Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Testing is not necessary since there is enough evidence on the effects of structurally similair degradation product, 2 -EH on fertility to conclude that tetrakis(2 -ethylhexane-1,3 -diolato)titanium is not toxic to reproduction. As the structurally similair substance hydrolyses rapidly (< 10 min) when it comes in contact with water or moisture (Brekelmans, M. J. C., 2013), intrinsic properties are related to the degradation products.

There are available subchronic toxicity studies conducted for 2-EH by Astill, (1996a, 1996b) revealing no effects on reproductive organs in adult animals up to the concentration of 125 mg/kg bw/day. In the developmental toxicity study by Nelson (1989) the reproduction parameters were unchanged when rats were exposed during days 0 -19 of gestation to 2 -EH at 850 mg/m³, the maximum achievable concentration without aerosol formation.

Most of the available studies suggest that TiO2 is biologically inert. TiO2 is insoluble in water and most ingested titanium is eliminated unabsorbed (Friberg, L. et al. 1986). Thus, TiO2 is not expected to cause any hazard on sexual function and fertility.


Effects on developmental toxicity

Description of key information

The weight of evidence on structurally similair substance, titanium tetrakis(2-ethylhexanolate), and studies from the structurally similair hydrolysis product, 2-ethylhexanol, indicates that doses required to cause developmental toxicity effects in animals are exceedingly high compared to doses normally used to assess the hazards of chemical substances. In an oral gavage study, 2-EH can elicit adverse effects on the reproductive system and on fertility in females at 650mg/kg bw/day, but there was no indication of teratogenicity at this dose level. In an inhalation study, no maternal toxicity, or no toxicity to reproduction or teratogenicity was seen with 2-EH following exposure at the highest achievable vapor concentration (850 mg/m3). In an inhalation study, no maternal toxicity, or no toxicity to reproduction or teratogenicity was seen with 2-EH following exposure at the highest achievable vapor concentration (850 mg/m3).

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of 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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
In accordance with REACH Annex XI, testing is not necessary since the substance undergoes immediate disintegration and there are sufficient data on cleavage products. The target substance hydrolyses rapidly (< 10 min) when it comes in contact with water or moisture. After hydrolysis no significant reaction products other than 2-ethylhexanol (2-EH) and non-hazardous hydrated titanium dioxide (TiO2) exist. Because of high reactivity of the target substance, the intrinsic properties are related to the main decomposition product, 2-EH. There is available subchronic inhalation toxicity study conducted for 2-EH to evaluate the repeated inhalation toxicity of the target substance. TiO2 is non-volatile and non-hazardous solid precipitate after hydrolysis having very low acute and long-term toxicity (US EPA, 1994; WHO, 1982). Based on above conclusions the target substance is regarded not to cause any inhalation hazard and thus no further testing is needed.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
Cited as Directive 87/302/EEC, part B, p. 24
Deviations:
yes
Remarks:
10 animals per group instead of 20
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
10 animals per group instead of 20
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: 68-85
- Weight at study initiation: 214-233
- Fasting period before study: no data
- Housing: singly, in stainless steel wire-mesh cages
- Diet: Kliba feed 343 ad libitum
- Water: ad libitum
- Acclimation period: at least 5 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 exposure:
PREPARATION OF DOSING SOLUTIONS:
Aqueous emulsions for gavage were freshly prepared every day under rapid stirring in doubly distileld water containing approx. 0.005% Cromophor EL

DIET PREPARATION
- Rate of preparation of diet (frequency): n.a
- Mixing appropriate amounts with (Type of food): n.a.
- Storage temperature of food: n.a.


VEHICLE
- Justification for use and choice of vehicle (if other than water): surfactant
- Concentration in vehicle:
- Amount of vehicle (if gavage): 0.005%
- Lot/batch no. (if required): no data
- Purity: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gas chromatography was used to verify test concentrations and stability during a 6-hr storage
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1 to 1:4
- Length of cohabitation: until successful
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
gestation day 6 through 15
Frequency of treatment:
daily
Duration of test:
20 days
No. of animals per sex per dose:
10 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: equimolar doses of 6 different alcohols including 2-EH were trested at 0, 1, 5, and 10 mmol/kg bw.
- Rationale for animal assignment (if not random): random
- Other:
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily



DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: throughout the study


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): n.a., gavage study
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): n.a., gavage study
- Time schedule for examinations:


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus and ovaries, fetuses


Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Dunnett's test: food consumption, body weight data, uterus weight before opening, placental and fetal weights, number of corpora lutea, implantations, pre- and post implantationloses, resorptions, and live and dead fetuses.
Fisher's exact test: conception rate, mortality of the dams, all fetal findings
Indices:
No data published
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
1300 mg/kg bw/day: significant toxicity (discoloration of liver and lung; pronounced clinical symptoms (nasal discharge, salivation, CNS depression); reduced food consumption, body weight loss; 6 mortalities.
650 mg/kg bw/day: slight maternal toxicity
130 mg/kg bw/day: no effect
Dose descriptor:
NOAEL
Effect level:
130 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
1300 mg/kg bw/day: increased early resorptions, high postimplantation loss; fetal body weights markedly reduced; increased incidences of skeletal malformations, variations, and retardations.
650 mg/kg bw/day: slightly decreased fetal weight; increased number of fetuses with skeletal variations and retardations
130 mg/kg bw/day: no effect
Dose descriptor:
NOAEL
Effect level:
130 mg/kg bw/day
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
650 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Read-across justifications and data matrices are presented in IUCLID section 13.    
    
    
    
    
    
    

130 mg/kg dose group:
No adverse substance-related effects on dams or fetuses.

650 mg/kg dose group:
* maternal toxic effects
- 2 dams with piloerection
* embryo/fetotoxic effects
- slightly reduced mean fetal body weights
- increased frequency of fetuses with skeletal variations
and retardations

1300 mg/kg dose group:
* maternal toxic effects
- markedly reduced food consumption during the whole
treatment period (days 6-15 p.c.)
- distinctly reduced mean body weights (day 10 -20 p.c.)
body weight loss during days 6-10 p.c. and reduced body
body weight gains during days 10-15 p.c.; markedly reduced
corrected body weight gain
- 6 animals found dead on days 9, 10 and 13 p.c.
- severe clinical sypmtoms like abdominal or lateral
position, unsteady gait and apathy
- light brown-gray discoloration of the liver in the animals
with intercurrent death; lund edema and emphysema in a
few animals, and hemometra in 1 dam which showed vaginal
hemorrage before death
- distinctly reduced mean uterus weight
* embryo/fetotoxic effects
- increased number of resorptions and consequently markedly
increased postimplantation loss
- markedly reduced mean fetal body weights
- one fetus with acaudia and atresia ani; increased
incidence of fetuses with dilated renal pelvis and/or
hydroureter higher number of fetuses with skeletal
malformations, variations and retardations.

2 -EH: maternal and developmental toxicity (publication, table 5)
Dose levels (mg/kg bw/day)
0 (water)
0 (vehicle)
130
650
1300
No. pregnant dams
9
10
10
10
9
Fetuses and litters examined
124/9
146/10
130/10
127/9
28/2
Maternal deaths
1/10(a)
6/10
Pregnant at termination
9
10
10
10
9
Clinical signs
(+)
++
Body weight(g) day 0
231.5
230.8
229.6
225.5
235.6
Body weight (g) day 20
375.0
384.2
377.4
367.1
308.9**
Uterus weight (g)
77.7
82.2
72.2
75.9
32.9**
Corpora lutea /dam
16.1
16.0
15.4
15.7
15.3
Implantation sites/dam
15.0
15.7
13.6
14.8
14.8
Dams with viable fetuses
9
10
10
9
2
Postimplantation loss (%)
8.2
7.0
5.0
4.5
54.7**
Live fetuses/dam
13.8
14.6
13.0
14.1
14.0
Resorptions (total/early/dam)
1.2/1.1
1.1/1.0
0.6/0.5
0.7/0.2
7.8**/7.8**
Fetal weight (g)
3.80
3.82
3.80
3.44**
2.86**
No. (and %) of fetuses with malformations
1 (0.8)
2 (1.4)
3 (2.3)
7 (5.5) 
5** (17.9)
No. (and %) of litters with malformations (b)
1(11)
2(20)
3(30)
4(44)
2(100)
No. (and %) of fetuses with variations (b)
46 (37)
46 (32)
41(32)
49 (39)
20 (71)**
No. (and %) of litters with variations (b)
8(89)
10(100)
9(90)
8(89)
2(100)
No. (and %) of fetuses with retardations (b)
28(23)
38(26)
31(24)
51(40)
15(54)**
No. (and %) of litters with retardations (b)
8(89)
10(100)
8(80)
9(100)
2(100)

(a) due to gavage error       (b) percentage rounded

**p0.01

2-EH: incidence (%) and type of fetal findings; selected data (publication, tabe 6)
Dose levels (mg/kg bw/day)
0 (water)
0 (vehicle)
130
650
1300
No. of fetuses and litters examined
124/9
146/10
130/10
127/9
28/2
Dilated renal pelvis
23 (6)
28 (9)
18 (8)
21 (7)
10 (2)
Hydroureter
1
3 (2)
2 (2)
1
3
Total skeletal variations
23 (7)
17 (6)
23 (8)
27 (7)
10 (2)
Total skeletal retardations
28 (8)
38 (10)
31 (8)
51 (9)
15 (2)
Conclusions:
The developmental toxicity of 2 -EH was investigated in a rat feed study for its potential for developmental toxicity. Pregnant female Wistar rats received 2-EH in the diet at concentrations of 0 (water), 0 (vehicle), 130, 650, 1300 mg/kg day gestation day 6 through 15. Following NOAELs were established: NOAEL maternal toxicity 130mg/kg/day, NOAEL toxicity to reproduction 130mg/kg/day, NOAEL teratogenicity 650mg/kg/day.
Executive summary:

The degradation product of Titanium tetrakis(2 -ethylhexanolate),2 -EH, was investigated in a OECD TG 414 study conducted under GLP, but using low rat numbers (10 instead of 20 pregnant females). This invalidates the study to some extend, but it provides weight of evidence for the developmental toxicity endpoint. Clear signs of developmental toxicity, but not teratogenicity, were seen in the absence of maternal toxicity.

Maternal toxicity was most severe at the high dose level and marginal at the intermediate dose level. At the low dose no maternal toxicity was noted. Therefore the NOAEL is 130 mg/kg/d for this endpoint under the conditions of this study.

Signs of embryo-/fetotoxicity were dose-dependently noted in dams showing signs of maternal toxicity at 650 and 1300 mg/kg/d. Therefore the NOAEL is 130 mg/kg/d for this endpoint under the conditions of this study.

Teratogenicity was noted in fetuses from the high dose dams only. Therefore the NOAEL is 650 mg/kg/d under the conditions of this study for teratogenicity.

Endpoint:
developmental toxicity
Type of 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:
comparable to guideline study with acceptable restrictions
Justification for type of information:
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 human health hazarda assessment of the 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.
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
low number of animals: 15 females instead of 25
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI, USA
- Age at study initiation: no data
- Weight at study initiation: 200-300 g at beginning of pregnancy
- Fasting period before study: no
- Housing: singly, in stainless steel mesh wire cages during gestation and exposure
- Diet: ad libitum (not during exposure)
- Water: ad libitum (not during exposure)
- Acclimation period: 1-2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24+/- 2
- Humidity (%): 50+/-10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Remarks:
air
Vehicle:
other: air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m³ whole body exposure chamber (hinners-type)
- Method of holding animals in test chamber: animals were caged
- Source and rate of air: heated compressed air
- Method of conditioning air: heating
- System of generating particulates/aerosols: a constant flow of reagent grade 2-EH was mixed with a metered volume of heated air (<80F°; i.e.<27°C). The vapor-air mixture was introduced into the mainstream of teh chamber airflow.
- Temperature, humidity, pressure in air chamber: 77+/-2F° (i.e. 25°C); relative humididty 50+/-15%
- Air flow rate: 0.5 m³/min
- Air change rate: 60/h
- Treatment of exhaust air: no data


TEST ATMOSPHERE
- Brief description of analytical method used:
(1) continous monitoring using a Miran1A infrared analyzer; records were taken every hour. Calibration checks were completed daily before and after the exposures.
(2) Charcoal tube samples were drawn 2 days/week and analyzed by gas chromatography, with partial verification of spiked samples of known concentration.
- Samples taken from breathing zone: yes


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Brief description of analytical method used:
(1) continous monitoring using a Miran1A infrared analyzer; records were taken every hour. Calibration checks were completed daily before and after the exposures.
(2) Charcoal tube samples were drawn 2 days/week and analyzed by gas chromatography, with partial verification of spiked samples of known concentration.
Details on mating procedure:
details not reported
Duration of treatment / exposure:
gestation day 1 - 19
Frequency of treatment:
daily, 7 hr/day
No. of animals per sex per dose:
15 females
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Duration of test: 19 days
- Dose selection rationale: the highest achievable concentration was used (850 mg/m³) which could be generated as a vapor while maintaining the chamber temperature <26°C. As no maternal toxicity was noted, there was no need to test lower concentrations.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly


BODY WEIGHT: Yes
- Time schedule for examinations: daily for the first week and weekly thereafter


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No; data were calculated on a weekly basis


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No; not applicable
- Time schedule for examinations:


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus, ovaries

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes:all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: No data
Statistics:
Multivariate analysis of variance (MANOVA) and analysis of variance (ANOVA) were used.
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
There was no effect except reduced feed consumption (approx. -10% compared to controls) and reduced body weight gain (-20% vs. controls) during gestation.
Dose descriptor:
NOAEC
Effect level:
ca. 850 mg/m³ air
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
ca. 850 mg/m³ air
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
see table below
Dose descriptor:
NOAEC
Effect level:
ca. 850 mg/m³ air
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
 Read-across justifications and data matrices are presented in IUCLID section 13.
    
    
    
    
    
    
    

There were no external, skeletal, or visceral malformations observed in any group.

Conclusions:
The developmental toxicity of 2-EH was investigated in a rat inhalation study for its potential for developmental toxicity. Pregnant female Sprague-Dawley rats were exposed to 2-EH at concentration of 850 mg/m3 during days 0-19 of gestation. Following NOAECs were established: NOAEC maternal toxicity 850mg/m3, NOAEC toxicity to reproduction 850mg/m3, NOAEC teratogenicity 850mg/m3.

No signs of maternal and fetal toxicity were noted in this inhalation study, where the maximum vapor concentration
was used which does not lead to formation of aerosol.
Executive summary:

Developmental toxicity of 2-EH was studied in a rat inhalation study that was conducted similar to OECD TG 414; the study is valid though less animals were used (n = 15) than suggested by the test guideline. The rats were exposed during days 0 -19 of gestation to 2 -EH at 850 mg/m³, the maximum achievable concentration without aerosol formation.

There were only minor signs of maternal toxicity, i.e. reduction of feed consumption (p<0.05) and body weight gain during gestation. The reproduction parameters were unchanged. There was no indication of developmental toxicity or teratogenicity, as the incidences of resorptions, the number of fetuses per litter, the sex ration, fetal weight, were all comparable to the control group. Moreover, there were no external, skeletal or visceral malformations observed in any group. The inhalation NOAEC for maternal toxicity, developmental toxicity and teratogenicity was therefore 850 mg 2-EH/m³.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
130 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
850 mg/m³
Study duration:
subacute
Species:
rat
Additional information

There is no developmental toxicity study available for the substance itself. Instead, relevant data from the degradation products is used to assess the developmental toxicity of tetrakis(2 -ethylhexane-1,3 -diolato)titanium. Read-across data from 2-ethylhexanol (2-EH) and titanium dioxide (TiO2) is used for assessment, because the target substance is hydrolytically unstable having the half-life less than 10 minutes (Brekelmans, M. J. C., 2013). Based on the rapid hydrolysis, the intrinsic properties are most likely related to these two decomposition products, structuraly similair (2 -EH) being the most relevant decomposition product for CSA. There are two studies available for 2-EH to provide weight of evidence for the developmental toxicity of tetrakis(2 -ethylhexane-1,3 -diolato)titanium. In the following paragraphs these studies are discussed in more detail. The developmental toxicity of 2-EH was investigated in an OECD TG 414 study conducted under GLP, but using low rat numbers (10 instead of 20 pregnant females). Pregnant female Wistar rats received 2-EH in the diet at concentrations of 0 (water), 0 (vehicle), 130, 650, 1300 mg/kg/day gestation day 6 through 15. Maternal toxicity was most severe at the high dose level and marginal at the intermediate dose level. At the low dose no maternal toxicity was noted. Therefore the NOAEL is 130 mg/kg/day for this endpoint under the conditions of this study. Signs of embryo-/fetotoxicity were dose-dependently noted in dams showing signs of maternal toxicity at 650 and 1300 mg/kg/day. Therefore the NOAEL is 130 mg/kg/day for this endpoint under the conditions of this study. Teratogenicity was noted in fetuses from the high dose dams only. Therefore the NOAEL is 650 mg/kg/day under the conditions of this study for teratogenicity. Developmental toxicity of 2-EH was studied in a rat inhalation study that was conducted similar to OECD TG 414; the study is valid though less animals were used (n = 15) than suggested by the test guideline. The rats were exposed during days 0 -19 of gestation to 2 -EH at 850 mg/m³, the maximum achievable concentration without aerosol formation. There were only minor signs of maternal toxicity, i.e. reduction of feed consumption (p < 0.05) and body weight gain during gestation. The reproduction parameters were unchanged. There was no indication of developmental toxicity or teratogenicity, as the incidences of resorptions, the number of fetuses per litter, the sex ration, fetal weight, were all comparable to the control group. Moreover, there were no external, skeletal or visceral malformations observed in any group. The inhalation NOAEC for maternal toxicity, developmental toxicity and teratogenicity was therefore 850 mg 2-EH/m³. The other decomposition product of tetrakis(2 -ethylhexane-1,3 -diolato)titanium is non-hazardous TiO2. Thus, it is concluded that there is no relevance to further evaluate TiO2 in the chemical safety assessment.

Justification for selection of Effect on developmental toxicity: via oral route:
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 Effect on developmental toxicity: via inhalation route:
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 weight of evidence on decomposition of this substance and the studies available from the struturally similair degradation products, 2 -ethylhexanol and hydrated titanium dioxide, indicate that there is currently no need for classification of tetrakis(2 -ethylhexane-1,3 -diolato)titanium concerning toxicity to reproduction or teratogenicity according to the CLP Regulation (EC) 1272/2008.