Tetraammineplatinum (II) diacetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In an OECD Test Guideline 421 reproduction and developmental toxicity screening study, to GLP, parental rats (12/sex/group) were administered tetraammineplatinum(II) dinitrate by oral gavage at up to 1000 mg/kg bw/day for 14 days pre-mating, through mating, and (for females) throughout gestation and up to lactation day 3. No adverse effects on reproductive parameters, or on development of offspring, were observed at any dose, resulting in a reproductive toxicity NOAEL of 1000 mg/kg bw/day (Hansen, 2015).

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 May 2014 - 07 July 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Guideline study, conducted to GLP.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Charles River Laboratories Germany GmbH
Sandhofer Weg 7
97633 Sulzfeld
Germany
- Age at study initiation (on test day 1): 73 days
- Weight at study initiation: males: 352.4 - 398.3 g; females: 231.0 - 291.4 g
- Fasting period before study: no data
- Housing: except during mating, the dams were housed singly in cages. No data on housing of males. Granulated textured wood was used as bedding material, and the cages were cleaned and changed once per week
- Diet (e.g. ad libitum): Commercial ssniff(r) R/Z V1324 was offered ad libitum
- Water (e.g. ad libitum): drinking water was offered ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 deg C
- Humidity (%): 55 +/- 15 % relative humidity
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light. About 150 lux at approximately 1.5 m room height

IN-LIFE DATES:
First administration (at age 73 days): 21 May 2014
End of in-life part (males): 18 June 2014
End of in-life part (females): 07 July 2014

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Test item formulations were freshly prepared once weekly. The test item, supplied as a solution, was further diluted in tap water to the appropriate concentrations.

VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 5 mL/kg bw/day
- Lot/batch no. (if required): not applicable
- Purity: not applicable

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: until pregnancy had occurred or two weeks
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: no
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): singly in a standard cage
- Any other deviations from standard protocol: one female, which showed no evidence of copulation after 14 days of mating, was sacrificed 16 days later

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of approximately 5 mL were taken from each of the weekly prepared test item formulations and stored at -20 deg C or colder until shipment to the GLP analytical laboratory.

Duration of treatment / exposure:

The animals were treated for the following periods:
- males: 2 weeks prior to mating, during the mating period, and approximately 2 weeks post mating until 28 days' dosing was completed. From test day 1 up to and including test day 28.
- females: Throughout the study. Beginning 2 weeks prior to mating up to and including day 3 post-partum. From test day 1 and test day 40 (first sacrificed females) or test day 47 (last sacrificed females).

Frequency of treatment:

Once daily.

Remarks:

Doses / Concentrations:
50 mg/kg bw/day
Basis:
nominal in water

Remarks:

Doses / Concentrations:
250 mg/kg bw/day
Basis:
nominal in water

Remarks:

Doses / Concentrations:
1000 mg/kg bw/day
Basis:
nominal in water

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: the dose levels were selected based on the results of a 14-day dose-range finding study (results not included here). A top dose of 1000 mg/kg/day was tested without apparent toxicity.

Positive control:

No.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
Signs of illness or reaction to treatment were recorded immediately after administration. Otherwise, animals were observed daily for behaviour, external appearance and nature of the faeces. Animals were checked regularly throughout the working day (07:00 - 15:45). On Saturdays and Sundays, regular checks were made between 07:00 and 11:00, with a final check at approximately 15:30. Further checks were made early in the morning and again in the afternoon of each working day, and up to around midday on weekends, to look for dead or moribund animals.

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of dosing, weekly thereafter, and at termination. During gestation, females were weighed on days 0, 7, 14 and 20, and within 24 hours of parturition and on day 4 post-partum.

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
Drinking water consumption was monitored by visual appraisal of the drinking water bottles throughout the study.

Oestrous cyclicity (parental animals):

No data.

Sperm parameters (parental animals):

No data. Histopathological examination of the testes and epididymides suggested no significant effect on spermatogenesis. This is supported by 100% pregnancies of mated females.

Litter observations:

STANDARDISATION OF LITTERS
Not applicable.

PARAMETERS EXAMINED
The following parameters were examined in offspring at birth and day 4 post-partum:
Number of pups (absolute); number of pups (per dam); number of still births (absolute and per dam); number of pups with malformations (absolute and per dam).

GROSS EXAMINATION OF DEAD PUPS:
yes, for external gross abnormalities.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All animals were sacrificed on test day 29, after a minimum total dosing period of 28 days.
- Maternal animals: Dams with offspring were sacrificed on day 4 post-partum. One female, which showed no evidence of copulation, was sacrificed 16 days after the last day of the mating period.

GROSS NECROPSY
- Gross necropsy consisted of external and internal macroscopic examination for any abnormalities or pathological changes. Special attention was paid to the reproductive organs.
- The numbers of implantation sites and corpora lutea were recorded.
- The ovaries, testes, epididymides, accessory sex organs (coagulating gland, preputial gland, prostate, seminal vesicle, uterus (including cervix and oviducts), and vagina) and all organs showing macroscopic lesions were preserved.

HISTOPATHOLOGY / ORGAN WEIGHTS
- The testes (2) and epididymides (2) of the male animals were weighed.
- Histopathologic examination was performed on the ovaries, testes and epididymides of all animals in the control and high-dose groups.
- Detailed histopathologic examination was performed on one testicle and one epididymis of all males in the control and high-dose groups, with special emphasis on the qualitative stages of spermatogenesis and histopathology of interstitial testicular structure.

Postmortem examinations (offspring):

Dead pups and pups killed on day 4 post-partum were carefully examined externally for gross abnormalities.

Statistics:

Analysis of normal distribution and homogeneity of variances was performed by using the SHAPIRO-WILKS test and the BARTLETT test. Data not normally distributed or with heterogeneous variances between the groups were stepwise log- or rank-transformed.

One-way analysis of variance (ANOVA) was performed with non-transformed or log-transformed data. The KRUSKAL-WALLIS test was used for rank-transformed data.

In case of significant differences (found by ANOVA or KRUSKAL-WALLIS test), inter-group comparisons with the control group were made by parametric or non-parametric DUNNETT multiple comparison tests (p ≤ 0.05 and p ≤ 0.01).

Other parametrical values, such as number and weight of the neonates, were analysed by the DUNNETT test (p ≤ 0.05 and p ≤ 0.01). Prior to the DUNNETT test homogeneity of variances was tested using the BARTLETT test. In case of heterogeneity of variances, the STUDENT's t-test was carried out (p ≤ 0.05 and p ≤ 0.01).

Statistical analyses of non-parametrical data like the reproductive indices were performed using the following settings:
FISHER exact test, n < 100; (p ≤ 0.05 and p ≤ 0.01)
or
Chi2 test, n ≤ 0.01 (p ≤ 0.05 and p ≤ 0.01)

Reproductive indices:

The following indices were calculated for each group:

Male fertility Index [%] = (No. of males with confirmed female insemination/Number of rats used) x 100
Female fertility Index [%] = (Number of pregnant rats/Number of rats used) x 100

The female fertility index reflects the total number of dams that had achieved pregnancy, including those, that delivered at term, aborted or had fully resorbed litters.

Gestation Index [%] = (Number of dams with live pups/Number of pregnant rats) x 100

Offspring viability indices:

For each litter and group the following indices were determined:

Birth Index [%] = (Total number of pups born (alive + dead)/Number of implantation scars) x 100
Live Birth Index [%] = (Number of pups alive on day 0/1 of lactation/Total number of pups (alive + dead)) x 100
Survival Index [%] = (Number of pups alive on day 4/Number of pups alive on day 0/1) x 100
Pre-implantation loss [%] = ((corpora lutea – implantations)/corpora lutea) x 100
Post-implantation loss [%] = ((implantations - living neonates)/implantations) x 100

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):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No effects

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
At 1000 mg/kg bw/day, a statistically significant (p <= 0.01) reduced body weight (reduced by 8.5% compared to controls) was noted for female rats on lactation day 4 only, and similarly for the body weight at autopsy. No effect on the body weight of male rats, or food consumption of either sex.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No effects

ORGAN WEIGHTS (PARENTAL ANIMALS)
No effects

GROSS PATHOLOGY (PARENTAL ANIMALS)
No effects

HISTOPATHOLOGY (PARENTAL ANIMALS)
No effects

Dose descriptor:

NOAEL

Remarks:

fertility/reproductive parameters

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No reproductive effects seen at highest tested dose

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No general systemic effects seen at highest tested dose

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

250 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No general systemic effects seen at 250 mg/kg bw/day

Dose descriptor:

LOAEL

Remarks:

general toxicity

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Decreased body weight at day 4 post-partum only.

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

VIABILITY (OFFSPRING)
No effects

CLINICAL SIGNS (OFFSPRING)
No effects

BODY WEIGHT (OFFSPRING)
No effects

ORGAN WEIGHTS (OFFSPRING)
No effects

GROSS PATHOLOGY (OFFSPRING)
No effects

HISTOPATHOLOGY (OFFSPRING)
No effects

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects seen in the F1 generation at highest tested dose

Reproductive effects observed:

not specified

Conclusions:

In an OECD Test Guideline 421 reproduction and developmental toxicity screening study, to GLP, parental rats (12/sex/group) were administered tetraammineplatinum(II) dinitrate by oral gavage at up to 1000 mg/kg bw/day for 14 days pre-mating, through mating, and (for females) throughout gestation and up to lactation day 3. No adverse effects on reproductive parameters, or on development of offspring, were observed at any dose, resulting in a reproductive toxicity NOAEL of 1000 mg/kg bw/day.

Executive summary:

The potential of a solution of tetraammineplatinum dinitrate(II) to adversely affect the fertility and reproductive parameters of CD rats was investigated in a reproductive and developmental screening study conducted according to OECD Test Guideline 421 and to GLP. The test material was administered by oral gavage for at least 28 days. Males were dosed for 14 days pre-mating and 14 days mating/post mating. Females were dosed for 14 days pre-mating, through gestation and up to post-partum day 3 (test day 40-47). Three dose groups (50, 250 and 1000 mg/kg bw/day) and a control group were used, each containing 12 animals of each sex.

 

Parental (F0) animals were observed for clinical signs of toxicity throughout the study, with body weights and food consumption monitored. At necropsy, animals were subjected to external and internal macroscopic examinations for any abnormalities or pathological changes. Special attention was paid to the reproductive organs. The numbers of implantation sites and corpora lutea were recorded. Histopathological examination was performed on the ovaries, testes and epididymides of all animals in the control and high-dose groups, with special emphasis on the qualitative stages of spermatogenesis and histopathology of interstitial testicular structure. A number of reproductive indices were calculated from the collected data (including mating, fertility and gestation indices).

 

The only clinical sign of toxicity was a significantly reduced body weight in high-dose females at the end of the study on post-partum day 4. There was no impact on food consumption in males or females. Thus, the NOAEL for general toxicity was considered to be 250 mg/kg bw/day.

 

No test item-related microscopic changes were noted in the reproductive organs, and there was no impact on fertility or on the measured reproductive parameters at any dose level. Thus, the NOAEL for reproductive toxicity was 1000 mg/kg bw/day, the highest dose tested.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Overall, good-quality database which meets REACH Standard Information Requirements.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No relevant data in humans were identified, or reproductive toxicity laboratory animal data with tetraammineplatinum(II) diacetate. However, a reliable reproduction/developmental screening toxicity study in rats has been conducted with tetraammineplatinum(II) dinitrate. Tetraammineplatinum dinitrate is considered to fall within the scope of the read-across category "tetraammineplatinum(II) salts". See section 13 in IUCLID for full read-across justification report.

 

The potential of a solution of tetraammineplatinum(II) dinitrate to adversely affect the fertility and reproductive parameters of CD rats was investigated in a reproductive and developmental screening study conducted according to OECD Test Guideline 421 and to GLP. The test material was administered by oral gavage for at least 28 days. Males were dosed for 14 days pre-mating and 14 days mating/post mating. Females were dosed for 14 days pre-mating, through gestation and up to post-partum day 3 (test day 40-47). Three dose groups (50, 250 and 1000 mg/kg bw/day) and a control group were used, each containing 12 animals of each sex. Parental (F0) animals were observed for clinical signs of toxicity throughout the study, with body weights and food consumption monitored. At necropsy, animals were subjected to external and internal macroscopic examinations for any abnormalities or pathological changes. Special attention was paid to the reproductive organs. The numbers of implantation sites and corpora lutea were recorded. Histopathological examination was performed on the ovaries, testes and epididymides of all animals in the control and high-dose groups, with special emphasis on the qualitative stages of spermatogenesis and histopathology of interstitial testicular structure. A number of reproductive indices were calculated from the collected data (including mating, fertility and gestation indices). The only clinical sign of toxicity was a significantly reduced body weight in high-dose females at the end of the study on post-partum day 4. There was no impact on food consumption in males or females. Thus, the NOAEL for general toxicity was considered to be 250 mg/kg bw/day. No test item-related microscopic changes were noted in the reproductive organs, and there was no impact on fertility or on the measured reproductive parameters at any dose level. Thus, the NOAEL for reproductive toxicity was 1000 mg/kg bw/day, the highest dose tested (Hansen, 2015).

Effects on developmental toxicity

Description of key information

In an OECD Test Guideline 421 reproduction and developmental toxicity screening study, to GLP, parental rats (12/sex/group) were administered tetraammineplatinum(II) dinitrate by gavage at 0, 50, 250 or 1000 mg/kg bw/day. No adverse effects on reproductive parameters or development of offspring were observed at any dose, resulting in a developmental NOAEL of 1000 mg/kg bw/day (Hansen, 2015).

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 May 2014 - 07 July 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Guideline study, conducted to GLP.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Charles River Laboratories Germany GmbH
Sandhofer Weg 7
97633 Sulzfeld
Germany
- Age at study initiation (on test day 1): 73 days
- Weight at study initiation: males: 352.4 - 398.3 g; females: 231.0 - 291.4 g
- Fasting period before study: no data
- Housing: except during mating, the dams were housed singly in cages. No data on housing of males. Granulated textured wood was used as bedding material, and the cages were cleaned and changed once per week
- Diet (e.g. ad libitum): Commercial ssniff(r) R/Z V1324 was offered ad libitum
- Water (e.g. ad libitum): drinking water was offered ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 deg C
- Humidity (%): 55 +/- 15 % relative humidity
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light. About 150 lux at approximately 1.5 m room height

IN-LIFE DATES:
First administration (at age 73 days): 21 May 2014
End of in-life part (males): 18 June 2014
End of in-life part (females): 07 July 2014

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Test item formulations were freshly prepared once weekly. The test item, supplied as a solution, was further diluted in tap water to the appropriate concentrations.

VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 5 mL/kg bw/day
- Lot/batch no. (if required): not applicable
- Purity: not applicable

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of approximately 5 mL were taken from each of the weekly prepared test item formulations and stored at -20 deg C or colder until shipment to the GLP analytical laboratory.

Details on mating procedure:

- Impregnation procedure: cohoused
If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: until pregnancy had occurred or two weeks
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: no
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): singly in a standard cage
- Any other deviations from standard protocol: one female, which showed no evidence of copulation after 14 days of mating, was sacrificed 16 days later

Duration of treatment / exposure:

The animals were treated for the following periods:
- males: 2 weeks prior to mating, during the mating period, and approximately 2 weeks post mating until 28 days' dosing was completed. From test day 1 up to and including test day 28.
- females: Throughout the study. Beginning 2 weeks prior to mating up to and including day 3 post-partum. From test day 1 and test day 40 (first sacrificed females) or test day 47 (last sacrificed females).

Frequency of treatment:

Once daily.

Duration of test:

40-47 days (for females)

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: the dose levels were selected based on the results of a 14-day dose-range finding study (results not included here). A top dose of 1000 mg/kg/day was tested without apparent toxicity.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
Signs of illness or reaction to treatment were recorded immediately after administration. Otherwise, animals were observed daily for behaviour, external appearance and nature of the faeces. Animals were checked regularly throughout the working day (07:00 - 15:45). On Saturdays and Sundays, regular checks were made between 07:00 and 11:00, with a final check at approximately 15:30. Further checks were made early in the morning and again in the afternoon of each working day, and up to around midday on weekends, to look for dead or moribund animals.

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of dosing, weekly thereafter, and at termination. During gestation, females were weighed on days 0, 7, 14 and 20, and within 24 hours of parturition and on day 4 post-partum.

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
Drinking water consumption was monitored by visual appraisal of the drinking water bottles throughout the study.

POST-MORTEM EXAMINATIONS: Yes
SACRIFICE
- Male animals: All animals were sacrificed on test day 29, after a minimum total dosing period of 28 days.
- Maternal animals: Dams with offspring were sacrificed on day 4 post-partum. One female, which showed no evidence of copulation, was sacrificed 16 days after the last day of the mating period.

GROSS NECROPSY
- Gross necropsy consisted of external and internal macroscopic examination for any abnormalities or pathological changes. Special attention was paid to the reproductive organs.
- The numbers of implantation sites and corpora lutea were recorded.
- The ovaries, testes, epididymides, accessory sex organs (coagulating gland, preputial gland, prostate, seminal vesicle, uterus (including cervix and oviducts), vagina) and all organs showing macroscopic lesions were preserved.

HISTOPATHOLOGY / ORGAN WEIGHTS
- The testes (2) and epididymides (2) of the male animals were weighed.
- Histopathologic examination was performed on the ovaries, testes and epididymides of all animals in the control and high-dose groups.
- Detailed histopathologic examination was performed on one testicle and one epididymis of all males in the control and high-dose groups, with special emphasis on the qualitative stages of spermatogenesis and histopathology of interstitial testicular structure.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

Dead pups and pups killed on day 4 post-partum were carefully examined externally for gross abnormalities.

- External examinations: Yes: [all]
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data

Statistics:

Analysis of normal distribution and homogeneity of variances was performed by using the SHAPIRO-WILKS test and the BARTLETT test. Data not normally distributed or with heterogeneous variances between the groups were stepwise log- or rank-transformed.

One-way analysis of variance (ANOVA) was performed with non-transformed or log-transformed data. The KRUSKAL-WALLIS test was used for rank-transformed data.

In case of significant differences (found by ANOVA or KRUSKAL-WALLIS test), inter-group comparisons with the control group were made by parametric or non-parametric DUNNETT multiple comparison tests (p ≤ 0.05 and p ≤ 0.01).

Other parametrical values, such as number and weight of the neonates, were analysed by the DUNNETT test (p ≤ 0.05 and p ≤ 0.01). Prior to the DUNNETT test homogeneity of variances was tested using the BARTLETT test. In case of heterogeneity of variances, the STUDENT's t-test was carried out (p ≤ 0.05 and p ≤ 0.01).

Statistical analyses of non-parametrical data like the reproductive indices were performed using the following settings:
FISHER exact test, n < 100; (p ≤ 0.05 and p ≤ 0.01)
or
Chi2 test, n ≤ 0.01 (p ≤ 0.05 and p ≤ 0.01)

Indices:

The following indices were calculated for each group:

Male fertility Index [%] = (No. of males with confirmed female insemination/Number of rats used) x 100
Female fertility Index [%] = (Number of pregnant rats/Number of rats used) x 100

The female fertility index reflects the total number of dams that had achieved pregnancy, including those, that delivered at term, aborted or had fully resorbed litters.

Gestation Index [%] = (Number of dams with live pups/Number of pregnant rats) x 100

For each litter and group the following indices were determined:

Birth Index [%] = (Total number of pups born (alive + dead)/Number of implantation scars) x 100
Live Birth Index [%] = (Number of pups alive on day 0/1 of lactation/Total number of pups (alive + dead)) x 100
Survival Index [%] = (Number of pups alive on day 4/Number of pups alive on day 0/1) x 100
Pre-implantation loss [%] = ((corpora lutea – implantations)/corpora lutea) x 100
Post-implantation loss [%] = ((implantations – living neonates)/implantations) x 100

Historical control data:

No data.

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
At 1000 mg/kg bw/day, a statistically significant (p <= 0.01) reduced body weight (reduced by 8.5% compared to controls) was noted for female rats on lactation day 4 only, and similarly for the body weight at autopsy. No effect on the body weight of male rats, or food consumption of either sex.

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effects

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No embryotoxicity / teratogenicity seen at highest tested dose

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

In an OECD Test Guideline 421 reproduction and developmental toxicity screening study, to GLP, parental rats (12/sex/group) were administered tetraammineplatinum(II) dinitrate by gavage at 0, 50, 250 or 1000 mg/kg bw/day. No adverse effects on reproductive parameters or development of offspring were observed at any dose, resulting in a developmental NOAEL of 1000 mg/kg bw/day.

Executive summary:

The potential of a solution of tetraammineplatinum dinitrate to adversely affect the development of CD rat pups was investigated in a reproductive and developmental screening study conducted according to OECD Test Guideline 421 and to GLP. The test material was administered by oral gavage for at least 28 days. Males were dosed for 14 days pre-mating and 14 days mating/post mating. Females were dosed for 14 days pre-mating, through gestation and up to post-partum day 3 (test day 40-47). Three dose groups (50, 250 and 1000 mg/kg bw/day) and a control group were used, each containing 12 animals of each sex.

 

Parental (F0) animals were observed for clinical signs of toxicity throughout the study, with body weights and food consumption monitored. At necropsy, animals were subjected to external and internal macroscopic examinations for any abnormalities or pathological changes. Special attention was paid to the reproductive organs. The numbers of implantation sites and corpora lutea were recorded. Histopathologic examination was performed on the ovaries, testes and epididymides of all animals in the control and high-dose groups, with special emphasis on the qualitative stages of spermatogenesis and histopathology of interstitial testicular structure. On postnatal day 4, pups were carefully examined for gross abnormalities at necropsy.

 

The only sign of toxicity was a significantly reduced body weight in high-dose females at the end of the study on post-partum day 4. Thus, the NOAEL for general toxicity was deemed to be 250 mg/kg bw/day.

 

There was no developmental toxicity effect at any dose level. Thus, the NOAEL for developmental toxicity was 1000 mg/kg bw/day, the highest dose tested.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Overall, good-quality database which meets REACH Standard Information Requirements.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No relevant data in humans were identified, or developmental toxicity laboratory animal data with tetraammineplatinum(II) diacetate. However, a reliable reproduction/developmental screening toxicity study in rats has been conducted with tetraammineplatinum(II) dinitrate. Tetraammineplatinum dinitrate is considered to fall within the scope of the read-across category "tetraammineplatinum(II) salts". See section 13 in IUCLID for full read-across justification report.

 

The potential of a solution of tetraammineplatinum(II) dinitrate to adversely affect the development of CD rat pups was investigated in a reproductive and developmental screening study conducted according to OECD Test Guideline 421 and to GLP. The test material was administered by oral gavage for at least 28 days. Males were dosed for 14 days pre-mating and 14 days mating/post mating. Females were dosed for 14 days pre-mating, through gestation and up to post-partum day 3 (test day 40-47). Three dose groups (50, 250 and 1000 mg/kg bw/day) and a control group were used, each containing 12 animals of each sex. Parental (F0) animals were observed for clinical signs of toxicity throughout the study, with body weights and food consumption monitored. At necropsy, animals were subjected to external and internal macroscopic examinations for any abnormalities or pathological changes. Special attention was paid to the reproductive organs. The numbers of implantation sites and corpora lutea were recorded. Histopathologic examination was performed on the ovaries, testes and epididymides of all animals in the control and high-dose groups, with special emphasis on the qualitative stages of spermatogenesis and histopathology of interstitial testicular structure. On postnatal day 4, pups were carefully examined for gross abnormalities at necropsy. The only sign of toxicity was a significantly reduced body weight in high-dose females at the end of the study on post-partum day 4. Thus, the NOAEL for general toxicity was deemed to be 250 mg/kg bw/day. There was no developmental toxicity effect at any dose level. Thus, the NOAEL for developmental toxicity was 1000 mg/kg bw/day, the highest dose tested (Hansen, 2015).

Toxicity to reproduction: other studies

Description of key information

No data identified.

Additional information

No data identified.

Mode of Action Analysis / Human Relevance Framework

No data identified.

Justification for classification or non-classification

No adverse effects on reproductive parameters (sexual function or fertility) or development of offspring were seen in a reliable guideline screening assay with tetraammineplatinum(II) dinitrate. As such, classification of tetraammineplatinum(II) diacetate for reproductive toxicity is not required, according to EU CLP criteria (EC 1272/2008).