Registration Dossier

Administrative data

Description of key information

All available acute oral toxicity studies within this category resulted in acute oral LD50 > 2000 mg/kg bw. 
All available acute dermal toxicity studies within the category resulted in acute dermal LD50 > 2000 mg/kg bw.
All available acute inhalation toxicity studies within the category resulted in acute inhalation LC50 > 5.7 mg/L.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given
Principles of method if other than guideline:
Application of a single oral dose to rats.
GLP compliance:
no
Test type:
standard acute method
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Additional information on strain: albino Wistar strain rats (or if necessary rats of other strains, as previously reported by the authors (1944))
- Weight at study initiation: 90 - 120 g
Route of administration:
oral: gavage
Vehicle:
water
Doses:
no data
No. of animals per sex per dose:
no data
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days

6 male rats were given a single dose of the test substance. One week later six more animals were given some other dosage and this procedure was repeated until two dosages differing by a multiple of ten were found one of which kills some or all animals and the other of which kills some or no animals within 14 days. An LD50 was then estimated on the assumption that the slope of a probit mortality vs. log dosage curve is the same as that of some structurally similar material which has been studied in more detail previously.
Sex:
male
Dose descriptor:
LD50
Effect level:
12 900 mg/kg bw
Based on:
test mat.
95% CL:
> 6.6 - < 17
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

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
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. According 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
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
(1981)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
(1992)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Version / remarks:
(1984)
Deviations:
no
Qualifier:
according to guideline
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 or test system 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 : 1500LI/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:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Report was limited. Study is not GLP conform. Exposure for 1 hour instead of 4 hours. No signature.
Principles of method if other than guideline:
Albino rats in groups of ten (5 males and 5 females) were exposed to concentrations of 20 mg/L for one hour and observed for two weeks.
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 180 - 300 g
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
other: no vehicle used
Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
1 h
Concentrations:
20 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 and weighing: weighing on day 0 and day 14, observation for signs of poisoning daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 20 mg/L air
Based on:
test mat.
Exp. duration:
1 h
Mortality:
No mortalities were observed.
Clinical signs:
other: No clinical signs were observed.
Body weight:
Body weight gain was normal.
Gross pathology:
No gross abnormalities were seen.
Table1: body weight (g)
rabbit Day0 Day14
1 208 330
2 240 364
3 246 392
4 260 368
5 232 294
6 200 198
7 212 232
8 200 222
9 202 212
10 220 248
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
DSD: not classified
CLP: not classified
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report which meets basic scientific principles. Test substance purity not given.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
purity of test substance not given, 10 male and female animals used per test group, 5 males and females sacrificed one day after exposure, only 2 concentrations were tested
GLP compliance:
not specified
Test type:
standard acute method
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River at Kingston, USA
- Age at study initiation: 10 weeks
- Weight at study initiation: 310 g - 387 g (male), 205 g - 268 g (female)
- Housing: in individual stainless steel wire cages during exposure, when not exposed housed in cages which conform to AALAC standards
- Diet: certified Purina rodent chow #5002, ad libitum except during exposure
- Water: tap water delivered via automatic system, ad libitum, except during expsoure
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 08-02-1988 To: 30-06-1988 and 01-07-1988
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber volume: 400 L
- System of generating particulates/aerosols: Aerosol was generated by use of Laskin nebulizers. Pressurized air passed through the hollow ste, of the nebulizer and exited at high velocity through holes in is side. This high velocity airstream passed over the top of hollow feed barrels and caused the aspiration of the liquid test material up into the feed barrel. The liquid was aerosolized as it is drawn into the airstream by the relative negative pressure there. The liquid was sheared into small droplets. The larger aerosol particles were removed by impaction on the walls of a glass container around the nebulizer and by impaction in a secondary glass impactor. The aerosol was diluted by the main airstream before entering the exposure chamber. The flask containing the nebulizer for the high dose was partially submerged in water maintained at about 40°C in order to maximize the aerosol concentration.

TEST ATMOSPHERE
- Brief description of analytical method used: Concentration of aerosol in the chamber was determined gravimetrically by drawing known volumes of air from the chamber through glass fiber filters and measuring the increase in weight of the filters. the weigth increase was divided by the volume of air sampled to give the aerosol concentration.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (see table1)
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gas Chromatography
Duration of exposure:
4 h
Concentrations:
0.5, 5.0 mg/L (3.2 mg/L was the highest practical concentration which could be achieved, as determined by analytical verification instead of 5 mg/L)
No. of animals per sex per dose:
10 (5 animals of each sex sacrificed one day after exposure)
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days, 5 males and 5 females of each group were sacrificed 1 day after exposure
- Frequency of observations and weighing: weighing on day 1, 2, 8 and 16, observations for mortality and toxic signs were carried out daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology
Statistics:
body weight: ANOVA and Tukeys multiple range test for comparison of control and exposed groups
organ weights: ANOVA and Duncans multiple range test in the Grosse Software System
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3.2 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality was observed.
Clinical signs:
other: No treatment-related toxicologically significant signs were noted.
Body weight:
Body weight was not affected by exposure.
Gross pathology:
No treatment-related effects were found.
Other findings:
- Organ weights: Organ weights were not affected by treatment.
- Histopathology: No treatment-related microscopic changes were observed in any of the organs examined (lungs, nasal turbinates, liver, kidney, tracheobronchial lymph node).
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
DSD: not classified
CLP: not classified
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Does not meet important criteria of today standard methods. The study was not reliable with regard to risk assessment, since the vapour concentration of the test substance was not sufficiently high.
Principles of method if other than guideline:
inhalation risk test, no further data
GLP compliance:
not specified
Test type:
other: inhalation risk test
Species:
mouse
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gas chromatography
Duration of exposure:
2 h
Concentrations:
17 mg/m³ (at 50 °C; saturated atmosphere)
No. of animals per sex per dose:
no data
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LC0
Effect level:
0.017 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
2 h
Remarks on result:
other: saturated atmosphere; no mortality; failure of redox processes, failure in liver and kidney function, changes in haematological and immunological parameters
Mortality:
No animal died within the study.
Other findings:
failure of redox processes, failure in liver and kidney function, changes in haematological and immunological parameters
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Does not meet important criteria of today standard methods. The study was not reliable with regard to risk assessment, since the vapour concentration of the test substance was not sufficiently high.
Principles of method if other than guideline:
inhalation risk test, no further data
GLP compliance:
not specified
Test type:
other: inhalation risk test
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gas chromatography
Duration of exposure:
4 h
Concentrations:
17 mg/m³ (at 50 °C; saturated atmosphere)
No. of animals per sex per dose:
no data
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LC0
Effect level:
0.017 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: saturated atmosphere; no mortality; failure of redox processes, failure in liver and kidney function, changes in haematological and immunological parameters
Mortality:
No animal died within the study.
Other findings:
failure of redox processes, failure in liver and kidney function, changes in haematological and immunological parameters
Endpoint conclusion
Endpoint conclusion:
no adverse effect 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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given
Principles of method if other than guideline:
Rabbits are epidermally treated with the undiluted test substance for 4 days.
GLP compliance:
no
Test type:
standard acute method
Species:
rabbit
Strain:
not specified
Sex:
not specified
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Undiluted test material was applied to the clipped skin of the rabbits trunk. The dose is retained under a flexible film of rubber, vinyl plastic or the like, selected to be impervious to the chemical.
Duration of exposure:
4 days
Doses:
no data
(several dosages differing by a multiple of 10)
No. of animals per sex per dose:
6 animals (overall)
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
no further information available
Sex:
not specified
Dose descriptor:
LD50
Effect level:
20 mL/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 was determined graphically.
Sex:
not specified
Dose descriptor:
LD50
Effect level:
19 220 mg/kg bw
Based on:
test mat.
Remarks on result:
other: calculated based on a density of 0.96 g/mL
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

Additional information

Justification for grouping of substances and read-across

The PFAE Linear (Polyfunctional Aliphatic Ester) category consists of 16 substances, well-defined mono-constituent substances as well as related UVCB substances, respectively with varying fatty alcohol chain lengths and branching. The distinguishing feature of this category of chemicals is that they are diester derivatives of common dicarboxylic acids: namely adipic (C6), azelaic (C9) and sebacic (C10) acids. The alcohol portion of the diesters generally falls in the C3-C20 carbon number range, including linear and branched, even and odd numbered alcohols. 

In order to avoid the need to test every substance for every endpoint, the category 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 from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Endpoint specific data matrix:

ID #

CAS

Acute toxicity: Oral

Acute toxicity: Inhalation

Acute toxicity: Dermal

1

6938-94-9 (a)

Experimental result:
LD50 > 5000 mg/kg bw

RA: CAS 16958-92-2
RA: CAS 103-23-1

RA: CAS 105-99-7

2

105-99-7

Experimental result:
LD50 = 12900 mg/kg bw

RA: CAS 16958-92-2
RA: CAS 103-23-1

Experimental result:
LD50 = 19220 mg/kg bw

3

110-33-8

Experimental result:
LD50 > 15800 mg/kg bw

RA: CAS 103-23-1

Experimental result:
LD50 > 7940 mg/kg bw

4

1330-86-5

RA: CAS 110-33-8
RA: CAS 105-99-7

RA: CAS 16958-92-2

RA: CAS 103-23-1

RA: CAS 105-99-7
RA: CAS 16958-92-2
RA: CAS 110-33-8

5

123-79-5 (b)

--

--

--

6

103-23-1

Experimental result:
LD50 = 24600 mg/kg bw

Experimental result:
LC50 > 5.7 mg/L air

--

7

68515-75-3

Experimental result:
LD50 > 15800 mg/kg bw (c)

--

--

8

33703-08-1

--

--

--

9

16958-92-2

Experimental result:
LD50 > 15000 mg/kg bw

Experimental result:
LC50 >3.2 mg/L air

Experimental result:
LD50 > 5000 mg/kg bw

10

85117-94-8

Experimental result:
LD50 > 2000 mg/kg bw

--

--

11

103-24-2

Experimental result:
LD50 > 2000 mg/kg bw

RA: CAS 16958-92-2
RA: CAS 103-23-1

Experimental result:
LD50 = 18300 mg/kg bw

12

897626-46-9

RA: CAS 103-24-2
RA: CAS 85117-94-8
RA: CAS 69275-01-0

RA: CAS 16958-92-2
RA: CAS 103-23-1

RA: CAS 69275-01-0
RA: CAS 103-24-2

13

7491-02-3

Experimental result:
LD50 > 4685 mg/kg bw

RA: CAS 16958-92-2
RA: CAS 103-23-1

RA: CAS 105-99-7
RA: CAS 110-33-8

14

109-43-3

Experimental result:
LD50 > 4700 mg/kg bw

RA: CAS 16958-92-2
RA: CAS 103-23-1

RA: CAS 105-99-7
RA: CAS 110-33-8

15

122-62-3

Experimental result:
LD50 > 4560 mg/kg bw

RA: CAS 16958-92-2
RA: CAS 103-23-1

RA: CAS 103-24-2
RA: CAS 69275-01-0

16

69275-01-0

Experimental result:
LD50 > 5000 mg/kg bw

--

Experimental result:
LD50 > 2000 mg/kg bw

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for these substances a full set of experimental results and/or read-across is given.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

(c) Original data source is not available and thus not used for read-across.

 

Acute oral toxicity

Diester of Adipic acid

CAS 6938-94-9

The acute toxicity via the oral route of Diisopropyl adipate (CAS 6938-94-9) has been investigated in mice in two studies similar to OECD guideline 401.

The acute oral toxicity of Diisopropyl adipate was investigated in 5 male NMRI mice, which received the undiluted test substance at a limit dose of 5000 mg/kg bw via oral gavage (Dufour, 1993). No mortality occurred during the 7-day observation period. Clinical signs were evident up to 1 h after dosing and included the occurrence of lethargy, half closed eyes and forced breathing. No effect on body weight was noted during the study period and necropsy revealed no substance-related findings. Based on the results, the oral LD50 value for male NMRI mice was considered to be greater than 5000 mg/kg bw.

In a further acute oral toxicity study, 10 Swiss Webster mice per group were gavaged with the test substance at a dose volume of 10, 15, 20, 25 mL/kg bw, equivalent to doses of 9300, 13950, 18600 and 23250 mg/kg bw based on a density of 0.93 g/mL (Levenstein, 1972). Mortalities occurred at all doses with incidences of 1/10 animals at 10 mL/kg bw, 4/10 animals at 15 mL/kg bw, 6/10 animals at 20 mL/kg bw and 10/10 animals at 25 mL/kg bw. The oral LD50 value was calculated according to the method of Litchfield and Wilcoxon (1949). Based on this calculation, the oral LD50 value for Swiss Webster mice was assumed to be 17.3 mg/mL, equivalent to a dose of 16089 mg/kg bw. However, this study is not reliable for risk assessment since the administered dose volumes were not considered appropriate for the used species.

In summary, the oral LD50 value of Diisopropyl adipate was greater than 5000 mg/kg bw.

 

CAS 105-99-7

The acute toxicity via the oral route of Dibutyl adipate (CAS 105-99-7) has been investigated in rats and mice in three studies.

In an acute oral toxicity study, Dibutyl adipate diluted in water was administered via gavage to 6 male Wistar rats at different doses (Smyth, 1951). One week later, 6 further animals were treated with another dose of the test substance and this procedure was repeated until two dosages differing by a multiple of ten were found, at which mortality was observed in some or all animals and at which some or no mortality occurred during the 14-day observation period. The oral LD50 was then estimated on the assumption that the slope of a probit mortality vs. log dosage curve is the same as that of a structurally related test material which has been studied more detailed previously. Based on the probit analysis, the oral LD50 value of Dibutyl adipate was estimated to be 12900 mg/kg bw.

In addition acute oral LD50 values of 16920 mg/kg bw for rats and 16800 mg/kg bw for mice were reported (Astapova et al., 1990). No further details were given and thus the presented data were not deemed suitable for risk assessment.

In summary, the oral LD50 value of Dibutyl adipate was greater than 12900 mg/kg bw.

 

CAS 110-33-8

The acute toxicity via the oral route of Dihexyl adipate (CAS 110-33-8) has been investigated in rats and mice in two studies.

The acute oral toxicity of Dihexyl adipate was investigated in a study similar to OECD guideline 401 (Birch, 1972). Groups of each 5 male and female Sprague Dawley rats were administered the test substance via oral gavage at dose levels of 10000, 12600 and 15800 mg/kg bw followed by an observation period of 7 days. Mortalities occurred during Days 1 and 3 of the study in 1 female as well as in 1 male and 1 female at dose levels of 12600 and 15800 mg/kg bw, respectively. No mortalities were observed at 10000 mg/kg bw during the whole study period. Clinical signs of toxicity in survivors included reduced appetite and reduced activity 2 to 3 days after application of the test substance. Furthermore, increasing weakness and collapse were observed. At study termination, body weights of males and females were comparable within the treatment groups. Autopsy of deceased animals revealed haemorrhage of the lung, decolouration of the liver and acute gastrointestinal inflammation. In surviving animals, no abnormal findings were observed in viscera at macroscopic examination. Based on the results of this study, the oral LD50 value for male and female Sprague Dawley rats was greater than 15800 mg/kg bw.

In a further acute oral toxicity study with the test substance, the LD50 value in mice was established at 19600 mg/kg (ECB, 2000).

In summary, the oral LD50 of Dihexyl adipate was greater than 15800 mg/kg bw.

 

CAS 103-23-1

The acute toxicity via the oral route of Bis(2-ethylhexyl) adipate (CAS 103-23-1) has been investigated in rats and mice.

In acute toxicity tests, groups of five males and five females of F344 rats and B6C3F1 mice, respectively, were administered a single dose of Bis(2-ethylhexyl) adipate in corn oil by gavage (NTP, 1982). Rats were administered doses of 80, 160, 310, 630, 1250, 2500, 5000, 10000, or 20000 mg/kg bw and mice received doses of 1250, 2500, 5000, 10000, or 20000 mg/kg bw. All surviving animals were killed after 14 days. The estimated LD50 values were 45000 mg/kg bw for male rats and 24600 mg/kg bw for female rats. The estimated LD50 value were 15000 mg/kg bw for male mice and 24600 mg/kg bw for female mice.

In summary, the oral LD50 value of Bis(2-ethylhexyl) adipate was 24600 mg/kg bw.

 

CAS 16958-92-2

The acute toxicity via the oral route of Bis(tridecyl) adipate has been investigated in rats in two studies.

The acute oral toxicity of Bis(tridecyl) adipate was investigated in Wistar rats according to OECD guideline 401 (Moreno, 1978). Groups of 5 Wistar rats per sex received the test substance via gavage at a limit dose of 15000 mg/kg bw. No mortalities were observed within the 14-day observation period. Diarrhoea was noted in all animals on the day of treatment and thereafter in 1 male and 1 female on day 1, in two males from day 2 until day 4 and in 1 male on day 13 and day 14, respectively. Other clinical signs during the 14-day observation period included lethargy, flaccidity, oily bodies, ptosis and chromorhinorrhoea. Based on the results of the study, the oral LD50 value was greater than 15000 mg/kg bw for male and female Wistar rats.

In a further acute oral toxicity study similar to OECD guideline 401, but reported in less detail, the test substance was administered to 5 male and 5 female Sherman-Wistar rats at a limit dose of 16000 mg/kg bw via oral gavage (Moldovan, 1973). No mortalities were observed up to the end of the 14-day observation period. No data on clinical signs, changes in body weights and gross pathology findings were reported. Based on these results, the oral LD50 value for male Wistar rats was greater than 16000 mg/kg bw.

Based on these results, the oral LD50 value of Bis(tridecyl) adipate was greater than 15000 mg/kg bw.

 

CAS 85117-94-8

The acute oral toxicity of Bis(2-octyldodecyl) adipate (CAS 85117-94-8) was investigated in a study similar to OECD guideline 401 (Dufour, 1994).

The test substance was administered to 5 female mice at a limit dose of 2000 mg/kg bw via oral gavage. No mortalities and no clinical signs of toxicity were noted up to the end of the 6-day observation period. The animals showed the expected body weight gain during the study.

Based on these results, the oral LD50 value of Bis(2-octyldodecyl) adipate for female NMRI mice was greater than 2000 mg/kg bw.

 

Diester of Azelaic acid

CAS 103-24-2

The acute toxicity via the oral route of Bis(2-ethylhexyl) azelate (technical product of CAS 103-24-2, purity 77.2%) has been investigated in rats in two studies.

In an acute oral toxicity study according to OECD guideline 401 and GLP, 5 male and 5 female Crj:CD(SD)IGS rats were administered Bis(2-ethylhexyl) azelate diluted in corn oil at a limit dose of 2000 mg/kg bw via gavage (Shirota, 2003). A similar constituted group of animals received the vehicle and served as control. No mortality occurred up to the end of the 14-day observation period. Clinical signs were restricted to soft faeces in control groups of both sexes 1 to 6 h after administration. No clinical signs were evident in male and female rats treated with the test substance. The body weights were not affected by treatment and gross pathology did not reveal any abnormal findings in treated animals. Under the conditions of this experiment, the oral LD50 value for male and female Crj:CD(SD)IGS rats was greater than 2000 mg/kg bw.

In a further acute oral toxicity study in 5 male Carworth-Wistar rats, an LD50 value of 8.72 mL/kg bw, corresponding to 7979 mg/kg bw/day based on a density of 0.915 g/mL, was derived after application of unknown dose levels of the test substance (Smyth et al., 1962).

In summary, the oral LD50 value of Bis(2-ethylhexyl) azelate was greater than 2000 mg/kg bw.

 

Diester of Sebacic acid

CAS 7491-02-3

The acute toxicity via the oral route of Diisopropyl sebacate (CAS 7491-02-3) has been investigated in rats and mice in two studies.

An acute oral toxicity study with Diisopropyl sebacate was performed with rats similar to OECD guideline 401 (Wallace, 1976). Groups of 5 animals per sex were gavaged with the undiluted test substance at a volume of 5 mL/kg bw, which was equivalent to a limit dose of 4685 mg/kg bw as calculated from a density of 0.937 g/mL. No mortalities were observed up to the end of the 14-day observation period. Clinical signs were prevalent within the first 96 h and comprised slight diarrhoea as well as wet and oily coat. No effects on eating habits and behaviour were noted during the study. Based on these results, the oral LD50 value for male and female rats was considered to be greater than 4685 mg/kg bw.

In a further acute oral toxicity study similar to OECD guideline 401, the test substance was administered to 5 female NMRI mice at a limit dose of 2000 mg/kg bw (Dufour, 1994). No mortalities and no clinical signs of toxicity were observed up to the end of the 6-day observation period. The body weight gain was within the normal range of animals of this strain. Based on these results, the oral LD50 value for female NMRI mice was greater than 2000 mg/kg bw.

In summary, the oral LD50 value of Diisopropyl sebacate was greater than 4685 mg/kg bw.

 

CAS 109-43-3

The acute toxicity via the oral route of Dibutyl sebacate (CAS 109-43-3) has been investigated in rats and mice in a total of four studies.

The acute oral toxicity of Dibutyl sebacate in rats was investigated in a study similar to OECD guideline 401 (Wallace, 1976). The animals were allocated to groups of 5 per sex and received the undiluted test substance via gavage at a dose volume of 5 mL/kg bw, which corresponded to a limit dose of 4700 mg/kg bw as calculated from a density of 0.94 g/mL. No mortalities were observed up to the end of the 14-day observation period. No clinical signs of toxicity were observed, except for the occurrence of unkempt coat 16-24 h after test substance administration. Based on these results, the oral LD50 value for male and female rats was greater than 4700 mg/kg bw.

In a further study on the acute oral toxicity of the test substance in rat, an oral LD50 value of 26250 mg/kg bw was derived (Astapova, 1990). The low risk for acute oral toxicity of the test substance was further supported in a study in male rats, in which all animals survived up to doses 16000 mg/kg bw (Smith, 1955). In mice, oral LD50 values of 19500 mg/kg bw to greater than 30080 mg/kg bw were reported (Astapova, 1990 and Lawrence, 1974).

In summary, the oral LD50 value of Dibutyl sebacate was greater than 4700 mg/kg bw.

 

CAS 122-62-3

The acute toxicity via the oral route of Bis(2-ethylhexyl) sebacate (CAS 122-62-3) has been investigated in rats and mice in two studies.

The acute oral toxicity of Bis(2-ethylhexyl) sebacate in rats was assessed in a study similar to OECD guideline 401 (Wallace, 1976). Five animals per sex were gavaged with the undiluted test substance at a volume of 5 mL/kg bw, which was equivalent to a limit dose of 4560 mg/kg bw as calculated from a density of 0.912 g/mL. No mortalities occurred up to the end of the 14-day observation period. Clinical signs of slight diarrhoea as well as wet and oily coat prevailed during the first 96 h after test substance administration. Eating habits and behaviour patterns remained unchanged during the observation period. Based on these result, the oral LD50 value for male and female rats was assumed to be greater than 4560 mg/kg bw.

In a further acute oral toxicity study similar to OECD guideline 401, the test substance was administered via gavage to 5 female NMRI mice at a limit dose of 2000 mg/kg bw (Dufour, 1994). No mortalities and no clinical signs of toxicity as well as no behavioural abnormalities were noted up to the end of the 6-day observation period. Body weight gain appeared normal during the study. Based on these results, the oral LD50 value for female NMRI mice was greater than 2000 mg/kg bw.

In summary, the oral LD50 value of Bis(2-ethylhexyl) sebacate was greater than 4560 mg/kg bw.

 

CAS 69275-01-0

In a GLP-compliant study according to EU Method B.1 and similar to OECD guideline 401, the acute oral toxicity of Bis(2-octyldodecyl) sebacate was studied in male and female Wistar rats (Potokar, 1986). The animals received the test substance in arachis oil at a limit dose of 5000 mg/kg bw and were observed for a period of 14 days. During the whole study, no mortalities were reported. Clinical signs included the incidence of piloerection 0.5 to 6 h post-application in all animals. Body weight gains for the animals were in the normal range over the whole study period, except for 1 female which showed a loss in body weight on Day 14. Necropsy and histopathological examination revealed no substance-related findings in any of the treated animals.

Under the conditions of this study, the oral LD50 value of Bis(2-octyldodecyl) sebacate was greater than 5000 mg/kg bw.

Acute inhalation toxicity

 

Diester of Adipic acid

CAS 105-99-7

Acute inhalation studies (inhalation risk tests) in rats and mice are available, in which rats and mice were exposed to saturated vapour of Dibutyl adipate (CAS 105-99-7) at an analytical concentration of 0.017 mg/L in air for a period of 2 h for mice or 4 h for rats (Astapova, 1990). In both species, no mortalities were observed during the study period. Adverse findings in the animals involved failure of redox processes, liver and kidney failure as well as changes in haematological and immunological parameters. However, the study was not reliable with regard to risk assessment, since the vapour concentration of the test substance was not sufficiently high and the test method did not fulfil today's standards.

 

CAS 110-33-8

The acute inhalation toxicity of Dihexyl adipate was investigated in an inhalation risk test in male rats (Birch, 1972). Due to the low volatility of the test substance, no vaporisation of the test material was possible. Thus, the study was not adequate for the assessment of acute inhalation toxicity of the test substance.

 

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 toxicity via the inhalation route of Bis(tridecyl) adipate (CAS 16958-92-2) has been investigated in rats in two studies.

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.

A further study was performed to investigate the acute inhalation toxicity of the test substance in rats (Anonymous, 1978). Five animals per sex were exposed to the test substance at a nominal concentration of 20 mg/mL (20000 mg/m³) in air for 1 h. No mortalities, no clinical signs of toxicity and no effects on body weights were noted during the 14-day observation period. At gross pathology no substance-related findings were observed. Therefore, the LC50 value for male and female rats was considered to be greater than 20 mg/L.

In summary, the LC50 value of Bis(tridecyl) adipate was greater than 3.2 mg/L air.

 

Diester of Azelaic acid

CAS 103-24-2

The acute inhalation toxicity of bis(2-ethylhexyl) azelate was investigated in a study in male and female albino rats in an inhalation risk test. Rats received a concentrated vapour/air mixture of the test substance for a period up to 8 h (Smyth et al., 1962). No mortalities occurred during a 14-day observation period. However, the study was not reliable with regard to risk assessment, since the vapour concentration of the test substance was not determined and the test method did not fulfil today's standards.

 

Diester of Sebacic acid

CAS 109-43-3

Studies investigating the acute inhalation toxicity of Dibutyl sebacate (CAS 109-43-3) are available, in which rodents were exposed 2 h (mice) or 4 h (rats) to a saturated atmosphere of the test substance, corresponding to a concentration of 0.0054 mg/L (Astapova, 1990). Abnormal findings in the animals involved impaired metabolism in tissue, failure in liver function, reduced reactivity and dystrophic processes in organs. Since no mortalities were observed during the study, an LC50 value greater than 0.0054 mg/L was derived in rats and mice. However, this study was not adequate for risk assessment, since the vapour concentration of the test substance was not sufficiently high and the test method did not fulfil today's standards.

 

Acute dermal toxicity

Diester of Adipic acid

CAS 105-99-7

In an acute dermal toxicity study, Dibutyl adipate (CAS 105-99-7) was investigated in 6 rabbits at several doses differing by a multiple of 10 (Smyth et al., 1951). The undiluted test substance was applied to the clipped skin of the trunk of the animals for 4 days under occlusive conditions.

The dermal LD50 of Dibutyl adipate was determined graphically and assumed to be 20 mL/kg bw, which corresponded to a dose of 19220 mg/kg bw based on a density of 0.96 g/mL.

 

CAS 110-33-8

An acute dermal toxicity of Dihexyl adipate (CAS 110-33-8) was performed similar to OECD guideline 402 in male and female New Zealand White rabbits (Birch, 1972). One animal was treated with the test substance at a dose level of 3160 and 5010 mg/kg bw, respectively. Two further animals were administered the test substance at a dose level of 7940 mg/kg bw. Application to the clipped skin was performed under occlusive conditions for a period of 24 h. No mortality occurred during the 14-day observation period. Clinical signs involved reduced appetite and decreased activity 2 to 4 days after test substance application. Body weight evolution appeared normal in animals treated with 3160 and 5010 mg/kg bw, whereas a slight reduction in body weight was observed in the animals treated with 7940 mg/kg bw. At necropsy, no macroscopic findings were observed in the viscera of any animal.

Based on these results, a dermal LD50 value of Dihexyl adipate greater than 7940 mg/kg bw was derived.

 

CAS 16958-92-2

The acute toxicity via the dermal route of Bis(tridecyl) adipate (CAS 16958-92-2) has been investigated in rabbits in two studies.

The acute dermal toxicity of Bis(tridecyl) adipate was investigated in New Zealand White rabbits at a limit dose of 5000 mg/kg bw according to the Federal Hazardous Substances Act Regulations (16 CFR 1500.40) (Moreno, 1978). The test substance at a limit dose of 5000 mg/kg bw was applied to the intact and abraded skin of 5 animals, respectively, under semi-occlusive conditions for a period of 24 h. No mortalities and no effects on the mean body weights were observed up to the end of the study. Diarrhoea occurred in 2/5 animals with intact skin and 2/5 animals with abraded skin during the 14-day observation period. A bloated abdomen was observed in a single animal (intact skin) on Day 13 and 14 of the study. Further clinical signs included emaciation in 2 animals (abraded skin) as well as lethargy in one of these animals. After exposure, the test substance was removed and skin irritation was assessed according to the Draize scoring system. Erythema (grade 1 or 2) was found in 9/10 animals, whereas edema (grade 1 or 2) was only observed in 3 animals. Based on these results, the dermal LD50 value for rabbits was found to be greater than 5000 mg/kg bw.

In a further acute dermal toxicity according to the Federal Hazardous Substances Act Regulations (16 CFR 1500.40), the abraded or intact skin of each 3 rabbits was exposed to the test substance at a limit dose of 2000 mg/kg bw for 24 h under semi-occlusive conditions (Moldovan, 1973). After exposure, residual test substance was removed and animals were observed for 14 days. No treatment-related mortalities occurred during the study period. Signs of systemic toxicity, effects on body weight and the results of gross pathology were not reported in the study. Under the conditions of this experiment, the dermal LD50 value for rabbits was greater than 2000 mg/kg bw.

In summary, the dermal LD50 value of Bis(tridecyl) adipate was greater than 5000 mg/kg bw.

 

Diester of Azelaic acid

CAS 103-24-2

The acute dermal toxicity of Bis(2-ethylhexyl) azelate was investigated in four male albino rabbits, which were treated with the test substance at dose volumes up to 20 mL/kg bw (Smyth et al., 1962). The test substance was applied onto the clipped skin of the entire trunk for 24 h under occlusive conditions. The animals were observed for a period of 14-day after test substance application. Clinical signs, mortality, body weight and gross pathology were not reported in the study. The LD50 value was calculated by the method of Thompson (Thompson, 1947) using the tables of Weil (Weil, 1952).

Based on this calculation, the dermal LD50 value of Bis(2-ethylhexyl) azelate was determined to be 20 mL/kg bw, which corresponded to a dose of 18300 mg/kg bw (based on a test substance density of 0.915 g/mL).

 

Diester of Sebacic acid

CAS 69275-01-0

The acute dermal toxicity of Bis(2-octyldodecyl) sebacate (CAS 69275-01-0) was tested in a GLP-conform study according to EU Method B.3 and similar to OECD guideline 402 (Potokar, 1986). The shaved dorsal skin of 5 Wistar rats per sex was exposed to the undiluted test substance at a limit dose of 2000 mg/kg bw for 24 h under occlusive 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. Body weight gains were not affected by treatment with the test substance in male and female animals. Necropsy and histopathological examination revealed no substance-related findings.

Based on these results, the dermal LD50 value of Di-(2-octyl-dodecyl) sebacate was greater than 2000 mg/kg bw.

 

Conclusion for acute toxicity

In summary, 23 studies are available studying the acute oral toxicity of PFAE linear category members resulting in oral LD50 values greater than 2000 mg/kg bw. For acute inhalation toxicity, two studies are available within the PFAE linear category. 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 from five category members consistently showed no effects at the limit dose of 2000 mg/kg bw.

Thus, the available data indicate a very low level of acute toxicity for the category members and thus no hazard for acute oral, inhalation and dermal toxicity was identified.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

 

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, 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". Since the group concept is applied to the members of the PFAE linear Category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the group concept, all available data on acute 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.