3-methyl-5-phenylpentanol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Introduction

Physico-chemical properties, the results on in vitro studies and acute and repeat dose toxicity studies with animals for 3-methyl-5-phenylpentanol have been used to determine a toxicokinetic profile. No QSARs have been performed on the substance, however information on structurally related substances have been taken into account.

Physico-chemical properties

The substance 3-methyl-5-phenylpentanol is a colourless to pale yellow liquid and has the molecular formula C12H18O with a molecular weight (MW) of 178.1 g/mol. It is slightly water soluble (0.39 g/L at 25°C) and has a Pow value of 2.7 at 25°C. 3-methyl-5-phenylpentanol possesses an alcohol group. It is neutral in nature, with a pH of 7 in water at the limit of solubility. It is readily biodegradable (Rudio, 1995; Melling, 1997), hence hydrolytic stability was not tested.

Absorption

Oral absorption

No oral absorption data is directly available for 3-methyl-5-phenylpentanol, but the potential for oral absorption of 3-methyl-5-phenylpentanol is not considered to be limited by its molecular weight, water solubility, or Pow. Data on a structurally similar material, phenylethyl alcohol (CAS 60-12-8, MW 122.16, Pow 1.36, water solubility 16 g/L at 20ºC, 22 g/L at 25ºC) showed oral absorption in rabbits and man to be 90% to 100% based on excretion of metabolites in urine (EFSA, 2009). Data from Robinson and Williams (1955) for a loosely structurally related compound, tertiary butylbenzene (CAS 98-06-6, MW 134.22, Pow 4.11, water solubility 29.5 mg/L) at 25ºC also confirm oral absorption of >90% in rabbits.

The Pow and water solubility of 3-methyl-5-phenylpentanol falls between those of phenylethyl alcohol and tertiary butylbenzene (see the Table below), hence these are not likely to result in a significantly different oral absorption value for 3-methyl-5-phenylpentanol. In addition although the molecular weight of 3-methyl-5-phenylpentanol is greater than these other molecules it is not of a size known to reduce oral absorption. Therefore it is reasonable to extrapolate the oral absorption from phenylethyl alcohol and tertiary butylbenzene to 3-methyl-5-phenylpentanol.

Comparison of the physical chemical properties of phenylethyl alcohol, tertiary butylbenzene and 3-methyl-5- phenylpentanol, and extrapolation of Oral absorption.

Substance	MW	Pow	Solubility	Oral absorption
Phenylethyl alcohol	122.16	1.36	16 - 22 g/L	90 - 100%
3-methyl-5-phenylpentanol	178.1	2.7	0.39 g/L	estimated >90%
Tertiary butylbenzene	134.22	4.11	0.0295 g/L	>90%

 

As far as could be discerned, the toxicity profiles of phenylethyl alcohol and 3-methyl-5-phenylpentanol do not differ greatly, strengthening the plausibility for read across for oral absorption and other TK parameters.

Systemic absorption for 3-methyl-5-phenylpentanol was apparent in acute lethality studies through lethargy, ataxia, adoption of the prone position at 590 mg/kg bw, or mortality (at higher doses), within the first 24 hours of dosing (Anon, 1980, Freeman 1980a). Recovery was apparent in survivors by 48 hours after dosing (Anon, 1980). The difference in the acute oral LD50 values in the Freeman 1980a study between males (2500 mg/kg) and females (1850 mg/kg), may indicate that there is some sex difference in absorption or metabolism of 3-methyl-5-phenylpentanol.

The acute oral LD50 values for phenylethyl alcohol in rats ranged between 1609 and 3100 mg/kg (TOXNET, 2012; EFSA, 2009). In a 4-month repeat dose oral toxicity study in rats documented in EFSA (2009), liver toxicity was evident, and the NOAEL was set at the only dose tested, 50.8 mg/kg bw/day. The study had no control group and the study is cited by EFSA as being of low validity. Data from developmental toxicity studies with phenylethyl alcohol also documented in EFSA 2009 did not contradict the data from the 4-month study.

Dermal absorption

No data are available on the dermal absorption of 3-methyl-5-phenylpentanol.

In an acute dermal toxicity study conducted up to 5000 mg/kg bw, no mortalities were observed in males, but the LD50 in females from the same study was 3200 mg/kg (Freeman 1980b). Body weight gains were slightly depressed in a dose related manner in males up to 5000 mg/kg, but a loss in body weight was seen in three of eight females during the 14-day observation period at the lowest dose tested (2000 mg/kg). Comparing this information with that from the acute oral toxicity study (clinical signs of ataxia, lethargy and prone position seen at the lowest dose tested, (Anon, 1980) a conservative dermal absorption value in rats might be approximated at 590 mg/kg / 2000 mg/kg * 100 = 30%. Dermal absorption in man is typically less than that in rat (EFSA, 2012), hence this dermal absorption figure of 30% in rats is likely to be a conservative overestimate for that in man.

Given the physical chemical properties of the test material (liquid substance, MW<500, Pow of 2.7, some solubility in water), the dermal absorption is expected to occur, but is not expected to be greater than 25% for undiluted material, in accordance with general principles set out under EFSA (2012).

Inhalation

Although inhalation of the test material is considered to be unlikely (Boiling point = 316, Vapour pressure = 0.04 Pa at 20ºC), in the absence of information to the contrary, absorption of any aerosol across the lungs is assumed to be 100%.

Distribution

Any material that is absorbed will be distributed via the blood to the liver, and other organs and tissues. Wide distribution is anticipated, including fatty tissues (Pow = 2.7).

Metabolism

Given the metabolism and excretion of phenylethyl alcohol and tertiary butylbenzene in man and/or rabbits, oxidation of almost all the absorbed dose of 3-methyl-5-phenylpentanol to the corresponding acid is anticipated, with excretion as the glucuronide (in rabbits) and amino acid conjugates in man (glutamine, glycine and taurine conjugates) (EFSA, 2009; Robinson and Williams, 1955). The difference in the acute oral LD50 values in the Freeman 1980a study between males (2500 mg/kg) and females (1850 mg/kg), may indicate that there is some sex difference in absorption or metabolism of 3-methyl-5-phenylpentanol.

Elimination

No data on 3-methyl-5-phenylpentanol is available, although data for phenylethyl alcohol and tertiary butylbenzene (EFSA, 2009; Robinson and Williams, 1955) would indicate that 90% to 100% would be eliminated within 24 hours of administration. Comparison of the available toxicity data for 3-methyl-5-phenylpentanol and phenylethyl alcohol does not contradict this.

Conclusion

For the purposes of human risk assessment there is sufficient information to consider that 3-methyl-5-phenylpentanol would be rapidly and completely absorbed, completely metabolised to amino acid conjugates, and excreted within 24 hours of oral administration. Human dermal absorption may be considered to be 25%. Inhalation absorption is assumed to be complete.

References

Author (year)	Title Source (where different from company) Company, Report No. GLP or GEP status (where relevant) Published or Unpublished
Anon (1980)	Acute oral Toxicity in Rats (LD50) Report number 34997 Non-GLP Unpublished
Cormack HL, Mullee D & Brooks PN (2000)	Citralis: Twenty-eight day repeated dose oral (gavage) toxicity study in the rat. Report number 48896 GLP Unpublished
EFSA (2009)	Flavouring Group Evaluation 14, Revision 1 (FGE.14Rev1) Phenethyl alcohol, aldehyde, acetals, carboxylic acid and related esters from chemical group 15 and 22 Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (AFC) (EFSA-Q-2003-157B). The EFSA Journal (2009) 930: 1-53
EFSA (2012)	Guidance on Dermal Absorption. The EFSA Journal(2012) 10(4): 2665
Freeman (1980a)	Acute oral Toxicity in Rats (LD50) Report number 34998 GLP Unpublished
Freeman (1980b)	Acute Dermal Toxicity in Rats (LD50) Report number 34999 GLP Unpublished
Melling JL (1997)	Determination of the Ready and Ultimate Biodegradability of Mefrosol in the Sealed Vessel Test  Report number SV-S100-01 GLP Unpublished
Robinson and Williams (1955)	The metabolism of alkylbenzenes. Tert.-butylbenzene. Biochemical Journal January; 59(1): 159–161
Rudio J (1995)	Ready Biodegradability of Phenoxanol according to OECD Guideline No. 301 F  Report number 95-E05 GLP Unpublished
TOXNET (2012)	Information from the Hazardous Substances Data Bank contained in http://toxnet.nlm.nih.gov Non-GLP Published