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Diss Factsheets

Administrative data

Description of key information

Repeated toxicity testing was considered unnecessary since this substance undergoes immediate disintegration and there are sufficient data on cleavage product for the most relevant exposure route. The intrinsic properties of this substance after repeated administration are related to the main degradation product 2-ethylhexanol.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-guideline study. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 42-43 days
- Weight at study initiation: 105-114 g (males); 86-97 g (females)
- Fasting period before study: no data
- Housing: singly in stainless steel cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Doses were prepared daily by dispersing 2EH in an aqueous solution of Cremophor EL (5 µg/100 ml) by ultra high speed sonication for 1 min.
Homogeneity was maintained by magnetic stirring throughout dosing.


VEHICLE
- Justification for use and choice of vehicle (if other than water): a surfactant (Cremophor) was used to facilitate mixing 2-EH with water
- Concentration in vehicle: 5 µg/100 ml
- Amount of vehicle (if gavage): dose volume was 10 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations and homogeneity were checked by gas chromatographic analysis of samples from each dose level at the start of the preliminary 11 -day studies and periodically in 13-week studies.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5/week
Remarks:
Doses / Concentrations:
0, 25, 125, 250, 500mg/kg bw /day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of preliminary 11-day studies
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: determination of peroxisome prolieferation (3 animals per dose level; Table [4])
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): random
Positive control:
not required
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected twice daily for morbidity or mortality, or once daily on nontreatment days. Clinical observations were
made daily.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at start and thereafter at weekly intervals


BODY WEIGHT: Yes
- Time schedule for examinations: at start and thereafter at weekly intervals


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): n.a.


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:



HAEMATOLOGY: Yes
- Time schedule for collection of blood: on study days 29 and 84.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: not specified
- Parameters examined: leucocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular
hemoglobin, mean corpuscular hemoglobin concentration, platelets and differential leucocytes, and reticulocytes


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on study days 29 and 84.
- Animals fasted: No data
- How many animals: not specified
- Parameters checked in table [1] were examined.


URINALYSIS: No
- Time schedule for collection of urine: n.a.
- Metabolism cages used for collection of urine: No
- Animals fasted: No data



NEUROBEHAVIOURAL EXAMINATION: No data



OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Adrenals, brains, kidneys, livers, stomachs, testes, and ovaries from all animals were weighed, and with other
organs and tissues listed in U.S. EPA Health Effects Guidelines (1987b) fixed in 4% formalin.
HISTOPATHOLOGY: Yes. All tissues from high dose and control animals were stained with hematoxylin—eosin and examined microscopically.
Lungs, livers (including gallbladders in mice), spleens, kidneys, stomachs, sternums, femurs, and femur bone marrows were examined microscopically at intermediate dose levels.
Skin, eyes, female mammary glands, thigh musculatures, and extraorbital lacrymatory glands were not examined in the absence of signs of toxicity.
Livers were also stained with oil red for lipid content and examined microscopically.
Other examinations:
Hepatic peroxisome proliferation: livers were removed at termination and weighed, and cyanide-insensitive pCoA
activities (Lazarow, 1981) and protein concentrations (Lowry et al, 1951) were determined (week 13; ancillary group; 3 animals per dose level)
Statistics:
Means and standard deviations were calculated for body weights, food and water consumption, clinical pathology results, and organ weights.
Values for test groups were compared with controls in the main study by ANOVA followed by Dunnett's test (Dunnett, 1955, 1964)
and in ancillary studies by ANOVA followed by Student's t test (Winer, 1971).
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no mortalities or clinical findings differing from controls at any treatment level.

BODY WEIGHT AND WEIGHT GAIN
There was decreased weight gain in male and female rats at 500 mg/kg, starting at Week 4 in males and Week 11 in females,
amounting to weight losses of 7% in males and 6% in females at termination (both p<0.01).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
n.a.

FOOD EFFICIENCY
n.a.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
n.a.

OPHTHALMOSCOPIC EXAMINATION
n.a.

HAEMATOLOGY
There was a 25% increase in reticulocyte numbers in male and female rats at 500 mg/kg in Week 13.

CLINICAL CHEMISTRY
Differences from controls rats were seen mostly at 84 days (data not shown).
Males at 500 mg/kg/day: 13% decreases in total protein and albumin concentrations.
Females at 250 mg/kg/day: 30 % decrease in serum ALT activities
Females at 500 mg/kg/day: 36% decreases in serum ALT activities;
16% decrease in serum cholesterol concentration

URINALYSIS
n.a.

NEUROBEHAVIOUR
n.a.

ORGAN WEIGHTS
Relative organ weights: significant differences from control rats were moderate and limited to the brain, kidneys, liver, stomach, and testes at 250 and 500 mg/kg. Organ weights were increased in both male and female rats (cf. table).


Table: Relative organ weights (a) in rats at termination of the 13-Week oral gavage rat study (b)

Males [Dose (mg/kg bw/day)] Females [Dose (mg/kg bw/day)]
0 250 500 0 250 500
--------------------------------------------------------------------
Brain 0.68 0.70 0.72** 1.07 1.1 1.1
Kidneys 0.69 0.75** 0.81** 0.77 0.81* 0.82**
Liver 2.77 2.98** 3.57** 2.67 2.88** 3.07**
Stomach 0.57 0.58 0.63** 0.71 0.75* 0.82**
Testes/Ovaries 1.11 1.16 1.17* 0.041 0.037* 0.039
--------------------------------------------------------------------------------------
values are mean organ/body weight ratios
there were no significant differences from controls in rats at 25 and 125 mg/kg bw/day
* p<0.05; ** p<0.01



GROSS PATHOLOGY
Gross lesions differing from controls in both species were seen at 500 mg/kg bw/day only. In rats 2/10 males and 4/10 females exhibited single
or multiple slightly elevated foci in the forestomach.

HISTOPATHOLOGY: NON-NEOPLASTIC
Dose-related findings in rats (data not shown) were limited to the forestomach and liver at 500 mg/kg.
Forestomach: there was a generalized acanthosis of the forestomach mucosa in 1/10 males with ballooning degeneration of the epithelial wall and acanthosis of the forestomach mucosa in 2/10 males and 5/10 females.
Liver: there was a moderate decrease in hepatic peripheral lobular fatty infiltration in 4/10 males and 2/10 females and adrenal ß-cell hyperplasia in 3/10 female rats.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
n.a.

HISTORICAL CONTROL DATA (if applicable)
n.a.

OTHER FINDINGS
Peroxisome proliferation:
In Week 13, increases in pCoA activity were 6.5-fold in male rats (p<0.001) and 3.4-fold in females (p<0.05) at 500 mg/kg . Reportedly, decreases in body weight gain were similar to those in the main study animals.

--------------------------------------------------------------------------------------
Dose (mg/kg bw/day)
0 25 125 250 500
--------------------------------------------------------------------
Mean PCoA activity (nanomol/min/mg of protein)
Males 3.38 4.49 5.21 6.24 22.0*
Females 2.95 4.54 5.01 6.6 9.92**
--------------------------------------------------------------------------------------
*p<0.001 and **p<0.05 by ANOVA/Students ttest
Dose descriptor:
NOEL
Effect level:
125 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: absence of treatment-related effects on target organs
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: absence of treatment-related systemic effects on target organs
Critical effects observed:
not specified
 Table: Relative organ weights (a) in rats at termination of the 13-Week oral gavage rat study (b)
    

        
Males [Dose (mg/kg bw/day)]

        
Females [Dose (mg/kg bw/day)]

      

      

        

        
0

        
250

        
500

        
0

        
250

        
500

      

      

        
Brain

        
0.68

        
0.70

        
0.72**

        
1.07

        
1.1

        
1.1

      

      

        
Kidneys

        
0.69

        
0.75**

        
0.81**

        
0.77

        
0.81*

        
0.82**

      

      

        
Liver 

        
2.77

        
2.98**

        
3.57**

        
2.67

        
2.88**

        
3.07**

      

      

        
Stomach 

        
0.57

        
0.58

        
0.63**

        
0.71

        
0.75*

        
0.82**

      

      

        
Testes/Ovaries

        
1.11

        
1.16

        
1.17*

        
0.041

        
0.037*

        
0.039

      

    

    


    
(a) values are mean organ/body weight ratios


    
(b) there were no significant differences from controls in rats at 25 and 125 mg/kg bw/day


    
* p0.05; ** p0.01     
    
    
    

Read-across justifications and data matrices are presented in IUCLID section 13.








 
  
  

Read-across justifications and data matrices are presented in IUCLID section 13.








Conclusions:
Valid subchronic oral gavage rat study. 
(1)  2-EH was moderately toxic at all dose levels up to and including 500 mg/kg bw/day; based 
- on lack of mortality and clinical signs; 
- moderately reduced body weights in groups at 500 mg/kg bw/day; 
- minor effects of low  relevance on clinicochemcial and hematological parameters
(2) Target organs were the liver, forestomach, and the kidneys; based on significantly increased relative organ weights at termination
(3) Local irritating effects prevailed; systemic effects were low; based on
- inflammation in the forestomach, 
- and lack of treatment-related findings in other organs, including testes
(4)  2-EH induces peroxisome proliferation in rats; observed at 500 mg/kg bw/day in rats of both sexes
(5)  The NOEL (no observable effect level) was 125 mg/kg bw/day. A NOAEL (no observable adverse effect level) was not derived, but may be estimated to be 250 mg/kg bw/day, based on the above
Executive summary:

      The subchronic effects of 2 -EH were studied in a 90-day oral gavage 
      study using male and female rats (10 animals per sex and dose). The test 
      dose levels were 0, 25, 125, 250, and 500 mg/kg bw/day, based on the 
      results of preliminary 11-day studies.
    


    

      Key results include:
    


    
    
      
  • 
        Mortalities or clinical findings were not different from controls
      
    • 

      
  • 
        Food consumption was comparable to controls
      
    • 

      
  • 
        Body weight gain was reduced in the high dose groups, resulting in 
        decreased terminal weights in males (-7%) and females (-6%); (both 
        p<0.01)
      
    • 

      
  • 
        Clinicochemical changes were seen in high dose groups (males:total 
        protein and albumin -13%; females: serum cholesterol -16%); biological 
        significance is unclear
      
    • 

      
  • 
        Hematology: reticulocytes were increased (25%) in high dose males and 
        females
      
    • 

      
  • 
        Organ weights: target organs were liver, forestomach, and kidneys; 
        based on increased relative weights (p<0.01) in male and female groups 
        at 250 and 500 mg/kg bw/day. No weight changes were noted at 25 and 
        125 mg/kg bw/day.
      
    • 

      
  • 
        Reproductive organs: relative weight of testes was increased, and that 
        of ovaries decreased, at 250 and 500 mg/kg bw/day.
      
    • 

      
  • 
        Histopathology revealed changes only in high dose animals. 
        Predominantly inflammatory changes in the forestomach which are 
        attributable to the irritation properties of 2 -EH
      
    • 

      
  • 
        2 -EH at 500 mg/kg bw/day caused peroxisome proliferation, as 
        evidenced by a statistically significant increase of the hepatic 
        cyanide-insensitive palmitoyl coenzyme A activity in male (p<0.001) 
        and female (p<0.05) rats in Week 13.
      
    • 

      
  • 
        The subchronic NOEL was 125 mg/kg bw/day in male and female rats. The 
        estimated NOAEL is 250 mg/kg bw/day.
      
    • 

    
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP guideline study.

Read-across justification:

The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance.

Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance.

The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol.

As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.
 
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at delivery:  7 weeks
- Weight at study initiation: males 238 (+/- 2.3) g; females 238 (170 +/- 2.2) g
- Housing: singly in wire cages
- Diet: e.g. ad libitum 
- Water: ad libitum
- Acclimation period: at least 5 days acclimation to the inhalation chamber

					
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark

					
IN-LIFE DATES: From:      day1  To: day 93 
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: whole-body inhalation chamber (glas/steel construction, volumes approx. 1.1 m³)
- Method of holding animals in test chamber: rats were kept individually in wire cages
- Test atmosphere generation: the test substance was delivered to heated evaporators by mean of metering pumps. The warmed air was mixed with compressed air and delivered to teh inhalation chamber.
- Source and rate of air: compressed air; variable rate
- Temperature, humidity, pressure in air chamber: 23.1 to 23.8°C; positive pressure 10.1 Pascal (ciontrol groups), negative pressure -10.2 Pascal (treated groups); 41.8 to 46.2% relative humidity
- Air flow rate: not reported in publication
- Air change rate: not reported in publication
- Treatment of exhaust air: not reported in publication

					
TEST ATMOSPHERE
- Brief description of analytical method used: samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
- Samples taken from breathing zone: yes

					
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days/week (total of 65 exposures)
Remarks:
Doses / Concentrations:
0, 15, 40 and 120 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
15 (SD 0.67), 39.9 (SD 1.33), 120 (SD 4.8) ppm
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: none
Positive control:
not required
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:  
- Time schedule: daily

					
DETAILED CLINICAL OBSERVATIONS:  yes
- Time schedule: pre-treatment and at termination

					
BODY WEIGHT: Yes
- Time schedule for examinations: weekly

					
FOOD CONSUMPTION: 
- Food consumption: no data contained in the publication; not required

					
FOOD EFFICIENCY:
- Body weight gain: yes, but no data contained in the publication; not required

					
WATER CONSUMPTION:  no data contained in the publication; not required

					
OPHTHALMOSCOPIC EXAMINATION:  yes
- Time schedule for examinations: pre-treatment and at termination
- Dose groups that were examined: all animals

					
HAEMATOLOGY:  Yes 
- Time schedule for collection of blood: at termination, day 94 of the study
- Anaesthetic used for blood collection:   No data
- Animals fasted: No data
- How many animals: all animals
- Parameters: white and red blood cells, hemoglobin, hematocrit, mean corpuscular volume. mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, differential blood count

					
CLINICAL CHEMISTRY:  Yes 
- Time schedule for collection of blood: at termination, day 94 of the study
- Animals fasted:  No data
- How many animals: No data
- Parameters: sodium, potassium, chloride, glucose, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, clotting time

					
URINALYSIS:  No data

		

					
OTHER:
- cyanide-insensitive palmitoyl-CoA oxidation in liver homogenates
- gross pathology of all animals at termination; determination of organ weights (lungs, liver, kidneys, adrenal glands, and testes)
- histopathology of organs/tissues required by guidelines, and all gross lesions
Sacrifice and pathology:
GROSS PATHOLOGY:  Yes
HISTOPATHOLOGY:  Yes 
Statistics:
- Mean values +/- standard deviation: body weight, body weight gain, hematological and clinical biochemistry parameters, absolute and relative organ weights.
Dunnett's test: comparison of exposure groups with the control group.
Analysis of variance subsequent to Dunnett's test:  body weight, body weight gain, hematological and clinical biochemistry parameters
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
1) Analysis of the daily inhalation chamber concentrations revealed that the values obtained closely fitted with the desired nominal level
Read-across justifications and data matrices are presented in IUCLID section 13.


2) There were no effects regarding the issues below noted at any dose level:

CLINICAL SIGNS AND MORTALITY

					
BODY WEIGHT AND WEIGHT GAIN

					
FOOD CONSUMPTION

					
FOOD EFFICIENCY

					
WATER CONSUMPTION

					
OPHTHALMOSCOPIC EXAMINATION

					
HAEMATOLOGY

					
CLINICAL CHEMISTRY

					
URINALYSIS

					
NEUROBEHAVIOUR

					
ORGAN WEIGHTS

					
GROSS PATHOLOGY

					
HISTOPATHOLOGY: NON-NEOPLASTIC

					
HISTOPATHOLOGY: NEOPLASTIC (if applicable)

					
Dose descriptor:
NOAEC
Effect level:
120  ppm (analytical)
Sex:
male/female
Basis for effect level:
other: overall effects

Dose descriptor:
NOAEC
Effect level:
638.4  mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: overall effects

Critical effects observed:
not specified
    Read-across justifications and data matrices are presented in IUCLID section 13.
    
    
    

Read-across justifications and data matrices are presented in IUCLID section 13.









  
    
  
  
  

Read-across justifications and data matrices are presented in IUCLID section 13.












 
    
  




Under the conditions of the test no treatment-related toxic
effects were found in male and female Wistar rats which were
exposed to 2-ethylhexanol vapor up to 120 ppm. T












  
  





The concentration of 120 ppm corresponds to the calculated 




















saturated vapor concentration at 20°C.














Executive summary:

      No treatment-related effects were noted in a OECD Guideline 413 study 
      (Subchronic Inhalation Toxicity: 90-Day) conducted under GLP conditions 
      and using male and female Wistar rats (10 rats per sex and dose). 
      Exposure levels were 0, 15, 40, and 120 ppm (120 ppm is equivalent to 
      saturation at 20°C). As there were no effects compared with the control 
      groups in either sex on body weight or body weight gain, clinical signs 
      of toxicity and mortality, hematological and clinical biochemistry 
      parameters, ophthalmological parameters, absolute or relative organ 
      weights including testes, or cyanide-insensitive palmitoyl-CoA oxidation 
      as a parameter for hepatic peroxisome proliferation, the NOAEC was 120 
      ppm, ie. 638.4 mg/m³ (Klimisch, 1998).
    
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
638 mg/m³
Study duration:
subchronic
Species:
rat
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP guideline study.

Read-across justification:

The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance.

Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance.

The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol.

As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.
 
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at delivery:  7 weeks
- Weight at study initiation: males 238 (+/- 2.3) g; females 238 (170 +/- 2.2) g
- Housing: singly in wire cages
- Diet: e.g. ad libitum 
- Water: ad libitum
- Acclimation period: at least 5 days acclimation to the inhalation chamber

					
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark

					
IN-LIFE DATES: From:      day1  To: day 93 
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: whole-body inhalation chamber (glas/steel construction, volumes approx. 1.1 m³)
- Method of holding animals in test chamber: rats were kept individually in wire cages
- Test atmosphere generation: the test substance was delivered to heated evaporators by mean of metering pumps. The warmed air was mixed with compressed air and delivered to teh inhalation chamber.
- Source and rate of air: compressed air; variable rate
- Temperature, humidity, pressure in air chamber: 23.1 to 23.8°C; positive pressure 10.1 Pascal (ciontrol groups), negative pressure -10.2 Pascal (treated groups); 41.8 to 46.2% relative humidity
- Air flow rate: not reported in publication
- Air change rate: not reported in publication
- Treatment of exhaust air: not reported in publication

					
TEST ATMOSPHERE
- Brief description of analytical method used: samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
- Samples taken from breathing zone: yes

					
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were analyzed at intervals of about 15 min by gas chromatography (GC-FID; column 1mx22 mm with 10% Triton x 305 on Supelcoport, 102/120 mesh; oven temperature 120 °C; c15-paraffin as internal standard)
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days/week (total of 65 exposures)
Remarks:
Doses / Concentrations:
0, 15, 40 and 120 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
15 (SD 0.67), 39.9 (SD 1.33), 120 (SD 4.8) ppm
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: none
Positive control:
not required
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:  
- Time schedule: daily

					
DETAILED CLINICAL OBSERVATIONS:  yes
- Time schedule: pre-treatment and at termination

					
BODY WEIGHT: Yes
- Time schedule for examinations: weekly

					
FOOD CONSUMPTION: 
- Food consumption: no data contained in the publication; not required

					
FOOD EFFICIENCY:
- Body weight gain: yes, but no data contained in the publication; not required

					
WATER CONSUMPTION:  no data contained in the publication; not required

					
OPHTHALMOSCOPIC EXAMINATION:  yes
- Time schedule for examinations: pre-treatment and at termination
- Dose groups that were examined: all animals

					
HAEMATOLOGY:  Yes 
- Time schedule for collection of blood: at termination, day 94 of the study
- Anaesthetic used for blood collection:   No data
- Animals fasted: No data
- How many animals: all animals
- Parameters: white and red blood cells, hemoglobin, hematocrit, mean corpuscular volume. mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, differential blood count

					
CLINICAL CHEMISTRY:  Yes 
- Time schedule for collection of blood: at termination, day 94 of the study
- Animals fasted:  No data
- How many animals: No data
- Parameters: sodium, potassium, chloride, glucose, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, clotting time

					
URINALYSIS:  No data

		

					
OTHER:
- cyanide-insensitive palmitoyl-CoA oxidation in liver homogenates
- gross pathology of all animals at termination; determination of organ weights (lungs, liver, kidneys, adrenal glands, and testes)
- histopathology of organs/tissues required by guidelines, and all gross lesions
Sacrifice and pathology:
GROSS PATHOLOGY:  Yes
HISTOPATHOLOGY:  Yes 
Statistics:
- Mean values +/- standard deviation: body weight, body weight gain, hematological and clinical biochemistry parameters, absolute and relative organ weights.
Dunnett's test: comparison of exposure groups with the control group.
Analysis of variance subsequent to Dunnett's test:  body weight, body weight gain, hematological and clinical biochemistry parameters
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
1) Analysis of the daily inhalation chamber concentrations revealed that the values obtained closely fitted with the desired nominal level
Read-across justifications and data matrices are presented in IUCLID section 13.


2) There were no effects regarding the issues below noted at any dose level:

CLINICAL SIGNS AND MORTALITY

					
BODY WEIGHT AND WEIGHT GAIN

					
FOOD CONSUMPTION

					
FOOD EFFICIENCY

					
WATER CONSUMPTION

					
OPHTHALMOSCOPIC EXAMINATION

					
HAEMATOLOGY

					
CLINICAL CHEMISTRY

					
URINALYSIS

					
NEUROBEHAVIOUR

					
ORGAN WEIGHTS

					
GROSS PATHOLOGY

					
HISTOPATHOLOGY: NON-NEOPLASTIC

					
HISTOPATHOLOGY: NEOPLASTIC (if applicable)

					
Dose descriptor:
NOAEC
Effect level:
120  ppm (analytical)
Sex:
male/female
Basis for effect level:
other: overall effects

Dose descriptor:
NOAEC
Effect level:
638.4  mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: overall effects

Critical effects observed:
not specified
    Read-across justifications and data matrices are presented in IUCLID section 13.
    
    
    

Read-across justifications and data matrices are presented in IUCLID section 13.









  
    
  
  
  

Read-across justifications and data matrices are presented in IUCLID section 13.












 
    
  




Under the conditions of the test no treatment-related toxic
effects were found in male and female Wistar rats which were
exposed to 2-ethylhexanol vapor up to 120 ppm. T












  
  





The concentration of 120 ppm corresponds to the calculated 




















saturated vapor concentration at 20°C.














Executive summary:

      No treatment-related effects were noted in a OECD Guideline 413 study 
      (Subchronic Inhalation Toxicity: 90-Day) conducted under GLP conditions 
      and using male and female Wistar rats (10 rats per sex and dose). 
      Exposure levels were 0, 15, 40, and 120 ppm (120 ppm is equivalent to 
      saturation at 20°C). As there were no effects compared with the control 
      groups in either sex on body weight or body weight gain, clinical signs 
      of toxicity and mortality, hematological and clinical biochemistry 
      parameters, ophthalmological parameters, absolute or relative organ 
      weights including testes, or cyanide-insensitive palmitoyl-CoA oxidation 
      as a parameter for hepatic peroxisome proliferation, the NOAEC was 120 
      ppm, ie. 638.4 mg/m³ (Klimisch, 1998).
    
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
638 mg/m³
Study duration:
subchronic
Species:
rat
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Repeated dose toxicity: dermal - local effects
Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Additional information

      Repeated oral toxicity 
    


    

      
    


    

      The weight of evidence approach is used to determine the hazard caused 
      by repeated administration of Titanium tetrakis(2-ethylhexanolate). 
      Relevant data from the substance itself but also from the decomposition 
      products, 2-ethylhexanol (2-EH) and titanium dioxide (TiO2) was 
      assessed. Read-across data from the decomposition products is used for 
      assessment, because the target substance is hydrolytically unstable 
      having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013). 
      2-EH is the most relevant decomposition product of the target substance 
      for CSA. TiO2 exists as solid insoluble precipitate having low 
      bioavailability and possessing very low acute and long-term toxicity (US 
      EPA, 1994; WHO, 1982). Thus, it is concluded that no further assessment 
      of TiO2 is needed for repeated dose toxicity.
    


    

      
    


    

      There is only one study available for the target substance. Based on the 
      results of this study the NOAEL was concluded to be higher than 1500 
      mg/kg bw/day (actual dose received, Hood, 1960). In this not reliable 
      study six male rats received test substance 1500 mg/kg bw orally total 
      of ten doses. Treatment caused a depressed rate of weight gain, 
      transitory discomfort and changes in the kidneys. Thus this substance is 
      concluded to be practically non-toxic. However, the possible cumulative 
      effect of titanium tetrakis(2-ethylhexanolate) on the kidney needs 
      further evaluation.
    


    

      
    


    

      The subchronic effects of 2 -ethylhexanol (2 -EH), the degradation 
      product of the target substance, were evaluated in two studies using 
      mice and rats (Astill, et al., 1996a, Astill et al., 1996b). Both 
      studies were conducted according to OECD 408 guideline and under GLP.
    


    

      
    


    

      In the 90-day oral gavage study male and female rats (10 animals per sex 
      and dose) were administered at dose levels 0, 25, 125, 250, and 500 
      mg/kg bw/day. No mortalities or no clinical findings were different from 
      controls. Food consumption was comparable to controls. However, the body 
      weight gain was reduced in the high dose groups. Changes in clinical 
      chemistry were seen in high dose groups (males: total protein and 
      albumin -13 %; females: serum cholesterol -16 %). Biological 
      significance of these changes is unclear. In Hematology reticulocyte 
      counts were increased (25 %) in high dose males and females. Organ 
      weights of liver, forestomach, and kidneys were increased in male and 
      female groups at 250 and 500 mg/kg bw/day. No weight changes were noted 
      at 25 and 125 mg/kg bw/day. Relative weight of testes was increased, and 
      that of ovaries decreased, at 250 and 500 mg/kg bw/day. Histopathology 
      revealed changes only in high dose animals. Predominantly inflammatory 
      changes were seen in the forestomach which are attributable to the 
      irritation properties of 2 -ethylhexanol (2 –EH). Furthermore, 2 -EH at 
      500 mg/kg bw/day caused peroxisome proliferation, as evidenced by a 
      statistically significant increase of the hepatic cyanide-insensitive 
      palmitoyl coenzyme A activity in male (p < 0.001) and female (p < 0.05) 
      rats in Week 13. Based on the above data the subchronic NOEL is 125 
      mg/kg bw/day in male and female rats. The estimated NOAEL is 250 mg/kg 
      bw/day.
    


    

      
    


    

      In the other study by Astill et al., (1996b) the subchronic effects of 2 
      -EH were studied in a 90-day oral gavage study using male and female 
      B6C3F1 mice (10 animals per sex and dose). The test dose levels were 0, 
      25, 125, 250, and 500 mg/kg bw/day, based on the results of preliminary 
      11-day studies. No mortalities or clinical findings were different from 
      controls. Food consumption and body weight gain was comparable to 
      controls. There were no changes in clinical chemistry or hematological 
      parameters at any dose level. A dose-related weight increase of liver 
      and forestomach was seen in males and females. However, no weight change 
      of male and female reproductive organs was noted. Histopathological 
      evaluation revealed a low incidence of inflammatory changes only in high 
      dose animals which were regarded to be incidental; possibly attributable 
      to the irritation properties of 2 –EH. Based on the above data, the 
      subchronic NOEL was 125 mg/kg bw/day in male and female rats. The 
      estimated NOAEL is 250 mg/kg bw/day.
    


    

      
    


    

      Repeated inhalation toxicity 
    


    

      
    


    

      There are no studies available for titanium tetrakis(2-ethylhexanolate) 
      itself. Since the substance hydrolyses rapidly ( < 10min) when it comes 
      in contact with water or moisture (Brekelmans, M. J. C., 2013), 
      read-across data from the decomposition products is used to evaluate the 
      potential hazard caused by titanium tetrakis(2-ethylhexanolate). After 
      hydrolysis no significant reaction products other than 2-ethylhexanol 
      (2-EH) and hydrated titanium dioxide (TiO2) exist. TiO2 is the solid 
      insoluble precipitate. Therefore, inhalation is unlikely route of human 
      exposure of this decomposition product and TiO2 is not further 
      considered in CSA.
    


    

      
    


    

      There is one OECD Guideline 413 study (Subchronic Inhalation Toxicity: 
      90 -Day) for 2 -ethylhexanol (2 -EH), where no treatment related adverse 
      effects was observed. Male and female Wistar rats (10 rats per sex and 
      dose) were exposed at levels 0, 15, 40, and 120 ppm (120 ppm is 
      equivalent to saturation at 20°C). As there were no effects compared 
      with the control groups in either sex on body weight or body weight 
      gain, clinical signs of toxicity and mortality, hematological and 
      clinical biochemistry parameters, ophthalmological parameters, absolute 
      or relative organ weights including testes, or cyanide-insensitive 
      palmitoyl-CoA oxidation as a parameter for hepatic peroxisome 
      proliferation, the NOAEC was 120 ppm, i.e. 638.4 mg/m³ (Klimisch, 1998). 
      No classification is needed, since there were no adverse effects noted 
      at concentration below the threshold value to trigger classification.
    


    

      
    


    

      Based on above information, titanium tetrakis(2 -ethylhexanolate) is 
      regarded not to cause any inhalation hazard.
    


    

      
    


    

      Repeated dermal toxicity 
    


    

      
    


    

      No valid study identified for titanium tetrakis(2-ethylhexanolate). 
      Testing is not necessary since the substance undergoes immediate 
      disintegration (half-life < 10 minutes). After hydrolysis no significant 
      reaction products other than 2-ethylhexanol (2-EH) and non-hazardous 
      hydrated titanium dioxide (TiO2) exist. As skin contact in use and 
      production of the target substance is not likely and adequate RMMs are 
      in use (see sections 9&10 of CSR), dermal route is not considered 
      relevant route of exposure for the target substance.
    


    

      
    


    

      In addition, 2-EH is regarded not to cause any hazard after dermal 
      application since absorption of the substance through skin is considered 
      negligible (Deisinger, 1994b). Furthermore, there is available acute 
      dermal toxicity study conducted for 2-EH showing very low toxicity 
      (Mürmann, 1987).
    


    

      
    


    

      Thus, titanium tetrakis(2-ethylhexanolate) is regarded not to cause any 
      hazard after repeated dermal application.
    

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No reliable study available for the substance itself. Based on the read-across data from the main decomposition product as the target substance is highly reactive (hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
No study available for the substance itself. Based on the read-across data from the main decomposition product as the target substance is highly reactive (hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
No study available for the substance itself. Based on the read-across data from the main decomposition product as the target substance is highly reactive (hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).
Justification for classification or non-classification

      The intrinsic properties of titanium tetrakis(2 -ethylhexanolate) 
      are related to the main degradation product; 2 -ethylhexanol. Based on 
      the observations made after the subchronic 2 -ethylhexanol exposures in 
      rats by oral and inhalation routes there is no need for classification 
      of the substance in accordance with the criteria of CLP Regulation 
      1272/2008 and the EU directive 67/548/EEC.