2-methyl-1-phenylpropan-2-ol

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance DMBC is an organic mono-constituent with a purity of >97% to <100% with a typical concentration of 99.5%.  

A full ADME toxicokinetic study in the rat is not available. The Research Institute of Fragrance Materials (RIFM) expert panel has indicated a proposed metabolic pathway for aryl akyl tertiary alcohols, including DMBC [1] and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) has indicated a metabolic pathway for DMBC [2]. The toxicokinetic analysis is based on these expert opinions, physicochemical and in vivo toxicological data. In vivo studies in rats covering the oral route (acute oral toxicity study, read-across pre-natal developmental toxicity study with PEA (CAS No. 60-12-8)), dermal route (read-across sub-chronic toxicity study (90 days) with PEA, read-across pre-natal developmental toxicity study with PEA) and inhalation route (read-across acute inhalational toxicity study with PEA) are available. Further details on the endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical properties, expert opinions and information in the dossier, DMBC is expected to be absorbed via the oral, dermal and inhalation routes. It will be distributed throughout the body including exposure to the developing fetus. DMBC is conjugated directly with glucuronic acid and excreted in the urine.

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

1. Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of DMBC in the body.

Absorption - oral

The molecular weight of DMBC(150 g/mol) is in the range for favourable oral absorption (<500 g/mol). DMBC is very soluble in water (13538 mg/L at 20°C) so should readily dissolve in the gastrointestinal fluids. The log Kow of DMBC (1.87 at 25°C) is in the range favourable for passive diffusion.

Absorption – dermal

The log Kow and water solubility of DMBC are in the favourable range for dermal absorption.

Absorption – inhalation

DMBC has a low volatility (0.07kPa at 20°C; 0.10kPa at 25°C) so exposure via the inhalation route is expected to be low however due to the end use as a fragrance in air-care and cosmetic products, exposure via the inhalation route will be considered. As a liquid, DMBC would readily diffuse/dissolve into the mucus lining the respiratory tract and it is sufficiently lipophilic (log Kow 1.87) to be absorbed directly across the respiratory tract epithelium. However, as a very hydrophilic substance with a molecular weight <200 g/mol, it may also be absorbed through aqueous pores or retained in the mucus and transported out of the respiratory tract.

Distribution/Metabolism/Excretion

Based on the molecular weight, water solubility, log Kow and structure, DMBC is likely to be widely distributed, and as a tertiary alcohol will be excreted unchanged as the parent substance in the urine.

2. Other data in the literature

DMBC is a member of the aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances [2]. The JECFA has concluded that as a tertiary alcohol, DMBC is metabolized primarily by conjugation with glucuronic acid and excreted in the urine. RIFM supports the conclusion that aryl alkyl tertiary alcohols like DMBC are conjugated with glucuronic acid and excreted in the urine [1].

3. Information from other studies in the dossier

Absorption - oral

In the acute oral toxicity key study (equivalent or similar to OECD 401), Osborne Mendel rats (5/dose/sex) were given DMBC and observed for 14 days. Deaths occurred between 1 hr and 3 days. Depression was evident within 10 mins and coma within 1 hour. The LD50 (male/female) is 1280 mg/kg bw with 95% confidence limits of 934 -1770 mg/kg bw.

In a read-across pre-natal developmental toxicity supporting study (equivalent or similar to OECD 414/GLP), PEA was administered to 28 female Crl:COBSCD(SD)B rats/group in the diet at dose levels of 0, 1000, 3000, or 10 000 ppm (equivalent to 0, 83, 266 and 799 mg/kg bw/day) from days 6 through 15 of gestation. There were no clinical signs of toxicity or mortality at any dosage level. No statistically significant maternal effects were observed during the study. Litter parameters, as assessed by mean values for embryo-fetal loss, litter sizes, sex ratios, and litter and mean fetal weights, were equivalent in control and PEA-exposed groups. The incidence, type, and distribution of fetal malformations, anomalies, and skeletal variants were statistically unaffected by maternal exposure to PEA at concentrations as high as 10 000 ppm (799 mg/kg bw/day). However, at the highest dosage level, a marginal delay in fetal ossification might have occurred, as a slightly higher incidence of fetuses with incomplete ossification of some skeletal elements, particularly the sacrocaudal vertebral arches, was observed. The maternal and developmental NOAELs were 266 mg/kg bw/day, based on a transient decrease in maternal feed consumption and body weight gains on GDs 6 and 7 and a slightly higher incidence of delayed ossification in some fetal skeletal elements.

Based on the physicochemical data and available in vivo toxicological data, there is systemic absorption after oral administration. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

Absorption – dermal

In the read-across combined dermal developmental and perinatal/postnatal reproduction toxicity key study (equivalent or similar to OECD 414/GLP), PEA (99.42%) or deionized water was administered dermally (occlusive) to 40 female Crl:CD(SD) rats at dose levels of 0, 140, 430 and 1400 mg/kg bw/day beginning on day 7 of presumed gestation and continuing through day 20 of presumed gestation. Twenty rats per dosage group were Caesarean-sectioned on day 21 of presumed gestation and 20 rats per dosage group were allowed to deliver their litters and were sacrificed on day 21 postpartum. Skin irritation was assessed using the Draize method. The maternal NOAEL is 430 mg/kg/day. The 1400 mg/kg/day dosage caused mortality and reductions in body weight and feed consumption. In addition, observations consistent with primary irritancy (erythema and flaking) occurred in most of the female rats that died or were euthanized. The developmental NOAEL for pups Caesarean-delivered on day 21 of gestation is 140 mg/kg/day. Maternal dosages of 430 and 1400 mg/kg/day caused reductions in fetal weight with corresponding delays in fetal skeletal ossification and an increase in the incidence of cervical ribs. All 12 fetuses in the two litters that had live fetuses in the 1400 mg/kg/day dosage group had one or more gross, soft tissue and/or skeletal alterations. The 1400 mg/kg/day dosage also produced embryo/fetal lethality. The NOAEL for viability and growth in the offspring naturally delivered and euthanized on day 21 of lactation is 430 mg/kg/day. The maternal dosage of 1400 mg/kg/day increased the incidence of perinatal mortality. As expected in dams that exhibited extensive maternal and embryo/fetal toxicity, several of the 24 live pups in the two litters that had live pups in the 1400 mg/kg/day dosage group on postpartum day 21 had a skeletal alteration. However, all apparent delays in ossification and increased incidences of a cervical rib at the 7th cervical vertebrae that were observed in the Caesarean delivered fetuses in the 430 mg/kg/day dosage group were resolved by DL 21.

Based on the physicochemical data and available in vivo toxicological data, there is systemic absorption after dermal administration. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption – inhalation

In a read-across acute inhalation toxicity study with PEA (equivalent or similar to OECD 403/GLP), a group of young adult Sprague Dawley strain rats (5/sex) were exposed to a test atmosphere of PEA for 4 hours (whole body) at a target concentration of 4.63 mg/L. Animals were then observed for 14 days. The mean achieved concentration was 1.38 ±0.19 mg/L (MMAD: 1.08 µm; GSD: 0.05). There were no deaths and no clinical changes of possible toxicological importance. Although small body weight losses occurred on the days following exposure the losses were generally made good by day 7 of the study. The LC50 male/female was > 4.63 mg/L (nominal concentration).

Based on the physicochemical data and available in vivo toxicological data, there is systemic absorption after inhalation administration. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted using a conservative approach.

Distribution/Metabolism/Excretion

Based on the physicochemical data, expert opinion and available in vivo toxicological data, DMBC will be distributed throughout the body including exposure to the developing fetus. The JECFA and RIFM both concur that DMPEC is conjugated directly with glucuronic acid and excreted in the urine.

1. RIFM Expert Panel (2012). A toxicological and dermatological assessment of aryl alkyl alcohols when used as fragrance ingredients. Food and Chemical Toxicology 50 (2012) S52–S99.

2. JECFA (2008). Safety evaluation of certain food additives. Who Food Additives Series:59. Prepared by the sixty-eighth meeting of the JECFA. World Health Organization, Geneva.