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

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

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.

4. DATA MATRIX
Oral (TEGME and TetraEGME). Multiple studies indicate the LD50 exceeds 10,000mg/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: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

October 1991 - March 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

GLP OECD Guideline study. Restriction due to testing on a mixture rather than pure substance.

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

not applicable

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.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Animals were fasted overnight prior to dosing, and were given a single oral dose of test material at 5000 mg/kg.

Doses:

5000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

After the single dose, animals were clinically observed six times on the day of dosing, and twice daily thereafter for 14 days. Necropsies were performed on day 15 and gross pathological lesions recorded.

Statistics:

not applicable

Preliminary study:

None of the animals died. Clinical signs included abasia/ataxia, hunched posture, piloerection, lachrymation, and later unkempt appearance with staining/soiling of fur in the anogenital region. Less common signs included lethargy in males, and bradypnea in female. Signs started to be evident after one hour, and resolution began to be seen by day 2 and recovery was complete by day 8 in all animals.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

None

Clinical signs:

other: Clinical signs included abasia/ataxia, hunched posture, piloerection, lachrymation, and later unkempt appearance with staining/soiling of fur in the anogenital region. Less common signs included lethargy in males, and bradypnea in female.

Gross pathology:

No pathology was found.

Other findings:

Not applicable

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Brake FLuid DOT4 is not expected to present an acute toxicity hazard by the oral route

Executive summary:

Male and female Fisher 344 rats were exposed to 5000 mg/kg Brake Fluid DOT4 and observed for 14 days. No mortality was observed. Transient clinical signs included abasia/ataxia, hunched posture, piloerection, lachrymation, and later unkempt appearance with staining/soiling of fur in the anogenital region. Less common signs included lethargy in males, and bradypnea in female. Body weight gain was not affected by treatment.

Cross-reference 2

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1960-1962

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Remarks:

Study report with basic details reported but sufficient to judge as reliable for inclusion.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Follows basic principles of an OECD401 but there is insufficient information to rank it as 'equivalent or similar'. A number of the observations normally now required are not reported.

GLP compliance:

no

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Carworth Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Own colony
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 90-120g
- Fasting period before study: not fasted
- Diet : Rockland rat diet

Route of administration:

oral: gavage

Vehicle:

other: see other information.

Doses:

4, 8, 16ml/kg

No. of animals per sex per dose:

5

Control animals:

other: A number of other substances were also tested in the same study

Details on study design:

- Duration of observation period following administration: 14 days
-Autopsies were performed on rats that died.
- Surviving rats were weighed at study termination.

Statistics:

LD50 value and precision estimated by method of Thompson (Bacteriol Rev, 11, 115, 1947) and tables of Weil (Biometrics, 8, 249 ,1952) (the method of moving average).

Sex:

male

Dose descriptor:

LD50

Effect level:

11.3 mL/kg bw

Mortality:

100% in top dose group, none in lower dose groups.

Gross pathology:

Animals that died showed congested lungs, mottled livers and kidneys and gastrointestinal tract irritation. The adrenals were slightly congested.

Individual animal results:

Dose (ml/kg)	Mortality	Day of death	Average weight gain (g)
16	5/5	All day 1
8	0/5	-	42.6 (SD=7.0)
4	0/5	-	31 (30)*

*One animal showed weight loss, one limited weight gain

LD50 is equivalent to 10500mg/kg

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Substance of low toxicity by the oral route.

Executive summary:

In an old study report where all basic experimental details were reported, an LD50 of 11.3ml/kg was established in male rats.

Synopsis

LD50 (male rats) = 11.3ml/kg

Cross-reference 3

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Remarks:

Scientifically reliable.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Fasting period before study: Approx. 16 hours before
- Diet: animals were deprived of food approximately 3-4 hours after application
- Water: Executive Board Swiss in plastic drinking bottles ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3 °C
- Humidity: 50+/-20 %
- Photoperiod: 12 hours a day

Route of administration:

oral: gavage

Vehicle:

water

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The temporal onset of symptoms was recorded. During this time the weight of the animals was determined.
.- Necropsy of survivors performed: yes, the Animals were killed at the end of follow-through using carbon dioxide, dissected, and examined for macroscopically visible changes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No deaths occurred from exposure to a lethal dose of 2000 mg/kg.

Clinical signs:

other: In addition to nonspecific symptoms, the animals showed an impairment of breathing and movement processes. These symptoms reversed within 3 days.

Gross pathology:

In the male showing a lag time in body weight gain, a deformation of the skull was found, macroscopically found a strongly reduced blood pooling in the brain and skull. A compound related effect was not apparent.

Other findings:

Squatting, and uncordinated legged gait, and irregular breathing was observed in females.

Interpretation of results:

not classified

Remarks:

Migrated information No data Criteria used for interpretation of results: EU

Executive summary:

In a guideline and GLP acute toxicitystudy , the LD50 of the substance methyltetraglycol was established to be above the single tested dose of 2000mg/kg.

Cross-reference 4

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

19 Feb 1974 - 01 Mar 1974

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

Principles of method if other than guideline:

Method: BASF-Test which follows in principle the methods described in OECD Guideline 401.
5 rats per sex and dose were treated simultaneously by gavage with preparations of the test substance in water. Group-wise documentation of clinical signs was performed over the 7 day study period. The clinical signs and findings were reported in summary form.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: male: 186g (mean), female 165g (mean)

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 35% for 10500 mg/kg and 15% for 1050 and 2257 mg/kg

Doses:

1050, 2257, 10500 mg/kg bw

No. of animals per sex per dose:

5 male and 5 female rats per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Necropsy of survivors performed: yes

Statistics:

On the basis of the observed lethality, the LD50 value was estimated or determined using a graphical evaluation of the dose response curve on probability paper.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 10 500 mg/kg bw

Mortality:

no mortality occured.

Clinical signs:

other: Signs of toxicity comprised at 10500 mg/kg: apathy, spastic gait, dyspnea, mouth and eyelid crust formation.

Gross pathology:

At necroscopy no abnormalities were observed.

Mean Body weights (g) MALES:

Dose group (mg/kg)	Day 0	Day 3	Day 7
1050	190	210	205
2257	199	228	222
10500	169	124	159

 

Mean Body weights (g) FEMALES:

Dose group (mg/kg)	Day 0	Day 3	Day 7
1050	165	184	167
2257	163	178	170
10500	168	192	178

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Executive summary:

In an acute oral toxicity study that followed the basic requirements of the OECD standard protocol guideline, male and female rats were exposed to single gavage doses of 2 -(2 -(2 -methoxyethoxy)ethoxy)ethanol at doses up to 10500mg/kg. The high dose animals showed apathy, spastic gait, dyspnea, mouth and eyelid crust formation and males also showed a sharp but transient drop in body. However, no mortality was reported implying that the LD50 is significantly in excess of the maximum dose tested.

Synopsis

LD50 (male, female) >10500mg/kg

Cross-reference 5

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Remarks:

Scientifically reliable.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

Principles of method if other than guideline:

No further information available.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 98 - 116 g (average weight 109 g)
- Fasting period before study: 16 hours
- Housing: wood shavings
- Diet (e.g. ad libitum): 2 hours after administration of the product the animals were again given food. The animals received as lining the lialtungsdiät Altromin Altromin 1324 the Company GmbH, Lage / Lippe ad libitum
- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

not specified

Doses:

Single dose

No. of animals per sex per dose:

10

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: weekly
- Necropsy of survivors performed: yes, after the end of follow-up rats were killed under anesthesia, dissected and macroscopically evaluated.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 15 000 mg/kg bw

Based on:

test mat.

Mortality:

1/10 died.

Clinical signs:

other: Animals exposed to 15,000 mg/kg exhibited staggering gait, ruffled fur, gasping respiration

Gross pathology:

The autopsy of the deceased animal at the end of test was macroscopically evaluated without specific findings.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: not specified

Executive summary:

In an acute oral toxicity study in rats that approximated to guideline, an LD50 of >15000mg/kg was established for the substance methyl tetraglycol.

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:

>= 10 500 mg/kg bw

Based on:

test mat.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met