Registration Dossier

Administrative data

Description of key information

The LD50 derived from the key studies were:
LD50 (oral, rat) >2000 mg/kg bw, according to OECD 401, Clariant, 1995;

LD50 (dermal, rat) > 2000 mg/kg bw, according to OECD 402, Shell, 2010.


B-TEGME and brake fluids were very well tolerated in rats after both acute oral and dermal dosing. LD50 values were both above the limit dose of 2000 mg/kg body weight for B-TEGME and brake fluids, therefore B-TEGME is considered to be very safe. Inhalation toxicity testing was waived based upon low vapour pressure.

Based on these results, B-TEGME is not acute toxic.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995-03-01 to 1995-03-15
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
31 July 1992
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: Partie 24, 05-Jan-1995; Product number / code: LP 1941
- Substance type: Borated Glycol Ether
- Expiration date of the lot/batch: stable until 05-Jul-1995
- Purity test date: Not provided
- Analytical purity: 97% (calculated after titration of boric acid)
Species:
rat
Strain:
Wistar
Remarks:
Hoe: WISKf (SPF71)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG, Kastengrund, SPF breed
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 181-187 g (M); 160-169 g (F)
- Fasting period before study: from about 16 hours before to 3-4 hours after treatment
- Housing: macrolon cages (type 4)
- Diet: Altromin 1324 rat diet (Altromin GmbH, Lage/Lippe), ad libitum
- Water: tap water in plastic bottles, ad libitum
- Acclimation period: not necessary (breeding at identical conditions)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1995-03-01 To 1995-03-15
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE: not applicable (undiluted)
VOLUME APPLIED: 1.85 mL/kg (density = 1.08 kg/l at 20°C)
CLASS METHOD: limit dose
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical observations twice every day (in the morning and in the afternoon), on weekends and holidays only once; weekly weighing
- Necropsy of survivors performed: yes
- Other examinations performed: no
Statistics:
Mean values & standard deviation were calculated.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
After application of 2000 mg/kg body weight no deaths in male and female animals occurred during the 14 day observation period.
Clinical signs:
No clinical signs were observed during the study.
Body weight:
Development of body weight was not impaired.
Gross pathology:
The animals were killed at the end of the observation period showed no macroscopically visible changes.

Table 2. Body weight and body weight gain (gram)

Male No.

Body weight

Body weight gain

Day 1

Day 8

Day 15

Day 0

Day 8

Day 15

1

187

251

280

0

64

93

2

182

245

285

0

63

103

3

185

244

280

0

59

95

4

181

239

275

0

58

94

5

182

246

285

0

64

103

Mean

183.4

245.0

281.0

0

61.6

96.6

S.D.

2.5

4.3

4.2

 

2.9

5.0

 

Female No.

Body weight

Body weight gain

Day 1

Day 8

Day 15

Day 0

Day 8

Day 15

1

160

190

204

0

30

44

2

164

190

198

0

26

34

3

169

191

217

0

22

48

4

165

199

213

0

34

48

5

163

186

204

0

23

41

Mean

164.2

191.2

207.2

0

27.0

43.0

S.D.

3.3

4.8

7.7

 

5.0

5.8

Interpretation of results:
GHS criteria not met
Conclusions:
LD50 > 2000 mg/kg body weight B-TEGME.
Executive summary:

In an oral acute toxicity study according to OECD 401, 5 male and 5 female animals were gavaged with the limit dose of 2000 mg/kg bw/d of the test substance.

After application neither deaths nor clinical symptoms occurred. Development of body weight was not impaired. The animals were killed at the end of the observation period of 14 days and showed no macroscopically visible changes.

Acute oral toxicity testing to B-TEGME in the Wistar rat yielded a median lethal dose level above 2000 mg/kg body weight in both male and female animals.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
For futher information, please refer to the Additional Information.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
The existing inhalation study is of poor documentation quality and was not considered for an assessment.
However, neither mortalities nor other adverse effects were observed.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010-01-20 to 2010-02-03
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Date of GLP signature 26/11/09
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: DEG4129165
- Purity : 89.8 %
- Date received: 03 December 2009
- Expiration date of the lot/batch: 31 October 2011

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature in the dark

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: specific gravity was determined and used to calculate the appropriate dose volume for the required dose level
- Final dilution of a dissolved solid, stock liquid or gel:

FORM AS APPLIED IN THE TEST: test material was used as supplied
Species:
rat
Strain:
Wistar
Remarks:
HsdRccHan: WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK
- Age at study initiation: eight to twelve weeks
- Weight at study initiation: at least 200 g (variation did not exceed ± 20% of the mean weight for each sex)
- Fasting period before study:
- Housing: individually during exposure/in groups of five, by sex for remainder of the study; suspended solid-floor polypropylene cages
- Diet: ad libitum (2014 Teklad Global Rodent diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK)
- Water: ad libitum, analyzed drinking water
- Acclimation period: at least five days under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-56%
- Air changes (per hr): at least 15/h
- Photoperiod (hrs dark / hrs light): 12 (06:00-18:00)/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
One day before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10 % of the total body surface.

Using available information on the toxicity of the test material, a single group of animals was treated as follows:

Dose Level Specific Gravity Dose Volume Number of Rats
(mg/kg) (ml/kg) Male Female
2000 1.070 1.87 5 5

The calculated volume of test material, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze, approximately 10 cm x 8 cm in size, was placed over the treatment area and semi-occluded with a piece of self adhesive bandage. The animals were caged individually for the 24 hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.

After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material. The animals were returned to group housing for the remainder of the study period.

The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.


Rationale: Dermal administration was used as this is one possible route of human exposure during manufacture, handling and use of the test item.


Duration of exposure:
24 hours
Doses:
2000 mg /kg body weight
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
On the day before treatment the back and flanks of each animal were clipped free of hair.

Dose Level Specific Gravity Dose Volume Number of Rats
(mg/kg) (ml/kg) Male Female
2000 1.070 1.87 5 5

The calculated volume of test material, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze, approximately 10 cm x 8 cm in size, was placed over the treatment area and semi-occluded with a piece of self adhesive bandage. The animals were caged individually for the 24 hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.

After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material. The animals were returned to group housing for the remainder of the study period.

The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourte The animals were returned to group housing for the remainder of the study period. Further information are given

After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31:

EVALUATION OF SKIN REACTIONS

Value: Erythema and Eschar Formation

0: No erythema
1: Very slight erythema (barely perceptible)
2: Well-defined erythema
3: Moderate to severe erythema
4: Severe erythema (beef redness) to slight eschar formation (injuries in depth)

Value: Oedema Formation

0: No oedema
1: Very slight oedema (barely perceptible)
2: Slight oedema (edges of area well-defined by definite raising)
3: Moderate oedema (raised approximately 1 millimetre)
4: Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure)

Any other skin reactions, if present were also recorded.

Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.

At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Rationale: Dermal administration was used as this is one possible route of human exposure during manufacture, handling and use of the test item.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits not reported.
Mortality:
No deaths occurred during the study.


Clinical signs:
No clinical signs were observed during the course of the study.
There were no signs of dermal irritation.
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Executive summary:

A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the undiluted test material to intact skin at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths, no signs of systemic toxicity, no signs of dermal irritation. All animals showed expected gains in bodyweight over the study period and there were no abnormalities at necropsy. The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
For futher information, please refer to the Additional Information.

Additional information

The key study for acute oral toxicity with B-TEGME (Clariant, 95.0103, 1995) yielded an LD50 greater than 2000 mg/kg body weight in both male and female rats. The study was performed according to OECD 401 and EU B.1 method, and was in compliance with GLP. There were no deaths, clinical signs, adverse effects on body weight or macroscopic changes. A supporting study (BASF, XXIII 535, 1974) even showed an LD50 value of more than 3000 mg B-TEGME/kg body weight, with clinical signs such as dyspnoe, slight apathy, ataxia, slight dehydration and acute heart dilatation with hyperaemia. The latter study was supportive (non-GLP).

Acute oral toxicity was also tested in rats in studies with brake fluids ; these studies were considered as supportive studies since also other components than B-TEGME were present in the brake fluids. In the study from Shell (Shell, SBGR.92.011, 1992) with brake fluid containing 17% B-TEGME, the LD50 was calculated to be greater than 850 mg B-TEGME /kg bw, based upon LD50 values of 5000 mg brake fluid/kg body weight for the mixture tested. The principal signs of reaction to treatment were abasia/ataxia, hunched posture, piloerection, lachrymation and, at a later stage, unkempt appearance and staining/soiling of the anogenital fur. Less common clinical signs were lethargy among male rats, bradypnoea among the females and prostration in rats of either sex. Recovery was advanced by day 2 and complete by day 8 and no macroscopic changes were apparent on day 15. In another study from Shell (Shell, SBGR.90.189, 1990) with brake fluid containing 37% B-TEGME, the LD50value was greater than 1850 mg B-TEGME/kg body weight based upon a LD50 value above 5000 mg brake fluid/kg body weight fot the mixture tested. Clinical signs included hunched posture, lachrymation, abasia, lethargy, unkempt appearance and encrustation of the periorbital zone. Recovery was complete by day 3 and no macroscopic changes were apparent during necropsy on day 15. Most likely other components of brake fluids may have contributed to the clinical signs observed in the animals.

The key study for acute dermal toxicity with B-TEGME was performed according to OECD 402 and EU B.2 and GLP guidelines (Shell, 2259-0065, 2010). A group of ten five male and five female Wistar rats was given a single, 24-hour, semi-occluded dermal application of the undiluted test material to intact skin at the limit dose of 2000 mg/kg bw. There were no deaths, clinica1 observations or signs of systemic toxicity; neither were there signs of dermal irritation. All animals showed expected gains in bodyweight over the study period and no abnormalities were detected at necropsy. The dermal LD50 was found to be greater than 2000 mg/kg bodyweight.

Acute dermal toxicity was also tested with brake fluids in studies, which were considered to be supportive as they contained a lower amount of B-TEGME as well as other components. The acute dermal LD50 of B-TEGME in a brake fluid containing 17% B-TEGME in rats was more than 340 mg B-TEGME/kg body weight based upon an LD50 greater than 2000 mg brake fluid/kg bw under occlusive dressing for 24 hours (Shell, SBGR 92.011, 1992). There were no clinical signs, adverse effects on body weight or macroscopic changes on day 15, except for some minor vascular congestion of the dermis underlying the site of application in some rats. The acute dermal LD50 of B-TEGME in a brake fluid containing 37% B-TEGME in rats was greater than 850 mg B-TEGME/kg body weight, based upon an LD50 of 2000 mg brake fluid/kg body weight under occlusive dressing for 24 hours (Shell, SBGR 90.189, 1990).

An acute inhalation toxicity study (Inhalation Risk Test, IRT) could not be used for assessment (Klimisch code 3) because of significant methodological deficiencies (substance weight increase instead of decrease during IRT, probably due to hygroscopic properties of the test substance. Therefore one can not be sure whether the animals were exposed to any test substance at all. (BASF, XXIII 535, 1974). Further inhalation toxicity testing was waived based upon a low vapour pressure (120 Pa at 20°C).

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for acute toxicity under Regulation (EC) No. 1272/2008.