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Toxicological information

Basic toxicokinetics

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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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Analytical purity: 99%
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals 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:
between 5-12 per time point/sex/dose
Control animals:
no
Positive control:
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.