Registration Dossier

Administrative data

Description of key information

Acute rral (OECD 401): LD50 > 2000 mg/kg bw 
Acute dermal: LD50 > 2000 mg/kg bw
Acute inhalation: RA-A from CAS 103-23-1: LC50 > 5.7 mg/L; RA-A from CAS 16958-92-2: LC50 > 3.2 mg/L
Studies on acute inhalation toxicity were available for the following Read Across substances (CAS No.): 103-23-1 and 16958-92-2

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:
9 Nov - 29 Nov 1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study with acceptable restrictions (test substance purtiy not given)
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
, lack of details on test substance
GLP compliance:
yes (incl. certificate)
Remarks:
Niedersächsisches Umweltministerium, Hannover, Germany
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Bor: WISW (SPF cbp)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann, Borchen, Germany
- Age at study initiation: no data
- Weight at study initiation: males: 222-240 g, females: 161-181 g
- Fasting period before study: from 16 h before until 3-4 h after administration
- Housing: up to 5 animals per Makrolon type III cage on sterilised soft wood bedding.
- Diet: Ssniff-R Alleindiät, Ssniff Spezialdiäten GmbH, Soest, Germany, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 9 - 29 Nov 1993
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2.17 mL/kg bw
Doses:
2000 mg/kg bw
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: 10 min, 1, 2, 6 and 24 h after application. Thereafter once daily.
- Frequency of weighing: On days 0, 7 and 14 p.a.
- Necropsy of survivors performed: yes, on all animals on day 14.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred.
Clinical signs:
No abnormal clinical signs were observed.
Body weight:
All animals showed the expected gain in body weight.
Gross pathology:
No test-item dependent findings were noted.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
29 Feb 1998 - 11 Mar 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study, tested with the source substance bis(2-ethylhexyl)l adipate (CAS 103-23-3). In accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
(1981)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
(1992)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Version / remarks:
(1984)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OTS 798.1150 (Acute inhalation toxicity)
Version / remarks:
(1992)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: SPF Wistar/Chbb:THOM
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: approximately 8-9 weeks
- Weight at study initiation: 284±9.5 g
- Housing: individually in cages type DK III (Becker, Germany) without bedding
- Diet: KLIBA rat/mouse/hamster laboratory diet 10 mm pellets (Klingentalmühle AG, Kaiseraugst, Switzerland), ad libitum during the post-exposure observation period
- Water: ad libitum during the post-exposure observation period
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Head-nose inhalation system INA 20 (glass-steel construction)
- Exposure chamber volume: approximately 55 L
- Method of holding animals in test chamber: the animals were restrained in tubes and their snouts projected into the inhalation chamber
- Source and rate of air: compressed air; supply air flow : 1500L/h, exhaust air flow: 1350 L/h
- Method of conditioning air: not specified (temperature and humidity were measured in 30 min-intervals). No surveillance of the oxygen content in the inhalation system was performed. The air change was judged to be sufficient to prevent oxygen depletion by the breathing of the animals and the concentration of the test substance used could not have a substantial influence on oxygen partial pressure .
- System of generating aerosol: Amounts of the test substance were supplied to the two-component atomizer by means of the piston metering pump. By means of compressed air, the aerosol was produced inside the aerosol mixing vessel and was passed through the cyclonic separator into the exposure system. Flow rate of the test substance preparation to the atomizer was 35.0 mL/h .
- Method of particle size determination: The following equipment was used for the particle size determination: Stack Sampler Mark III (Andersen), Vacuum Compressed Air Pump (Millipore), Sampling probe (internal diameter 6.9 mm), Limiting orifice 3 L/min, Balance: Sartorius M3P and Sartorius LC 1201S. Before sampling, the impactor was assembled with preweighed glass-fiber collecting discs, and a backup particle filter. The impactor was connected to the vacuum pump and one sample was taken from the breathing zone of the animals not earlier than 30 minutes after the beginning of the exposure. The sample volume was 9 L. After sampling the impactor was taken apart and the collecting discs and the backup particle filter were re-weighed. The amounts of material adsorbed to the walls of the impactor and in the sampling probe (wall losses) were also determined quantitatively.
- Temperature, humidity, pressure in air chamber: 21.5 °C, 2.1% rel. humidity

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric determination of the inhalation atmosphere concentration.
- Samples taken from breathing zone: yes (immediately adjacent to the animals' noses)

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: please refer to table 1
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.4 µm/3.0
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric
Duration of exposure:
4 h
Concentrations:
5.7 mg/L
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: A check for overt clinical signs of toxicity or mortality as well as a check for the presence of feed and drinking water was made twice a day on workdays and once daily on weekends and public holidays. Detailed clinical observations were recorded for each animal separately several times during exposure and at least once on each workday in the observation period.
- Frequency of weighing: prior to exposure, after 7 days and after 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
A Probit analysis was performed.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.7 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality occurred throughout the study period.
Clinical signs:
other: Clinical examination revealed irregular and accelerated respiration as well as attempts to escape and piloerection. No clinical signs could be detected from post dosing day 5 onward.
Body weight:
All animals of this study gained body weight as expected.
Gross pathology:
No gross pathological abnormalities were detected in the animals at study termination.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substance.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions; analytical purity of test material not specified
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
analytical purity of test material not specified
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: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 11-12 weeks
- Weight at study initiation: mean for males 323 g, mean for females 210 g, body weight variation did not exceed ± 20% of the sex mean
- Housing: individually housed in labeled Macrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 05 Jan 2010 To: 19 Jan 2010
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 25 cm² for males and 18 cm² for females
- % coverage: 10
- Type of wrap if used: surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage, a piece of Micropore tape was additionally used for fixation of the bandages in females only

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test substance was removed with tap water.
- Time after start of exposure: 24h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.20 mL/kg bw



Duration of exposure:
24 h
Doses:
2000 mg/kg bw
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: Mortality/Viability: Twice daily; Body weights: Days 1 (pre-administration), 8 and 15; Clinical signs: at periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Flat posture and/or chromodacryorrhoea was observed among several animals on Day 1. Scales were seen in the treated skin-area of several animals between Days 4 and 13.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for grouping of substances and read-across

There are no data available on the acute inhalation toxicity of diisodecyl azelate (CAS 28472-97-1). In order 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, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of acute toxicity

CAS

Chemical name

Molecular weight

Acute toxicity Oral

Acute toxicity inhalation

Acute toxicity dermal

28472-97-1 (a)

Diisodecyl azelate

468.75

Experimental result:
LD50 >2000 mg/kg bw (rat)

WoE:

RA: CAS 103-23-1

RA: CAS 16958-92-2

Experimental result:
LD50 >2000 mg/kg bw (rat)

103-23-1 (b)

Bis(2-ethylhexyl) adipate

370.57

--

Experimental result:
LC50 >5.7 mg/L air (analytical)

--

16958-92-2

Bis(tridecyl) adipate

454.73 -566.94

--

Experimental result:
LC50 >3.2 mg/L air (analytical)

--

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for diisodecyl azelate (CAS 28472-97-1). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Acute oral toxicity

CAS 28472-97-1

An acute oral toxicity study with diisodecyl azelate was performed according to OECD guideline 401 (Bien, 1993). Male and female Bor: WISW (SPF cbp) rats were orally exposed to a single dose volume of 2.17 mL/kg bw of the test substance to achieve a dose of 2000 mg/kg bw in a limit test. No abnormal clinical signs or body weight changes were observed in the 14 days observation period. No deaths occurred. Therefore the LD50 under the given conditions was set to >2000mg/kg bw.

 

Acute inhalation toxicity

CAS 103-23-1

The acute inhalation toxicity of Bis(2-ethylhexyl) adipate (CAS 103-23-1) was investigated in a limit test conducted according to OECD guideline 403 and GLP (Gamer, 1998). 5 Wistar rats per sex were exposed to the test substance as a liquid aerosol (MMAD= 1.4 µm) at an analytically determined concentration of 5.688 mg/L for 4 h using a nose/head only exposure system. No mortality occurred throughout the study period. Clinical signs of toxicity included irregular and accelerated respiration as well as attempts to escape and piloerection and were completely subsided from post dosing day 5 onward. Body weights were not affected by treatment and no abnormalities were noted at gross pathology. Based on these results, the LC50 value for male and female Wistar rats was assumed to be greater than 5.7 mg/L air.

 

CAS 16958-92-2

The acute inhalation toxicity of Bis(tridecyl) adipate was investigated in a study similar to OECD guideline 403 (Dalbey, 1989). Groups of 10 Sprague Dawley rats per sex were exposed to analytical atmosphere concentrations of the test aerosol of 0.5 and 3.2 mg/L (highest achievable dose) for 4 h using a whole body exposure system. In addition, 10 control animals per sex were sham-exposed. An interim sacrifice of 5 males and 5 females of each group was performed 1 day after exposure to the test aerosol. No mortality and no clinical signs of toxicity were observed in any of the animals during the 1- or 14-day observation period. Body and organ weights were not affected by treatment and no abnormalities were noted at gross pathology. The histopathological examination did not reveal any substance-related changes in any of the organs examined (lungs, nasal turbinates, liver, kidney and tracheobronchial lymph node). Based on these results, the LC50 value for male and female Sprague Dawley rats was assumed to be greater than 3.2 mg/L air.

 

Acute dermal toxicity

CAS 28472-97-1

The dermal route was tested in male and female Wistar rats according to OECD guideline 402 (van Otterdijk, 2010). Dermal exposure of 2000 mg diisodecyl azelate /kg bw for 24 h led to no mortalities within the observation period of 14 days. Flat posture and/or chromodacryorrhoea was observed among several animals on Day 1. Scales were seen in the treated skin-area of several animals between Days 4 and 13. Body weight gain was assumed to be normal in this study and no abnormalities were found at macroscopic post mortem examination of the animals. The LD50 for acute dermal exposure of diisodecyl azelate was set to be >2000 mg/kg bw.

 

Conclusions for acute toxicity

In summary, the acute oral toxicity study with diisodecyl azelate (CAS 28472-97-1) showed a LD50 value greater than 2000 mg/kg bw. For acute inhalation toxicity, two studies are available from the structurally similar substances bis(2-ethylhexyl) adipate (CAS 103-23-1) and bis(tridecyl) adipate (CAS 16958-92-2). From these studies LC50 values, of >3.2 and > 5.7 mg/L air were determined for male and female rats at the highest achievable doses. Acute dermal toxicity data with diisodecyl azelate (CAS 28472-97-1) showed no effects at the limit dose of 2000 mg/kg bw.

Thus, the available data on diisodecyl azelate (CAS 28472-97-1) and structural analogues indicate a very low level of acute toxicity and thus no hazard for acute oral, dermal and inhalation toxicity was identified.

 


Justification for selection of acute toxicity – oral endpoint
There is only one study available.

Justification for selection of acute toxicity – inhalation endpoint
Hazard assessment is conducted by means of read-across from structural analogues. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substances and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for selection of acute toxicity – dermal endpoint
There is only one study available.

Justification for classification or non-classification

Based on substance-specific studies and read-across from structurally similar substances, the available data on the acute oral, dermal and inhalation toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.