reaction mass of 3,6,9,12-tetraoxotridecan-1-ol and 3,6,9,12,15-pentaoxahexadecan-1-ol

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substances are either components of this multi-constituent substance or contain members of the same homologous series (ethylene glycol methyl ethers.). Physicochemical properties are very similar. One of the source substances is a mixture where one of the main components is the target substance (35-40%). This if nothing else helps justify bridging. It is assumed that there is no interaction between the components of the multi-constituent substance and that therefore the data from the components individually can be used to predict the properties of the two components when in combination .

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target: Multiconstituent substance of Tetraethylene glycol methyl ether (TetraEGME) and pentaethylene glycol methyl ether
Source: Tetraethylene glycol methyl ether (TetraEGME) Triethylene glycol methyl ether (TEGME) and a formulated brake fluid. The latter is primarily a mixture of TEGME, TetraEGME and PentaEGME that is partially borated. The borate ester hydrolyses rapidly in the presence of water so the test substance for this end point can be considered a mixture of the parent glycol ether and boric acid (4.5%).
Impurities: Both the source and target substances will contain the same impurities as they are produced in the same process, therefore they will have similar impurity profiles and impurities will not impact on the validity of the read across. The formulated brake fluid contains members of the butyl glycol ethers, but the presence of these would not lead to an underestimation of toxicity.

3. ANALOGUE APPROACH JUSTIFICATION
See hypothesis above. There is data by the oral route that shows toxicity is negligible. Data on TEGME (repeat dose toxicity) suggests that toxicity by the dermal route is <10% that of the oral route, which would suggest dermal toxicity is unlikely to be greater than by the oral route.

4. DATA MATRIX
Oral (TEGME and TetraEGME). Multiple studies indicate the LD50 exceeds 10,000mg/kgbw. Dot 4: Limit test indicates LD50>2000mg/kgbw
Dermal: TEGME: LD50=7100mg/kgbw .Dot 4: Limit test indicates LD50>2000mg/kgbw
Using data from TetraEGME to predict the toxicity of a multi-constituent of Tetra and PentaEGME therefore appears to be a justified approach. It is sufficient to provide the data required for this end point and to determine classification outcomes.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1960-62

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Acceptable, study containing basic data which suggests that basic scientific principles have been met. This is sufficient to judge the results reliable as a contribution to the understanding of the toxicity of this substance.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Study pre-dates guidelines. Similar to one day cuff method of Draize (J Pharmac Exp Therap, 82, 377, 1944)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: ~2.5kg
- Age at study initiation: 3-5 months.
- Other: albino rabbits used.
- Diet: Rockland rabbit diet

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Fur removed from entire trunk area by clipping
- % coverage:
- Type of wrap if used: impervious plastic film (VINYLITE)

OTHER
- Animals immobilised during 24 hour exposure period.

Duration of exposure:

24 hours

Doses:

2.5, 5.0, 10, 20ml/kg

No. of animals per sex per dose:

2, 4, 2, 1 respectively.

Control animals:

other: no but a large number of other substances also tested which acted as reference materials.

Details on study design:

- Duration of observation period following administration: 14 days after wrap removed following 24 hour exposure.

Statistics:

The moving average method was used to calculate the LD50

Sex:

male

Dose descriptor:

LD50

Effect level:

7.1 mL/kg bw

Mortality:

All animals in top two dose groups died but none in lower two dose groups.

Clinical signs:

other: Marked erythema seen. Otherwise no signs in lower two dose groups.

Gross pathology:

Hihg dose animal and one of the 10ml/kg animals showed internal and lung hemorrhage. Livers were congested and kidneys pale and possibly swollen.

Results:

Dose (ml/kg)	Mortality	Day of death	Average weight gain (g)
10	2/2	Both day 4
5	0/4	-	135 (SD=163)
2.5	0/2	-	100 (SD=130)

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Executive summary:

In an acute dermal toxicity in rabbits in which key basic details were reported, an LD50 of 7.1ml/kg was obtain. Exposure was under occluded conditions.

Synopsis

LD50=7.1ml/kg

Cross-reference 2

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

GLP, OECD Guideline study. Restriction is that it is a mixture rather than pure substance that has been tested

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

As the material rapidly hydrolyses in the presence of water, the test substance can be considered to be a predominantly mixture of TEGME and TetraEGME.

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Rats were acclimated for five days in stainless steel cages with up to three rats/cage. Food and drinking water were provided ad libitum. Experimental rooms were maintained at 19-23C and 30-70% humidity on a 12-hour light cycle.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

A single dose of test material was placed onto shaved dorsal skin, andheld in place by gauze and covered with waterproof adhesive tape for 24 hours.

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

Animals were observed six times on the day of dosing, and twice daily thereafter for clinical signs until day 14. Body weights were taken on day 8 and day 14. Animals were necropsied on day 15 and any gross pathology recorded.

Statistics:

not reported

Preliminary study:

No mortality or clinical signs were found related to treatment. Body weights were not significantly affected by treatment. Gross pathology found minor vascular congestion of the dermis in 2 male and 3 female animals at the site of application.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

None

Clinical signs:

other: None

Gross pathology:

Minor vascular congestion at site of application on day 15

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Brake Fluid DOT4 was found to not be acutely hazardous by acute dermal exposure in rats.

Executive summary:

Brake Fluid DOT4 was administered to skin of male and female F344 rats at a dose of 2000 mg/kg. No mortality, clinical signs, or effects on body weight were found. Some minor vascular changes to the skin at the application site were the only findings. Brake Fluid DOT4 can be considered practically non-hazardous by acute dermal exposure on the basis of this study.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

2,5,8,11-tetraoxatridecan-13-ol; 2-[2-(2-methoxyethoxy)ethoxy]ethan-1-ol

EC Number:

915-389-0

Molecular formula:

C9H20O5 and C11H24O6

IUPAC Name:

2,5,8,11-tetraoxatridecan-13-ol; 2-[2-(2-methoxyethoxy)ethoxy]ethan-1-ol

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met