Bis(2-ethylhexan-1-olato)bis(pentane-2,4-dionato-O,O')titanium

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

chronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

417 mg/m³

Study duration:

subchronic

Species:

rat

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Effects on Developmental toxicity

2-ethylhexanol

In an inhalation study by Nelson (1989, 1990) no maternal toxicity or developmental toxicity was noted in a rat inhalation study that was conducted similar to OECD TG 414; the study is valid though less animals (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.

 

Pentane-2,4-dione

(Union Carbide Corp. Bushy Run Research Center)

Based on a significantly reduced body weight gain in the 400 ppm exposure group the

NOAEL/LOAEL derived for maternal toxicity is 200 and 400 ppm (= 834 / 1,668 mg/m3 = 288.2 / 576.4mg/kg bw/d assuming a respiratory minute volume of 0.24 l/min and an average weight of 250 g/rat), respectively. The NOAEL for developmental toxicity is 50 ppm (= 209 mg/m3 = 72.2mg/kg bw/d), respectively, which is based on reduced fetal weights in male fetuses at 200 and in male and female fetuses at 400 ppm and a consistent pattern of reduced fetal ossification at 400 ppm. [cited from UNEP SIDS 2001].

 

 

Based on overall findings, the inhalation NOACE was 400 ppm (d) (read from pentane-2,4-dione).

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

2-ethylhexanol is the main hydrolysis of the target substance, properties of which are used for read-across.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

low number of animals: 15 females instead of 25

Principles of method if other than guideline:

low number of animals: 15 females instead of 25

GLP compliance:

not specified

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

Exposure apparatus: 0.5 m³ whole body exposure chamber (hinners-type)
Method of holding animals in test chamber: animals were caged

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

gestation day 1 - 19

Frequency of treatment:

daily, 7 hr/day

Duration of test:

19 days

Dose / conc.:

850 mg/m³ air (analytical)

No. of animals per sex per dose:

15 females

Control animals:

yes, concurrent vehicle

Details on study design:

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.

Clinical signs:

no effects observed

Number of abortions:

no effects observed

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 850 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 850 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 850 mg/m³ air

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: teratogenicity

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

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

Executive summary:

As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

pentane-2,4-dione is the main hydrolysis of the target substance, properties of which are used for read-across.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Fischer 344

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

gestational days (GD) 6-15

Frequency of treatment:

6 h/day consecutive days

Duration of test:

13 days (treatment), animals were sacrificed on GD 21

Dose / conc.:

0 ppm (analytical)

Dose / conc.:

50 ppm (analytical)

Dose / conc.:

200 ppm (analytical)

Dose / conc.:

400 ppm (analytical)

No. of animals per sex per dose:

25 females

Control animals:

yes, concurrent vehicle

Details on study design:

Timed-pregnant Fischer F-344 rats (Harlan Fischer F-344/HarBR) were exposed to 2,4-pentanedione vapour by inhalation on gestational days (gd) 6 to 15 at exposure target concentrations of 0, 50, 200 and 400 ppm (0, 52.7, 202 and 398 ppm mean analytical concentrations, respectively) to evaluate the embryotoxic and fetotoxic (including teratogenic) potential of the TS administered during organogenesis.

The day a copulation plug was found was designated gestational day (gd) 0. Twenty-five plug-positive females were assigned to each experimental group. Clinicalobservations were recorded daily, and maternal body weights were taken on gd 0, 6, 9, 12, 15 and 18. At scheduled necropsy on gd 21 (CO2 asphyxiation), dams were evaluated for body weight, liver and thymus weights, gravid uterine weight, and status of implantation sites (i.e. resorptions, dead fetuses, live fetuses). Maternal brains were removed, fixed and examined histopathologically. Live fetuses were dissected from the uterus, counted, weighed and sexed and examined for external abnormalities.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

reduced body weight gain

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 200 ppm (analytical)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

LOAEC

Effect level:

ca. 400 ppm (analytical)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

reduced fetal weights
reduced fetal ossification in the 200 and 400 ppm group

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 50 ppm (analytical)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Key result

Dose descriptor:

LOAEC

Effect level:

ca. 200 ppm (analytical)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 400 ppm (analytical)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 400 ppm (analytical)

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

Key result

Developmental effects observed:

no

Conclusions:

Based on a significantly reduced body weight gain in the 400 ppm exposure group the NOAEC/LOAEC derived for maternal toxicity is 200 and 400 ppm, respectively. The NOAEC/LOAEC for developmental toxicity is 50 and 200 ppm, respectively, which is based on reduced fetal weights in male fetuses at 200 ppm and in male and female fetuses at 400 ppm and a consistent pattern of reduced fetal ossification at 400 ppm. The NOAEL for embryotoxicity and teratogenicity is 400 ppm (highest dose tested).

Executive summary:

As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

Reference 3

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

Justification for type of information:

pentane-2,4-dione is the main hydrolysis of the target substance, properties of which are used for read-across.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Fischer 344

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

gestational days (GD) 6-15

Frequency of treatment:

6 h/day consecutive days

Duration of test:

13 days (treatment), animals were sacrificed on GD 21

Dose / conc.:

0 ppm (analytical)

Dose / conc.:

50 ppm (analytical)

Dose / conc.:

200 ppm (analytical)

Dose / conc.:

400 ppm (analytical)

No. of animals per sex per dose:

25 females

Control animals:

yes, concurrent vehicle

Details on study design:

Timed-pregnant Fischer F-344 rats (Harlan Fischer F-344/HarBR) were exposed to 2,4-pentanedione vapour by inhalation on gestational days (gd) 6 to 15 at exposure target concentrations of 0, 50, 200 and 400 ppm (0, 52.7, 202 and 398 ppm mean analytical concentrations, respectively) to evaluate the embryotoxic and fetotoxic (including teratogenic) potential of the TS administered during organogenesis.

The day a copulation plug was found was designated gestational day (gd) 0. Twenty-five plug-positive females were assigned to each experimental group. Clinicalobservations were recorded daily, and maternal body weights were taken on gd 0, 6, 9, 12, 15 and 18. At scheduled necropsy on gd 21 (CO2 asphyxiation), dams were evaluated for body weight, liver and thymus weights, gravid uterine weight, and status of implantation sites (i.e. resorptions, dead fetuses, live fetuses). Maternal brains were removed, fixed and examined histopathologically. Live fetuses were dissected from the uterus, counted, weighed and sexed and examined for external abnormalities.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

reduced body weight gain

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 200 ppm (analytical)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

LOAEC

Effect level:

ca. 400 ppm (analytical)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

reduced fetal weights
reduced fetal ossification in the 200 and 400 ppm group

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 50 ppm (analytical)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Key result

Dose descriptor:

LOAEC

Effect level:

ca. 200 ppm (analytical)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 400 ppm (analytical)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 400 ppm (analytical)

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

Key result

Developmental effects observed:

no

Conclusions:

Based on a significantly reduced body weight gain in the 400 ppm exposure group the NOAEC/LOAEC derived for maternal toxicity is 200 and 400 ppm, respectively. The NOAEC/LOAEC for developmental toxicity is 50 and 200 ppm, respectively, which is based on reduced fetal weights in male fetuses at 200 ppm and in male and female fetuses at 400 ppm and a consistent pattern of reduced fetal ossification at 400 ppm. The NOAEL for embryotoxicity and teratogenicity is 400 ppm (highest dose tested).

Executive summary:

The study was conducted on pentane-2,4 -dione, the strucural analogue and also the hydrolysis product of the target substance. As the target substance is hydrolytically unstable, its intrinsic property lies in the the hydrolysis products. The result is used as weight of evidence approach in hazard assessment.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

209 mg/m³

Study duration:

subchronic

Species:

rat

Justification for classification or non-classification

Based on the studies, there's no adverse effect on reproduction observed. Therefore, there is no need for classification as reproductive toxicity according to CLP Regulation.