Titanium, diethylene glycol ethylene glycol triisopropanolamine complexes

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Extensive data has been determined for the key degradation products showing an absence of systemic toxic effects, rapid metabolism of organic components and lack of accumulation of titanium salts.  Performing further animal studies is not justified on the basis of the existing toxicity review.

Link to relevant study records

Reference

Reference 1

Endpoint:

one-generation reproductive 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:

guideline study

Justification for type of information:

Read across valid as the substnace tested is also titanate complex with glycol and alkylamine, degrading in water to similar degradation products.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

water

Remarks:

distilled water

Details on exposure:

Method of administration or exposure: Gavage

Mass median aerodynamic diameter:
Not applicable

Frequency of treatment:

Dosing regime (males): 7 days/week
Dosing regime (females): 7 days/week

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

60 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

1 200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Male: 28 animals at 0 mg/kg or mg/l
Male: 28 animals at 60 mg/kg or mg/l
Male: 28 animals at 300 mg/kg or mg/l
Male: 28 animals at 1200 mg/kg or mg/l
Female: 28 animals at 0 mg/kg or mg/l
Female: 28 animals at 60 mg/kg or mg/l
Female: 28 animals at 300 mg/kg or mg/l
Female: 28 animals at 1200 mg/kg or mg/l

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related clinical signs observed during the course of the study.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

At 1200 mg/kg 3 animals (2 males, 1 female) died as a result of dosing trauma.

At 300 mg/kg two females were found dead and one female was killed in extremis during the maturation phase of the study.
The deaths were consistent with dosing trauma.

At 30 mg/kg one male was killed in extremis during the mating phase of the study. Diuresis was observed on the day of termination. Post mortem observations included distension with haemorrhagic walls of the urinary bladder. In addition the prostrate was oedematous.

One female was killed in extremis during the lactation phase of the study. The deaths was consistent with dosing trauma.

At 0 mg/kg one male was killed in extremis during the post maturation phase of the study. On the day of termination there was clinical evidence of respiratory distress. Post mortem examination showed a jellified mass within the thorax.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no significant treatment-related intergroup differences in male or female bodyweight gain.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There were no significant treatment-related intergroup differences in male or female food consumption or food conversion.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

There were no findings observed for selected males or females, either pretest or during week 10 of the study.

Haematological findings:

no effects observed

Description (incidence and severity):

There were no toxicologically significant intergroup differences in male or female blood haematological values.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There were no toxicologically significant intergroup differences in male or female blood chemistry values.

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

At 1200 mg/kg there was a treatment-related effect on the stomachs of both males and females. Within the forestomach, subepithelial cell infiltrates, occasionally with associated acanthosis of the limiting ridge was observed. With the glandular stomach there was an increased incidence and severity of agglomeration of secretion and goblet cell hyperplasia.
At 300 and 60 mg/kg there were no treatment-related effects on the stomach.

All the remaining morphological changes were those commonly observed in laboratory maintained rats of this age and strain.

Other effects:

no effects observed

Reproductive performance:

no effects observed

Description (incidence and severity):

There were no significant treatment-related effects upon male or female mating or conception rates. The majority of pre-coital intervals were within the normal four to five day period. The distribution of pre-coital intervals were comparable for all groups.

Gestation and Parturition:

There were no significant treatment-related effects on the gestation or parturition indices. The distribution of gestation lengths were comparable for all groups, with the majority of gestation lengths being between twenty-two and twenty-three days.


Necroscopy Findings:

There were no significant treatment-related intergroup differences in the type of incidence of macroscopic anomalies observed for both males and females. The types of anomaly observed were those typically observed for this type of study.

Dose descriptor:

NOEL

Effect level:

ca. 300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Dose descriptor:

NOEL

Effect level:

> 1 200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

no

Clinical signs:

no effects observed

Description (incidence and severity):

There were no significant treatment-related intergroup differences in the type and incidence of clinical signs observed for offspring throughout lactation. The clinical signs were those commonly observed in this type of study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no significant treatment-related intergroup differences in both the mean total litter weight or mean individual offspring bodyweight throughout lactation. There were no significant treatment-related intergroup differences in offspring maturation, as denoted by the onset and completion of landmarks of development, throughout lactation.

Litter Size, Sex and Offspring Viability:

There were no siginificant treatment-related intergroup differences in the mean total number of offspring born.
Subsequent offspring viability throughout lactation was comparable for all groups including controls. There were no significant intergroup differences in the offspring sex ratios at either days 1 or 21 of lactation.

Offspring Reflexological Assessment:

There were no significant treatment-related intergroup differences in offspring reflexological responses.


Offspring Necroscopy Findings:

There were no significant treatment-related intergroup differences in the incidence and type of observations seen at post mortem examination of offspring from either the imterim and terminal necroscopy. The type of findings are those commonly observed for this study type.

Dose descriptor:

NOEL

Generation:

F1

Based on:

test mat.

Sex:

male/female

Remarks on result:

not measured/tested

Critical effects observed:

no

Reproductive effects observed:

no

Reference 2

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

water

Remarks:

distilled water

Details on exposure:

Method of administration or exposure: Gavage

Mass median aerodynamic diameter:
Not applicable

Frequency of treatment:

Dosing regime (males): 7 days/week
Dosing regime (females): 7 days/week

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

60 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

1 200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Male: 28 animals at 0 mg/kg or mg/l
Male: 28 animals at 60 mg/kg or mg/l
Male: 28 animals at 300 mg/kg or mg/l
Male: 28 animals at 1200 mg/kg or mg/l
Female: 28 animals at 0 mg/kg or mg/l
Female: 28 animals at 60 mg/kg or mg/l
Female: 28 animals at 300 mg/kg or mg/l
Female: 28 animals at 1200 mg/kg or mg/l

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related clinical signs observed during the course of the study.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

At 1200 mg/kg 3 animals (2 males, 1 female) died as a result of dosing trauma.

At 300 mg/kg two females were found dead and one female was killed in extremis during the maturation phase of the study.
The deaths were consistent with dosing trauma.

At 30 mg/kg one male was killed in extremis during the mating phase of the study. Diuresis was observed on the day of termination. Post mortem observations included distension with haemorrhagic walls of the urinary bladder. In addition the prostrate was oedematous.

One female was killed in extremis during the lactation phase of the study. The deaths was consistent with dosing trauma.

At 0 mg/kg one male was killed in extremis during the post maturation phase of the study. On the day of termination there was clinical evidence of respiratory distress. Post mortem examination showed a jellified mass within the thorax.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no significant treatment-related intergroup differences in male or female bodyweight gain.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There were no significant treatment-related intergroup differences in male or female food consumption or food conversion.

Ophthalmological findings:

no effects observed

Description (incidence and severity):

There were no findings observed for selected males or females, either pretest or during week 10 of the study.

Haematological findings:

no effects observed

Description (incidence and severity):

There were no toxicologically significant intergroup differences in male or female blood haematological values.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There were no toxicologically significant intergroup differences in male or female blood chemistry values.

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

At 1200 mg/kg there was a treatment-related effect on the stomachs of both males and females. Within the forestomach, subepithelial cell infiltrates, occasionally with associated acanthosis of the limiting ridge was observed. With the glandular stomach there was an increased incidence and severity of agglomeration of secretion and goblet cell hyperplasia.
At 300 and 60 mg/kg there were no treatment-related effects on the stomach.

All the remaining morphological changes were those commonly observed in laboratory maintained rats of this age and strain.

Other effects:

no effects observed

Reproductive performance:

no effects observed

Description (incidence and severity):

There were no significant treatment-related effects upon male or female mating or conception rates. The majority of pre-coital intervals were within the normal four to five day period. The distribution of pre-coital intervals were comparable for all groups.

Gestation and Parturition:

There were no significant treatment-related effects on the gestation or parturition indices. The distribution of gestation lengths were comparable for all groups, with the majority of gestation lengths being between twenty-two and twenty-three days.


Necroscopy Findings:

There were no significant treatment-related intergroup differences in the type of incidence of macroscopic anomalies observed for both males and females. The types of anomaly observed were those typically observed for this type of study.

Dose descriptor:

NOEL

Effect level:

ca. 300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Dose descriptor:

NOEL

Effect level:

> 1 200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

no

Clinical signs:

no effects observed

Description (incidence and severity):

There were no significant treatment-related intergroup differences in the type and incidence of clinical signs observed for offspring throughout lactation. The clinical signs were those commonly observed in this type of study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

There were no significant treatment-related intergroup differences in both the mean total litter weight or mean individual offspring bodyweight throughout lactation. There were no significant treatment-related intergroup differences in offspring maturation, as denoted by the onset and completion of landmarks of development, throughout lactation.

Litter Size, Sex and Offspring Viability:

There were no siginificant treatment-related intergroup differences in the mean total number of offspring born.
Subsequent offspring viability throughout lactation was comparable for all groups including controls. There were no significant intergroup differences in the offspring sex ratios at either days 1 or 21 of lactation.

Offspring Reflexological Assessment:

There were no significant treatment-related intergroup differences in offspring reflexological responses.


Offspring Necroscopy Findings:

There were no significant treatment-related intergroup differences in the incidence and type of observations seen at post mortem examination of offspring from either the imterim and terminal necroscopy. The type of findings are those commonly observed for this study type.

Dose descriptor:

NOEL

Generation:

F1

Based on:

test mat.

Sex:

male/female

Remarks on result:

not measured/tested

Critical effects observed:

no

Reproductive effects observed:

no

Conclusions:

At a dose level of 1200 mg TILCOM AT35/kg bodyweight there was a minor histopathological effect upon the stomachs of both males and females. There was no effect on either sex during the in-life phase of the study and no effect on either reproductive performance or offspring growth and survival. The no effect level for adult toxicity was therefore 300 mg TILCOM AT35/kg bodyweight. The no effect level for reproductive performances was in excess of 1200 mg TILCOM AT35/kg bodyweight.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 200 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

At a dose level of 1200 mg/kg bodyweight there was a minor histopathological effect upon the stomachs of both
males and females. There was no effect on either sex during the in-life phase of the study and no effect on either reproductive
performance or offspring growth and survival. The no effect level for adult toxicity was therefore 300 mg/kg
bodyweight. The no effect level for reproductive performances was in excess of 1200 mg/kg bodyweight.

Extensive data has been determined for the key degradation products showing an absence of systemic toxic effects, rapid metabolism of organic components and lack of accumulation of titanium salts. Performing further animal studies is not justified on the basis of the existing toxicity review.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Extensive data has been determined for the key degradation products showing an absence of systemic toxic effects, rapid metabolism of organic components and lack of accumulation of titanium salts.  Performing further animal studies is not justified on the basis of the existing toxicity review.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available