Registration Dossier

Administrative data

Description of key information

Oral (similar to OECD 401), rat: LD50 > 5000 mg/kg bw (limit test)

Dermal (OECD 402), rabbit: LD50 > 5000 mg/kg bw (limit test)

All data read-across from the source substance bis(2-(2-butoxyethoxy)ethyl)adipate (CAS No. 141-17-3)

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:
21 Oct 1996 - 4 Nov 1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted generally according to an accepted and published method. Experimental documentation was limited but adequate for the purposes of this summary.
Qualifier:
according to
Guideline:
EPA OTS 798.1175 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
lack of details on test substance
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Ace Animals, Inc., Boyertown, PA, USA- Age at study initiation: approximately 6 - 9 weeks- Weight at study initiation: 222 - 254 g- Fasting period before study: 18 hours- Housing: stainless steel, indirect bedding- Diet: Lab Diet Certified Rodent Diet #5002, ad libitum- Water: ad libitum- Acclimation period: 14 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 19 - 24 (65 - 75 °F)- Photoperiod (hrs dark / hrs light): 12/12IN-LIFE DATES: From: To: 21 Oct 1996 - 4 Nov 1996
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
After 18 hours of fasting and prior to dosing, all rats (5 male: 5 female) were weighed and marked with ear clips. The weight variations of animals did not exceed ±20%. Individual doses were administered on the basis of body weight using a stainless steel intragastric feeding needle. Volumes of dose were 1.1 to 1.2 mL in all cases.
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
other: not required
Details on study design:
- Duration of observation period following administration: animals were observed at 1, 3, 6 and 24 hours and daily thereafter for a total of 14 days.- Frequency of observations and weighing: at least once daily- Necropsy of survivors performed: complete gross necropsy performed on animals sacrificed at the end of the 14-day observation period. Sacrifice was accomplished via carbon dioxide asphyxiation.- Other examinations performed: animals were observed for signs of pharmacological activity and drug toxicity
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
A single male rat died by the 24 hour observation period.
Clinical signs:
Depression was noted in the single male animal that died. Slight depression was recorded in a single other male rat but this resolved by the 24 hour observation period. All other male rats appeared normal.Slight depression was noted in 3/5 female rats but these signs resolved by the 24 hour observation period.Red anal and urethral discharges were noted, with peri-anal hair loss. These signs resolved in all animals by observation Day 13.
Body weight:
Initial body weights:Males: 244 - 252 gFemales: 222 - 224Interim body weights (Day 7):Males: 289 - 313 gFemales: 242 - 258 gAll surviving animals gained weight.
Gross pathology:
In 3 female rats, a red discharge was noted around the nose. The small intestines appeared moderately reddened. The stomachs appeared ulcerated.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable (Klimisch score 2) study from a source substance with similar structures. Read-across is justified based on the fact that both source and target substances are ethylene glycol monobutyl ether substituted diesters of adipic acid. While the source substance contains diethylene glycol monobutyl ether substituents, the main constituents of the target substance contain tri- and/or tetraethylene glycol monobutyl ethers. As a similar metabolic fate of the di-, tri- and tetraethylene glycol monobutyl ethers can be expected, the source and the target substance share similar properties with respect to their environmental fate, ecotoxicological and toxicological profile and reading across of data is suitable. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006 (REACH).

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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:
25 Oct 2012 - 19 Dec 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
(2008)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
(1998)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: males: 8 - 9 weeks; females: 12 - 14 weeks
- Weight at study initiation: males: 231 - 250 g; females: 208 - 234 g
- Housing: individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 160812)
- Diet: Altromin 1324 maintenance diet for rats and mice (lot no. 1039), ad libitum
- Water: tap water, sulphur acidified to a pH value of approximately 2.8, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: not less than 10%
- Type of wrap if used: The dressing consisted of a gauze-dressing and non-irritating tape and was fixed with an additional dressing in a suitable manner.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): using aqua ad injectionem (Ampuva, lot no. 19FG30HA, expiry date: 06/2015)
- Time after start of exposure: 24 h

TEST MATERIAL
The test item was used as delivered by the sponsor.
Duration of exposure:
24 h
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: several times on the day of dosing (once during the first 30 minutes and with special attention given during the first 4 hours post-dose) and once daily until the end of the observation period thereafter
- Frequency of weighing: on day 1 (prior to the application) and on days 8 and 15
- Necropsy of survivors performed: yes (in case of findings during gross pathological examination, the tissues were preserved for a possible histopathological evaluation)
- Other examinations performed: Primary Skin Irritation using the Draize Scoring System
Sex:
male/female
Dose descriptor:
LD50
Effect level:
>= 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred throughout the study period.
Clinical signs:
No signs of systemic toxicity were observed throughout the study period. Signs of dermal irritation after a single dose application were noted in females only: scratches (2/5) on Days 7-11; desquamation (1/5) on Days 7-11; eschar (1/5) on Days 9-11. However, neither oedema, nor erythema were noted in any of the animals.
Body weight:
The body weight development of all male and female animals was within the expected range.
Gross pathology:
With the exception of acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection, no specific gross pathological changes were recorded for any animal.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable (Klimisch score 2) study from a source substance with similar structures. Read-across is justified based on the fact that both source and target substances are ethylene glycol monobutyl ether substituted diesters of adipic acid. While the source substance contains diethylene glycol monobutyl ether substituents, the main constituents of the target substance contain tri- and/or tetraethylene glycol monobutyl ethers. As a similar metabolic fate of the di-, tri- and tetraethylene glycol monobutyl ethers can be expected, the source and the target substance share similar properties with respect to their environmental fate, ecotoxicological and toxicological profile and reading across of data is suitable. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006 (REACH).

Additional information

Justification for grouping of substances and read-across

The read-across approach uses 'bis(2-(2-butoxyethoxy)ethyl)adipate' (CAS No. 141-17-3) as structurally similar source substance to transfer (read-across) data to the target substance 'reaction mass of bis[2-[2-(2-butoxyethoxy)ethoxy]ethyl]adipate and [2-[2-(2-butoxyethoxy)ethoxy]ethyl](3,6,9,12-tetraoxahexadecyl)adipate' (EC No. 943-330-9). The common feature of the source substance and the target substance is that they are diester derivatives of adipic acid, containing only even numbered and linear ethoxylated side chains. Both carboxylic functions of adipic acid are used to form esters with ethylene glycol monobutyl ethers of varying length. While the side chains of the target substance contain tri- and/or tetraethylene glycol monobutyl ether moieties, the side chains in the source substance are made up solely of diethylene glycol monobutyl ether. Thus, the ethylene glycol monobutyl ether substituents in the target substance contain 1 or 2 additional ethylene glycol monobutyl ether units. Although the constituents of the target substance are hence larger in size and have a higher molecular weight, it can be assumed that no significant steric hindrance is introduced when compared to the smaller side chains of the source substance. All parts of the ethylene glycol monobutyl ether side chains are freely rotatable due to the fact that neither a ring system nor π-bonds exert any constraints on rotatability. Therefore, it is feasible to assume an identical environmental and metabolic fate of both substances. In order to avoid the need to test every substance for every endpoint, the read-across from an analogue substance concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted using adequate and reliable data from the source substance in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006 (REACH). Structural similarity and similarities in properties and/or activities of the source and target substance are the basis of read-across.

No data regarding acute toxicity obtained with the target substance are available and therefore read-across of adequate information from the source substance is used.

Acute oral toxicity

A key study (Consumer Products Testing, 1997a) was conducted according to the EPA OTS 798.1175 test guideline (simillar to OECD TG 401) and in compliance with GLP (limit test). Five Wistar rats per sex received the undiluted test item by oral gavage at the limit dose of 5000 mg/kg bw. A single male rat died during the 14-day observation period and showed depression before death. Slight depression was recorded in a single other male rat, but this resolved by the 24-h observation point. All other male rats appeared normal. Slight depression was noted in 3/5 females, which resolved within 24-h post dosing. Red anal and urethral discharges were noted, with peri-anal hair loss, which was resolved in all animals by observation day 13. Body weight gain was as expected in all animals. Based on these results, the oral LD50 was determined to be > 5000 mg/kg bw for both male and female rats.

Acute dermal toxicity

A key study (BSL, 2013a) was conducted according to OECD TG 402 and in compliance with GLP (limit test). The shaved dorsal skin of 5 Wistar rats per sex was exposed to the undiluted test substance at a limit dose of 5000 mg/kg bw for 24 h under semiocclusive conditions. After removal of the test substance, animals were observed for a period of 14 days. No mortality and no clinical signs of toxicity were observed up to the end of the observation period. Signs of slight dermal irritation were noted in females only, including scratches (2/5), desquamation (1/5) and eschar (1/5). The body weight development of all male and female animals was within the expected range. Necropsy revealed no substance-related findings. Based on these results, the dermal LD50 was determined to be > 5000 mg/kg bw for both male and female rats.

Acute inhalation toxicity

There are no data regarding the acute inhalation toxicity of the target substance. However, accounting for Regulation (EC) No. 1907/2006 (REACH), Annex VIII, 8.5.3 Column 2, and for animal welfare reasons, performing an acute toxicity study with inhalative exposure is not scientifically necessary and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

Conclusion on acute toxicity

Reliable and adequate studies performed with the source substance are available investigating the acute oral and dermal toxicity. Both studies yield LD50 values of > 5000 mg/kg bw for male and female rats. The available data, therefore, indicate a very low level of acute toxicity for the source substance and thus, no hazard for acute oral and dermal toxicity is identified for the target substance either.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 (REACH) information on intrinsic properties of substances may be generated by means other than tests, e.g. using information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI states that “substances whose physico-chemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Thus, data gaps can be filled by a read-across approach from a structural analogue source substance to avoid unnecessary animal testing.

The analogue concept is also used to derive the C&L of the target substance taking the properties of the source substance into account. Based on the analogue concept, all available data on acute toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification.