2-(2-(2-butoxyethoxy)ethoxy)ethanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A published study that is reported in sufficient detail to judge it as sufficiently reliable to add to the overall understanding of the toxicokinetic assessment of this substance.

Data source

Reference

Reference Type:

publication

Title:

Toxicokinetics of inhaled 2-butoxyethanol and its major metabolite 2-butoxyacetic acid, in F344 rats and B6C3F1 mice.

Author:

Sabourin PJ, Medinsky MA, Birnbaum LS, Griffith WC, Dill JA, Lee KM, Bates DJ, Andersen DJ, Johnson RE, Chou BJ, Burka LT, Roycroft JH.

Year:

1998

Bibliographic source:

Tox Appl Pharmac, 153, 227-42

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

As part of a chronic study, the rate of elimination of butoxyethanol exposure was followed over the lifetime of exposure of the animals to establish the effect of animal age on toxicokinetics of elimination

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

2-butoxyethanol

EC Number:

203-905-0

EC Name:

2-butoxyethanol

Cas Number:

111-76-2

Molecular formula:

C6H14O2

IUPAC Name:

2-butoxyethanol

Details on test material:

Analytical purity: 99%

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

no data

Duration and frequency of treatment / exposure:

6h/day, 5 days/week, 104 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
31.2, 62.5, 125ppm

No. of animals per sex per dose / concentration:

between 5-12 per time point/sex/dose

Control animals:

no

Positive control reference chemical:

none

Details on study design:

no further data

Details on dosing and sampling:

no further data

Statistics:

no data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:

The 2-butoxyethanol blood concentrations showed a rapid drop after the cessation of exposure. The elimination t1/2 for 2-butoxyethanol after 1 day of exposure was < 10 min, this t1/2 does not depend on the dose level. Increases in the initial blood concentration of 2-butoxyethanol and Area Under the Curve (AUC) were proportional to exposure concentration, supporting that elimination of 2-butoxyethanol from the blood follows linear kinetics. The rate of 2-butoxyethanol elimination from blood slowed with increasing days of exposure, but not markedly. Male rats generally exhibited larger AUC than females, indicating a lower blood clearance of 2-butoxyethanol. The rate constant was not significantly different between sexes, implying that the volume of distribution, rather than the rate of elimination may be responsible for the sex-related difference in 2-butoxyethanol clearance. Unlike 2-butoxyethanol, butoxyacetic acid was not rapidly cleared from the systemic circulation. The butoxyacetic acid concentrations in the blood did not start to decline until 20 to 80 min post exposure. It seems that butoxyacetic acid was eliminated from blood following saturable, nonlinear kinetics. The rate constant was not constant, decreasing as 2-butoxyethanol exposure concentrations increased. As the rate of butoxyacetic acid production reflects the 2-butoxyethanol elimination, it seems that the nonlinear characteristics of butoxyacetic acid kinetics likely result from butoxyacetic acid distribution or elimination processes. When the number of exposure days increased, the rate of butoxyacetic acid elimination tended to decrease. Females eliminated butoxyacetic acid more slowly than males (smaller k, longer t1/2 and larger AUC). The maximum blood concentration was also higher in females at each exposure concentration. In mice, elimination of butoxyacetic acid was faster than rats when compared at common exposure concentrations. Female rats excreted less butoxyacetic acid than males regardless of exposure concentration. Excretion of butoxyacetic acid tended to increase with time.

Toxicokinetic parameters

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 10-42 mins

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

2-butoxyacetic acid

Any other information on results incl. tables

2-butoxyethanol elimination rate over time at 62.5ppm exposure

	C0(mg/g)		Rate constant k		T1/2 (min)		AUC (mg/min/g)
	M	F	M	F	M	F	M	F
1d	1.86	1.59	0.0793	0.0809	8.74	8.56	23.5	19.6
2w	3.06	2.24	0.0828	0.0839	8.37	8.26	36.9	26.8
3m	0.54	0.47	0.0166	0.0248	41.66	27.9	32.3	18.9
6m	1.31	0.69	0.0308	0.0230	22.51	30.20	42.5	29.9
12m	1.08	0.97	0.0354	0.0439	19.6	15.79	30.5	22.0

2-butoxyethanol elimination rate over time at 125ppm exposure

	C0(mg/g)		Rate constant k		T1/2 (min)		AUC (mg/min/g)
	M	F	M	F	M	F	M	F
1d	4.27	3.11	0.0735	0.0736	9.43	9.42	58.1	42.3
2w	5.36	4.10	0.082	0.0852	8.45	8.13	65.3	48.1
3m	3.17	2.75	0.0379	0.0411	18.30	16.87	83.6	67
6m	3.58	3.58	0.0514	0.0589	13.47	11.76	69.6	60.7
12m	2.23	1.33	0.0347	0.0342	19.96	20.28	64.3	38.8

C₀is the amount of 2-butoxyethanol in blood immediately post exposure, k is the elimination rate constant (min-1) and AUC is the blood concentration versus time curve in ug/min/g).

Butoxyacetic acid urinary excretion rate at 62.5ppm.  Toxicokinetic parameters

	k		T1/2 (min)		AUC (mg/min/g)
	M	F	M	F	M	F
1d	0.0174	0.0109	39.9	63.7	5541	8228
2w	0.0168	0.0088	41.2	78.4	4849	10605
3m	0.0168	0.0094	41.3	73.7	-	-
6m	0.0099	0.0090	70.3	76.8	-	-
12m	0.0139	0.0087	49.8	79.6	7279	8445
18m	0.0067	0.0122	103.3	56.7	9351	8976

Butoxyacetic acid urinary excretion rate at 125ppm.  Toxicokinetic parameters

	k		T1/2 (min)		AUC (mg/min/g)
	M	F	M	F	M	F
1d	0.011	0.0031	63.2	224.1	19010	33403
2w	0.0116	0.0053	59.5	130.2	13597	37943
3m	0.0059	0.0039	117.9	178.8	13554	29094
6m	0.0035	0.0018	195.9	395.8	14142	26485
12m	0.0037	0.0024	187	283.4	16649	25897
18m	0.0023	0.0058	297.5	119.3	30768	25745

Note that only the data from the concentrations that were also tested in mice in the same study are included for comparison purposes.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
2-butoxethanol is readily eliminated from the blood stream independent of concentration, i.e. with linear kinetics. The elimination rate of the butoxyacetic metabolite from blood decreased with increased exposure concentration (non linear kinetics.). Older animals seemed to eliminate the substance more slowly than young animals. The half life for elimination is less than 10 minutes in younger animals and follows linear kinetics. However, the metabolite butoxyacetic acid has a much longer half life which increases as exposure increases, suggesting more easily saturated metabolism pathways.

Executive summary:

A toxicokinetic study in male and rats was carried out during a chronic exposure study to assess the impact of age on toxicokinetics.   2-butoxethanol is readily eliminated from the blood stream in a manner independent of concentration, i.e. with linear kinetics. The elimination rate of the butoxyacetic metabolite from blood decreased with increased exposure concentration (non linear kinetics.). Older animals seemed to eliminate the substance more slowly than young animals and females were slower than males. The half life for elimination varied between 8 and 42 minutes and follows linear kinetics. However, the metabolite butoxyacetic acid has a much longer half life which increases as exposure increases, suggesting more easily saturated metabolism pathways. The half life at 62.5ppm exposure varied between 40 and 103 mins and at 125ppm between 60 and 300mins.