Reaction mass of 5,8,11,14-Tetraoxaoctadecane and 5,8,11,14,17-Pentaoxaheneicosane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

2012/2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Scientifically well performed and well-documented; No GLP Rationale for grouping: structural similarity given by the presence of ”butyl-O-CH2CH2 -O-“ at terminal position; systemic exposure to 2-butoxyacetic acid and/or butoxyethoxyacetic acid as common mode of action; comparable toxicity profiles after prolonged exposure

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Objective of study:

excretion

metabolism

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The urine samples that were obtained in the 28-day oral toxicity study was analyzed for the presumed toxic metabolite 2-butoxyacetic acid. The study comprised method development, validation and analysis of 2-butoxyacetic acid in the urine samples.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-butoxyethyl) ether

EC Number:

204-001-9

EC Name:

Bis(2-butoxyethyl) ether

Cas Number:

112-73-2

Molecular formula:

C12H26O3

IUPAC Name:

1,1'-[oxybis(ethane-2,1-diyloxy)]dibutane

Constituent 2

Reference substance name:

DEGDBE

IUPAC Name:

DEGDBE

Test material form:

gas under pressure: refrigerated liquefied gas

Details on test material:

Name: Diethyleneglycoldibutylether
CAS No.: 112-73-2
Chemical Name: Bis(2-butoxyethyl)ether

Active Components: 100%

Physical State: liquid
pH: 6, 5-7, 5 (25oC, 100 g/L i-propanol/ water 4:1)

Storage: Room Temperature (RT)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration and frequency of treatment / exposure:

Duration: 28 day
Frequency: once per day

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 100, 250, 750 mg/kg bw

No. of animals per sex per dose / concentration:

5

Control animals:

yes, concurrent vehicle

Results and discussion

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

2-Butoxyacetic acid could be identified in the urine samples obtained from rats treated with DEGDBE.
The quantification of the 2-Butoxyacetic acid revealed a dose dependently increasing 2-butoxyacetic acid concentration with increasing treatment doses. The values obtained for the 8 day treatment and 28 day treatmend were comparable. The values obtained for the recovery animals (after recovery of 2,3, and 14 days ) were very low, nearly comparable to those of controls.

The values obtained for control animals were either under the detection limit (1 mg/L) or low.

Any other information on results incl. tables

Result Evaluation

-      2-Butoxyacetic acid could be identified. The values obtained were dose-dependent and ranged up to 1400 ± 600 mg/L.

-      In general, the values obtained for males and females were comparable. The values obtained for samples of D29 and dose of 100 mg/kg bw were different. Significantly higher values were obtained for females (70 ± 55 vs. 210 ± 65 mg/L).

-      The values obtained for D9 and D29 were in the comparable range.

-      The values obtained for animals that were allowed to recover (D30, 31 and D43) were very low compared to the values obtained for D9 or D29.

-      A significant level of 2-butoxyacetic acid could be found in some of the samples obtained from the control animals. No analytical reason could be identified. Whether the control animals were contaminated with DEGDBE or the samples not correctly labeled remains unclear. However, these values were still near to detection limit and lower than those found for treated animals. The integrity of the study was not negatively influenced.

Overview of the obtained values:

Table: Urinary 2-Butoxyacetic acid in rats treated with DEGDBE D9 and D29 refers to rats treated for 8 days and 28 days; D30, D31, D43 refers to rats treated for 28 days and allowed to recover for 1,2 and 14 days.
Dose [mg/kg bw]	Sample Collection day	Urinary Concentration [mg/L]
		Male	Female
0	D9	2 ± 3 (n = 5)	17 ± 11 (n = 5)
	D29	6 ± 13 (n = 5)	LOD (n = 5)
	D31	3 ± 4 (n = 5)	2 ± 1 (n = 5)
	D43	LOD (n = 5)	LOD (n = 5)
25	D9	22 ± 11 (n = 5)	29 ± 20 (n = 5)
	D29	63 ± 42 (n = 5)	49 ± 39 (n = 5)
100	D9	201 ± 117 (n = 4)	263 ± 132 (n = 4)
	D29	70 ± 55 (n = 3)	210 ± 65 (n = 4)
250	D9	534 ± 341 (n = 4)	946 ± 470 (n = 5)
	D29	460 ± 372 (n = 5)	368 ± 102 (n = 5)
750	D9	1384 ± 630 (n = 5)	1336 ± 614 (n = 5)
	D29	1065 ± 910 (n = 5)	753 ± 910 (n = 3)
	D30	-	165 ± 7 (n = 2)
	D31	21 ± 12 (n = 5)	91± 34 (n = 4)
	D43	12 ± 14 (n = 5)	10± 5 (n = 4)

Validation of the analytical method

 

Precision:

For validation purposes the precision was investigated with seven runs of a spiked sample (with about 40 mg/L 2-BAA). The following result was obtained:

RSD

4.8 %

Linearity:

The linearity was tested with nine levels from 0.5 mg/L up to 42 mg/L. A linear analysis function can be assumed. No outliers were observed.

Sxo	< 0.1 mg/L
Vxo	0.4 %

 Accuracy / Recovery:

The accuracy was tested with spiked samples of different urines with different concentrations between 0 and 429 mg/L. Because some of the samples had to be diluted, the recovery was determined for diluted samples too. The rates of recovery were:

Lowest Rate of Recovery	86.0 %
Mean Rate of Recovery	105.1 %
Highest Rate of Recovery	129.5 %

 Limit of Quantification:

The limit of quantification was determined to be 1 mg/L. Based on the results of the linearity tests are the following values:

LOD	0.2 mg/L
LOQ	0.4 mg/L

 

Robustness:

Random samples were tested with a GC/FID method without changing the sample preparation method. External standard (ESTD) was used for calibration. The results were comparable to the results with CI-GC/MS.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The bioaccumulating property of the registration substance is derived based on the read-across approach.
Rats were treated with diethylenglycoldibuthylether(DEGDBE) via gavage for up to 28 days and the their urines were analyzed for the presumed toxic metabolite 2-butoxyacetic acid (2-BAA). Comparable values were obtained after treatment of 8 and 28 days and very low values for recovery animals. No bioaccumulating property of DEGDBE could be derived.
Likewise, no significant bioaccumulating property can be predicted for the registration substance.

Executive summary:

The repeated dose toxicity of the registration substance was assessed based on the read-across. DEGDBE is considered to be one of the appropriate source chemical.

Rats were treated via gavage with DEGDBE at doses of 0. 25. 100. 250 and 750 mg/kg bw for up to 28 days. The 24 -h urine samples were collected after 8 day and 28 day treatment and after recovery phase of up to 14 days and analyzed for the presumed toxic metabolite 2 -butoxyacetic acid (2 -BAA). The obtained values were dose dependent and ranged to 1400 ± 600 mg/L. Comparable values were obtained in the samples of 28 -day treatment, indicating that steady-state of 2 -BAA systemic burden was established within the treatment period. Efficient 2 -BAA clearance could be demonstrated by low levels of 2 -BAA for recovery animals. No significant bioaccumulating property could be derived for DEGDBE.

Likewise, no significant bioaccumulating property can be predicted for the registration substance.