract of Hamamelis virginiana L. (Martelli et al., 1978). Volume of use: The worldwide volume of use (1996) as a fragrance ingredient is between I and 10 metric tons.
Biological data
Acute toxicity Oral studies: The acute oral LD so in rats exceeded 5.0 g/kg based on no deaths in 10 animals tested at that dose. 10 healthy, male Wistar rats with initial body weights of 204-268 g were dosed orally at a dose level of 5.0 g/kg/body weight. Observations for mortality and/or systemic effects were made 3-4 hr post dose and once daily thereafter for 14 days. Gross necropsy was carried out on all animals. Clinical signs observed during the study included lethargy, diarrhea and isolated instances of chromorhinorrhea. All animals appeared normal by day 12. Necropsy revealed consolidated lungs in one animal. Gross observations at necropsy were normal for all other animals (RIFM, 1980a). Dermal studies: The dermal LD so in rabbits exceeded 5.0 g/kg based on no deaths in 10 animals tested at that dose. Male and female (seven male/three female) healthy, New Zealand White rabbits with initial body weights of 1.9-2.8 kg received one dermal application of diisobutyl adipate at a dose of 5.0 g/kg. The test material was applied to clipped, intact or abraded abdominal skin under occluded patches for 24 hr of contact. Observations for mortality and/or systemic effects were made daily for 14 days. Dermal reactions were scored on days I, 7 and 14 by the Draize scoring system. Gross necropsy was conducted on all animals. Clinical signs observed during the study included alopecia, diarrhea, yellow nasal discharge and mucus in feces, all of which were observed in one or two animals; lethargy was also observed in four animals. Necropsy revealed liver abnormalities in one male and reduced body weight in one female. Gross observations at necropsy were normal for all other animals (RIFM, 1980a). Intraperitoneal studies: In a preliminary screen done prior to a reproductive study, female Sprague-Dawley rats (five/dose) with initial body weights of 175-225 g received graded doses of diisobutyl adipate by ip injection. Observations for mortality were made over a 7-day period. The calculated LD so was reported to be 5.95 ml/kg (95% CI 4.69-7.54 ml/kg) (no further details given) (Singh, 1973). Skin irritation Human studies: No irritation was observed after a 48-hr closed patch test with 20% in petrolatum on the backs of29 healthy, male and female volunteers (RIFM, 1980b). Animal studies: As part of the acute dermal LD so study in rabbits described above, the dermal reactions on day I consisted of very slight (six rabbits) to well defined erythema (four rabbits) and very slight (four rabbits) to slight edema (one rabbit) (RIFM, 1980a). Skin sensitization Human studies: A maximization test (Kligman, 1966; Kligman and Epstein, 1975) was carried out with 20% diisobutyl adipate in petrolatum on 29 healthy, male and female volunteers. The test concentration of 20% was based on a reported maximum use concentration of 2% in consumer products. Application was under occlusion to the same site on the forearms of all subjects for five alternate-day 48-hr periods. Patch sites were pretreated for 24 hr with 5% aqueous sodium lauryl sulfate (SLS) under occlusion for the initial patch only. Following a 1O-14-day rest period, challenge patches were applied under occlusion to fresh sites for 48 hr. Challenge applications were preceded by 30-min applications of 5% aqueous SLS under occlusion on the
c. S. Letizia et al.
S54
left side whereas the test material was applied without SLS treatment on the right side. A fifth site challenged with petrolatum served as control. No reactions were observed that were considered significantly irritant or allergic (RIFM, 1980b). Reproductive studies Animal studies: Diisobutyl adipate was evaluated for its embryonic-fetal toxicity and teratogeniceffects in female Sprague-Dawley rats with initial body weights of 175-225 g. Groups of five female rats (five/dose) were housed with one male in a large cage with food and water ad lib. The onset of gestation was established by the presence of sperm in the vaginal smear and was designated at day 0 with the following day being day I of the gestation period. The female rats were then moved to individual cages. On days 5, 10 and 15 of gestation the rats were administered undiluted diisobutyl adipate by ip injection at dose levels of 0.1983, 0.595, 1.19 and 1.9833 ml/kg which were one-thirtieth, one-tenth, one-fifth and one-third of the previously determined LD so (see ip LD so study described above). Three control groups received injections with either 10 ml/ kg distilled water, or 10 ml/kg normal saline or 10 ml/kg cottonseed oil. In addition, a "blunt needle injection" control group was also included in which a dull needle was inserted in the same manner as used for the other ip injections but no substance was actually injected. The rats were sacrificed on day 20 of gestation. The following parameters were investigated: number of corpora lutea, resorption sites, viable and dead fetuses, fetal weight, gross abnormalities, skeletal malformations and visceral abnormalities. Results from the "blunt needle injected" control rats were used as the baseline. Data from the other three control groups were combined to calculate a 95% CI for a "pooled volume control" in regard to resorptions and gross and skeletal abnormalities. The two highest dose levels produced one fetal death at each dose level. Fetal weight was reduced at all dose levels, but this was only considered to be statistically significant at the two highest dose levels. One visceral abnormality, an imperforate anus, was observed at the highest dose level. Gross abnormalities were observed at the three highest dose levels but were only considered to be significantly increased over the "pooled control" at dose levels of 0.595 and 1.9833 ml/kg, A significant increase in resorption sites or in skeletal malformations was not observed at any dose level as compared to the "pooled control". There were no gross, skeletal or visceral abnormalities observed at the lowest dose level (Singh et al., 1973). Genotoxicity Bacterial studies: In an Ames test (Ames et al., 1975) using Salmonella typhimurium strains TA97, TA98, TAIOO and TAI02 and Escherichia coli strain WP2/pKMI01 with and without rat liver S-9 metabolic activation, doses of 200-10,000 Ilg/plate in dimethyl sulfoxide were not mutagenic (Hachiya and Takizawa, 1994). Cytotoxicity Human studies: Cultured epithelial cells derived from human skin (lTC-17) were exposed to diisobutyl adipate which had been dispersed in cultured medium using an ultrasonic emulsion method. The cells were incubated for 24 hr with 1% diisobutyl adipate. Cell viability was then estimated by the Neutral Red dye uptake test. Controls were untreated. Results were given as a cytotoxic index and a cytotoxic score. The control cytotoxic index was 100 and the control cytotoxic score was O. Diisobutyl adipate was found to be toxic to the cultured cells with a cytotoxic index of 17 and a cytotoxic score of 4 (Chiba et al., 1989).
Status
Canadian Domestic Substances List European Inventory of Existing Commercial Chemical Substances Indicative Non-Exhaustive List TSCA Inventory List
Registered Registered 205-450-3 Listed Registered
References Ames B.N., McCann J. and Yamaskai E. (1975) Methods for detecting carcinogens and mutagens with the Salmonella! mammalian-microsome mutagenicity test. Mutation Research 31, 347-363. [Submitted only for the methodology] Chiba K. and Tohyama K. (1989) Safety evaluation of oil ingredients for cosmetic using cell culture system. Journal of the Japanese Cosmetic Science Society 13, 194-202. Hachiya N. and Takizawa Y. (1994) Mutagenicity of plastics additives. Japanese Journal of Mutagenicity Tests on Chemicals 3, 147-154.
Fra grance raw materi als monograph s
S55
Kligman A.M. (1966) The identification of contact allergens by hum an assay. III . The maximizat ion test. A procedure for screening and rating contact sensitizers. Journal oj In vestigative Dermatology 47, 393-409 . [Submitted onl y for the methodolog y] Kligman A.M. and Epstein W. (1975) Upda ting the maximiz ation test for ident ifying contact allergens. Contact Derma titis 1, 231-23 9. [Submitted only for the methodology ] Martelli A., Bicchi C. and Fr attini C. (1978) Hamamelis water (distilled water of Ham amelis virginiana Linnaeus). Pa rt 2. Identification of the essent ial oil components by GLC and GLC -MS. Rlvista ltaliana di Essenze , Profumi , Pia/lie Off. , Aromat .. Syndets , Sap oni , Cosmet ., Aerosols 60, 261-264. Research Institute for Fragran ce Materials, Inc. (1980a) Acute toxicity study in rat s and rabbits. RIFM report number 1774, June 25. Research Institute for Fragrance Mate rials, Inc. (I980b) Hum an maximizati on studies. RIFM report numbe r 1790, Jun e 2. Singh A.R., Lawrence W.H . and Autian J. (1973) Embryonic-fetal toxicity and terat ogenic effects of adipic acid esters in rat s. Journal of Pharmaceuti cal Sciences 62,1 596-1600. TNO (1994) Volatile Compounds in Food, 6th edn, Suppl , 5, cd. H. Maarsc, C.A. Visscher , LiC. Willemsens, L.M . Nijssen and M.H . Boelens. TNO Nut rition a nd Food Research, Zeist, Th e Netherl and s.