Registration Dossier
Registration Dossier
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EC number: 848-537-7 | CAS number: 1912392-88-1
Toxicological information
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
No reproductive toxicity study with HHPA-TEAH is available, thus the reprotoxicity is addressed with existing data on HHPA and TEAH as detailed in the ‘HHPA-TEAH ReadAcross justification’ document (Section 13.2).
For the purpose of hazard assessment of HHPA-TEAH, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, conducted acording to GLP
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Specific details on test material used for the study:
- TMAH (Lot No. 40914), Vehicle: water, purity: over 99.9•%
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Details on exposure:
- Doses: 0, 1, 5, 20 mg/kg bw/day
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until copulation occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of gestation). - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Male: 14 days before mating to the day before scheduled death through mating (total 32 days)
Female: 14 days before mating to 3 days after delivery through mating and gestation periods - Frequency of treatment:
- daily
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 1 mg/kg bw/day
- Dose / conc.:
- 5 mg/kg bw/day
- Dose / conc.:
- 20 mg/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Positive control:
- no
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Signs recorded include: changes in salivation, locomotor activity, fur, eyelid opening or closure
BODY WEIGHT: Yes
- Time schedule for examinations: The male animals were weighed on Day 1 and 3 of dosing, and weekly thereafter. The female animals were weighed on Day 1, 3 and 7 of dosing, weekly thereafter until delivery, and PND 0 and 4. Body weights of the live pups were also recorded. - Oestrous cyclicity (parental animals):
- no data
- Sperm parameters (parental animals):
- no data
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, clinical signs, ody weights and weight gain (PND 4). At the termination of the experiment (PND 4), all animals including pups were sacrificed and autopsied.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external gross abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
At the termination of the experiment (PND 4) all surviving animal (male, female, pups) were sacrificed
GROSS NECROPSY
HISTOPATHOLOGY / ORGAN WEIGHTS - Postmortem examinations (offspring):
- SACRIFICE
At the termination of the experiment (PND 4), all F1 pups were sacrificed and autopsied.
GROSS NECROPSY
HISTOPATHOLOGY / ORGAN WEIGTHS - Statistics:
- Statistical analysis : Bartlett's test, one-way analysis of variance, Dunnett's test, Kruskal-wallis test, chi-square test
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Salivation was observed on the 4th day of administration and later in male and female rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH.
In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the female animals and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4) was observed.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A significant decrease in food consumption was observed at 20 mg/kg bw/day on Day 3 in male animals and on gestation day (GD) 20 in female animals.
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- Critical effects observed:
- not specified
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effect up to the highest dose tested (20 mg/kg bw/day)
- Reproductive effects observed:
- not specified
- Conclusions:
- In a reproductive/developmental toxicity screening test in rats [OECD TG 421], TMAH was administered by gavage at doses of 0, 1, 5 and 20 mg/kg bw/day. No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
- Executive summary:
In a reproductive/developmental toxicity screening test according to OECD TG 421, Sprague-Dawley rats (10/sex/group) were orally administered TMAH (by gavage) at doses of 0, 1, 5 and 20 mg/kg bw/day.
No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, conducted acording to GLP
- Justification for type of information:
- Information on read-across approach
Selected endpoints for the human health hazard assessment of di(tetraethylammonium)hexahydroxoplatinate (IV) (HHPA-TEAH) are addressed by read-across, using a combination of data on hexahydroxoplatinate (HHPA) and tetraethylammonium hydroxide (TEAH) (or its substance analogue tetramethylammonium hydroxide (TMAH)). This way forward is acceptable, since HHPA-TEAH has a narrow stability and rapidly dissociates to HHPA and TEAH in acidic (e.g. gastric) environment.
The hazard information of HHPA and TEAH (or TMAH) was obtained from existing REACH registration dossiers via a license-to-use obtained by the registrant.
Detailed information justifying this read-across approach and listing/summarising the available toxicity data of HHPA-TEAH, HHPA and TEAH respectively, are reported in the ‘HHPA-TEAH ReadAcross justification’ document attached in IU section 13.2.
For the purpose of hazard assessment of HHPA-TEAH, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. - Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Specific details on test material used for the study:
- TMAH (Lot No. 40914), Vehicle: water, purity: over 99.9•%
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Details on exposure:
- Doses: 0, 1, 5, 20 mg/kg bw/day
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until copulation occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of gestation). - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Male: 14 days before mating to the day before scheduled death through mating (total 32 days)
Female: 14 days before mating to 3 days after delivery through mating and gestation periods - Frequency of treatment:
- daily
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 1 mg/kg bw/day
- Dose / conc.:
- 5 mg/kg bw/day
- Dose / conc.:
- 20 mg/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Positive control:
- no
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Signs recorded include: changes in salivation, locomotor activity, fur, eyelid opening or closure
BODY WEIGHT: Yes
- Time schedule for examinations: The male animals were weighed on Day 1 and 3 of dosing, and weekly thereafter. The female animals were weighed on Day 1, 3 and 7 of dosing, weekly thereafter until delivery, and PND 0 and 4. Body weights of the live pups were also recorded. - Oestrous cyclicity (parental animals):
- no data
- Sperm parameters (parental animals):
- no data
- Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, clinical signs, ody weights and weight gain (PND 4). At the termination of the experiment (PND 4), all animals including pups were sacrificed and autopsied.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external gross abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
At the termination of the experiment (PND 4) all surviving animal (male, female, pups) were sacrificed
GROSS NECROPSY
HISTOPATHOLOGY / ORGAN WEIGHTS - Postmortem examinations (offspring):
- SACRIFICE
At the termination of the experiment (PND 4), all F1 pups were sacrificed and autopsied.
GROSS NECROPSY
HISTOPATHOLOGY / ORGAN WEIGTHS - Statistics:
- Statistical analysis : Bartlett's test, one-way analysis of variance, Dunnett's test, Kruskal-wallis test, chi-square test
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Salivation was observed on the 4th day of administration and later in male and female rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH.
In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the female animals and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4) was observed.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A significant decrease in food consumption was observed at 20 mg/kg bw/day on Day 3 in male animals and on gestation day (GD) 20 in female animals.
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- Critical effects observed:
- not specified
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effect up to the highest dose tested (20 mg/kg bw/day)
- Reproductive effects observed:
- not specified
- Conclusions:
- In a reproductive/developmental toxicity screening test in rats [OECD TG 421], TMAH was administered by gavage at doses of 0, 1, 5 and 20 mg/kg bw/day. No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
The NOAEL of the structural analogue tetraethylammonium hydroxide (TEAH) is considered to be 5 mg/kg bw/day
The calculated NOAEL for di(tetraethylammonium)hexahydroxoplatinate(IV) based on the read-across strategy and taken into account the maximum content of TEAH = 5 mg/kg bw/day / 0.528 (weight %) = 9.47 mg/kg bw/day - Executive summary:
In a reproductive/developmental toxicity screening test according to OECD TG 421, Sprague-Dawley rats (10/sex/group) were orally administered TMAH (by gavage) at doses of 0, 1, 5 and 20 mg/kg bw/day.
No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
The most sensitive NOAEL of the structural analogue tetraethylammonium hydroxide (TEAH) is considered to be 5 mg/kg bw/day
The calculated NOAEL for di(tetraethylammonium)hexahydroxoplatinate(IV) based on the read-across strategy and taken into account the maximum content of TEAH = 5 mg/kg bw/day / 0.528 (weight %) = 9.47 mg/kg bw/day
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- other: combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 September 2014 - 30 June 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, conducted according to GLP.
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the 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, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany.
- Age at study initiation: 67 days (at first test item administration).
- Weight at study initiation: males: 326.4 - 402.7 g; females: 189.4 - 246.0 g (at first test item administration).
- Fasting period before study: no data.
- Housing: animals were housed singly, except during the mating period.
- Diet (e.g. ad libitum): certified commercial diet, offered ad libitum.
- Water (e.g. ad libitum): tap water, offered ad libitum.
- Acclimation period: 8 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature of 22degC +/- 3degC (maximum range).
- Humidity (%): relative humidity of 55% +/- 15% (maximum range).
- Air changes (per hr): no data.
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light, about 150 lux.
IN-LIFE DATES:
From: July 2014.
To: 23 October 2014 (males); 14 November 2014 (females). - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: test item formulations were prepared once weekly and stored in a tightly closed container at room temperature (+10 to +25 degC) until use.
DIET PREPARATION
- Rate of preparation of diet (frequency): not applicable.
- Mixing appropriate amounts with (Type of food): not applicable.
- Storage temperature of food: not applicable.
VEHICLE
- Justification for use and choice of vehicle (if other than water): the test substance was found to be unstable in water and other aqueous vehicles. Stability for 7 days in corn oil was demonstrated in an identity and stability investigation, and thus corn oil was taken forward as the vehicle for this study.
- Concentration in vehicle: 20, 60 or 200 mg test item/mL vehicle.
- Amount of vehicle (if gavage): 5 mL/kg bw/day.
- Lot/batch no. (if required): Batch nos. 13249003 and 13249006, Caesar & Loretz GmbH, 40721 Hilden, Germany.
- Purity: no data. - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until pregnancy occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of pregnancy).
- After successful mating each pregnant female was caged (how): except during mating, animals were housed singly. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of approximately 10 mL were collected once weekly, at the time of preparation of the formulation, and analysed for homogeneity and concentration.
- Duration of treatment / exposure:
- Males were dosed from test days 1-35 (inclusive), including 2 weeks prior to mating, the mating period and approximately 2 weeks post-mating. Females were dosed from test day 1 (2 weeks prior to mating), throughout mating and gestation, until day 3 post-partum or the day before sacrifice (from test day 41 for the first sacrificed females to test day 58 for the last sacrificed female).
- Frequency of treatment:
- Once daily.
- Remarks:
- Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
300 mg/kg bw/day
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 12.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose levels were selected based a 14-day dose range finding study conducted at the same testing laboratory. In the dose range finding study, male and female rats were treated with 1000 mg test item/kg bw/day. No animal died prematurely, there were no test item-related adverse effects, and no test item-related changes noted at necropsy.
- Rationale for animal assignment (if not random): computer-generated randomisation programme.
- Rationale for selecting satellite groups: not applicable.
- Post-exposure recovery period in satellite groups: not applicable.
- Section schedule rationale (if not random): not applicable. - Positive control:
- No.
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: before and after dosing and, additionally, regularly throughout the working day (7:00 to 15:45 on Monday to Friday; 7:00 to 11:00 with a final check at 15:00 on Saturday and Sunday).
- Cage side observations included any behavioural changes, signs of illness or reaction to treatment. Skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns were recorded, together with the onset, intensity and duration of any signs observed.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly, once before the first administration and once a week thereafter.
- Signs recorded included: changes in skin, fur, eyes, mucous membranes; occurrence of secretions, excretions and autonomic activity; changes in gait, posture and response to handling; behavioural changes.
BODY WEIGHT: Yes
- Time schedule for examinations: males and females were weighed on the first day of dosing, weekly thereafter, and at termination. During gestations, females were weighed on days 0, 7, 14 and 20, within 24 hours of parturition (day 1 post-partum), and day 4 post-partum.
FOOD AND WATER CONSUMPTION:
- Food consumption for each animal determined: Yes.
- Food intake per animal was determined using the total amount of food given to and left by each animal.
- Drinking water consumption for each animal determined: Yes, by daily visual appraisal throughout the study. - Oestrous cyclicity (parental animals):
- No data.
- Sperm parameters (parental animals):
- No data.
- Litter observations:
- STANDARDISATION OF LITTERS
Not applicable.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, alive and dead, as an absolute number and number per dam; stillbirths (absolute and per dam); postnatal mortality (pup numbers were recorded at parturition and post-partum day 4); presence of gross anomalies (absolute/per dam).
GROSS EXAMINATION OF DEAD PUPS:
Yes. dead pups were carefully examined externally for gross abnormalities. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were sacrificed on test day 36.
- Maternal animals: All surviving dams with offspring were sacrificed on day 4 post-partum.
- Females showing no signs of littering were sacrificed 24 days after the last day of the mating period.
GROSS NECROPSY
- Adult animals were examined macroscopically at sacrifice for any abnormalities or pathological changes, with particular attention given to the reproductive organs.
- The number of implantation sites and corpora lutea were recorded.
HISTOPATHOLOGY / ORGAN WEIGHTS
The epididymides, mammary glands (females only), ovaries, prostate, seminal vesicle, testes, uterus (including cervix and oviducts) and vagina of all adult animals were preserved and examined histopathologically. The epididymides, testes, ovaries and uterus (including cervix and oviducts) of all animals were weighed individually before fixation. - 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 using the Shapiro-Wilks test and the Bartlett test.
One-way analysis of variance was performed using Anova or the Kruskal-Wallis test.
Intergroup comparisons, in the case of significant differences, were made using the Dunnett test.
Statistical analyses of non-parametrical data were performed using Fisher's exact test or the Chi-squared test. - 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
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No general systemic or reproductive effects seen at highest tested dose
- Clinical signs:
- not examined
- 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:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No general systemic effects seen in the F1 generation at highest tested dose
- Reproductive effects observed:
- not specified
- Conclusions:
- In an OECD Test Guideline 422 combined repeated dose and reproductive/developmental toxicity screening study in rats, involving the gavage administration of dihydrogen hexahydroxyplatinate for at least 35 days (including 2-weeks pre-mating and throughout mating), no effects on any measured reproductive or fertility parameters were observed. The systemic and reproductive NOAEL was the highest tested dose (1000 mg/kg bw/day).
- Executive summary:
In a combined repeated dose toxicity and reproductive/developmental toxicity screening study, conducted according to OECD Test Guideline 422 and to GLP, CD rats (12/sex/group) were orally administered dihydrogen hexahydroxyplatinate by stomach tube (gavage) at doses of 0, 100, 300 or 1000 mg/kg bw/day. Males were dosed for 35 days (2 weeks pre-mating, during the mating period and for approximately 2 weeks post-mating). Females were dosed for 14 days pre-mating, through mating, gestation and up to post-partum day 3 (test day 41-58).
There were no reported changes to reproductive parameters (including number of corpora lutea, implantation sites, number of pups, fertility and gestation indices, birth index and pre- and post-implantation losses). The systemic and reproductive NOAEL was the highest tested dose (1000 mg/kg bw/day).
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- other: combined repeated dose and reproduction / developmental screening
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 18 September 2014 - 30 June 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, conducted according to GLP.
- Justification for type of information:
- Information on read-across approach
Selected endpoints for the human health hazard assessment of di(tetraethylammonium)hexahydroxoplatinate (IV) (HHPA-TEAH) are addressed by read-across, using a combination of data on hexahydroxoplatinate (HHPA) and tetraethylammonium hydroxide (TEAH) (or its substance analogue tetramethylammonium hydroxide (TMAH)). This way forward is acceptable, since HHPA-TEAH has a narrow stability and rapidly dissociates to HHPA and TEAH in acidic (e.g. gastric) environment.
The hazard information of HHPA and TEAH (or TMAH) was obtained from existing REACH registration dossiers via a license-to-use obtained by the registrant.
Detailed information justifying this read-across approach and listing/summarising the available toxicity data of HHPA-TEAH, HHPA and TEAH respectively, are reported in the ‘HHPA-TEAH ReadAcross justification’ document attached in IU section 13.2.
For the purpose of hazard assessment of HHPA-TEAH, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. - Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the 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, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany.
- Age at study initiation: 67 days (at first test item administration).
- Weight at study initiation: males: 326.4 - 402.7 g; females: 189.4 - 246.0 g (at first test item administration).
- Fasting period before study: no data.
- Housing: animals were housed singly, except during the mating period.
- Diet (e.g. ad libitum): certified commercial diet, offered ad libitum.
- Water (e.g. ad libitum): tap water, offered ad libitum.
- Acclimation period: 8 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature of 22degC +/- 3degC (maximum range).
- Humidity (%): relative humidity of 55% +/- 15% (maximum range).
- Air changes (per hr): no data.
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light, about 150 lux.
IN-LIFE DATES:
From: July 2014.
To: 23 October 2014 (males); 14 November 2014 (females). - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: test item formulations were prepared once weekly and stored in a tightly closed container at room temperature (+10 to +25 degC) until use.
DIET PREPARATION
- Rate of preparation of diet (frequency): not applicable.
- Mixing appropriate amounts with (Type of food): not applicable.
- Storage temperature of food: not applicable.
VEHICLE
- Justification for use and choice of vehicle (if other than water): the test substance was found to be unstable in water and other aqueous vehicles. Stability for 7 days in corn oil was demonstrated in an identity and stability investigation, and thus corn oil was taken forward as the vehicle for this study.
- Concentration in vehicle: 20, 60 or 200 mg test item/mL vehicle.
- Amount of vehicle (if gavage): 5 mL/kg bw/day.
- Lot/batch no. (if required): Batch nos. 13249003 and 13249006, Caesar & Loretz GmbH, 40721 Hilden, Germany.
- Purity: no data. - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until pregnancy occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of pregnancy).
- After successful mating each pregnant female was caged (how): except during mating, animals were housed singly. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of approximately 10 mL were collected once weekly, at the time of preparation of the formulation, and analysed for homogeneity and concentration.
- Duration of treatment / exposure:
- Males were dosed from test days 1-35 (inclusive), including 2 weeks prior to mating, the mating period and approximately 2 weeks post-mating. Females were dosed from test day 1 (2 weeks prior to mating), throughout mating and gestation, until day 3 post-partum or the day before sacrifice (from test day 41 for the first sacrificed females to test day 58 for the last sacrificed female).
- Frequency of treatment:
- Once daily.
- Remarks:
- Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
300 mg/kg bw/day
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 12.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose levels were selected based a 14-day dose range finding study conducted at the same testing laboratory. In the dose range finding study, male and female rats were treated with 1000 mg test item/kg bw/day. No animal died prematurely, there were no test item-related adverse effects, and no test item-related changes noted at necropsy.
- Rationale for animal assignment (if not random): computer-generated randomisation programme.
- Rationale for selecting satellite groups: not applicable.
- Post-exposure recovery period in satellite groups: not applicable.
- Section schedule rationale (if not random): not applicable. - Positive control:
- No.
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: before and after dosing and, additionally, regularly throughout the working day (7:00 to 15:45 on Monday to Friday; 7:00 to 11:00 with a final check at 15:00 on Saturday and Sunday).
- Cage side observations included any behavioural changes, signs of illness or reaction to treatment. Skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns were recorded, together with the onset, intensity and duration of any signs observed.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly, once before the first administration and once a week thereafter.
- Signs recorded included: changes in skin, fur, eyes, mucous membranes; occurrence of secretions, excretions and autonomic activity; changes in gait, posture and response to handling; behavioural changes.
BODY WEIGHT: Yes
- Time schedule for examinations: males and females were weighed on the first day of dosing, weekly thereafter, and at termination. During gestations, females were weighed on days 0, 7, 14 and 20, within 24 hours of parturition (day 1 post-partum), and day 4 post-partum.
FOOD AND WATER CONSUMPTION:
- Food consumption for each animal determined: Yes.
- Food intake per animal was determined using the total amount of food given to and left by each animal.
- Drinking water consumption for each animal determined: Yes, by daily visual appraisal throughout the study. - Oestrous cyclicity (parental animals):
- No data.
- Sperm parameters (parental animals):
- No data.
- Litter observations:
- STANDARDISATION OF LITTERS
Not applicable.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, alive and dead, as an absolute number and number per dam; stillbirths (absolute and per dam); postnatal mortality (pup numbers were recorded at parturition and post-partum day 4); presence of gross anomalies (absolute/per dam).
GROSS EXAMINATION OF DEAD PUPS:
Yes. dead pups were carefully examined externally for gross abnormalities. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were sacrificed on test day 36.
- Maternal animals: All surviving dams with offspring were sacrificed on day 4 post-partum.
- Females showing no signs of littering were sacrificed 24 days after the last day of the mating period.
GROSS NECROPSY
- Adult animals were examined macroscopically at sacrifice for any abnormalities or pathological changes, with particular attention given to the reproductive organs.
- The number of implantation sites and corpora lutea were recorded.
HISTOPATHOLOGY / ORGAN WEIGHTS
The epididymides, mammary glands (females only), ovaries, prostate, seminal vesicle, testes, uterus (including cervix and oviducts) and vagina of all adult animals were preserved and examined histopathologically. The epididymides, testes, ovaries and uterus (including cervix and oviducts) of all animals were weighed individually before fixation. - 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 using the Shapiro-Wilks test and the Bartlett test.
One-way analysis of variance was performed using Anova or the Kruskal-Wallis test.
Intergroup comparisons, in the case of significant differences, were made using the Dunnett test.
Statistical analyses of non-parametrical data were performed using Fisher's exact test or the Chi-squared test. - 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
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No general systemic or reproductive effects seen at highest tested dose
- Clinical signs:
- not examined
- 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:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No general systemic effects seen in the F1 generation at highest tested dose
- Reproductive effects observed:
- not specified
- Conclusions:
- In an OECD Test Guideline 422 combined repeated dose and reproductive/developmental toxicity screening study in rats, involving the gavage administration of dihydrogen hexahydroxyplatinate for at least 35 days (including 2-weeks pre-mating and throughout mating), no effects on any measured reproductive or fertility parameters were observed. The systemic and reproductive NOAEL was the highest tested dose (1000 mg/kg bw/day).
The calculated NOAEL for di(tetraethylammonium)hexahydroxoplatinate(IV) based on the read-across strategy and taken into account the maximum content of dihydrogen hexahydroxyplatinate = 1000 mg/kg bw/day / 0.536 (weight %) = 1865 mg/kg bw/day - Executive summary:
In a combined repeated dose toxicity and reproductive/developmental toxicity screening study, conducted according to OECD Test Guideline 422 and to GLP, CD rats (12/sex/group) were orally administered dihydrogen hexahydroxyplatinate by stomach tube (gavage) at doses of 0, 100, 300 or 1000 mg/kg bw/day. Males were dosed for 35 days (2 weeks pre-mating, during the mating period and for approximately 2 weeks post-mating). Females were dosed for 14 days pre-mating, through mating, gestation and up to post-partum day 3 (test day 41-58).
There were no reported changes to reproductive parameters (including number of corpora lutea, implantation sites, number of pups, fertility and gestation indices, birth index and pre- and post-implantation losses). The systemic and reproductive NOAEL was the highest tested dose (1000 mg/kg bw/day).
The calculated NOAEL for di(tetraethylammonium)hexahydroxoplatinate(IV) based on the read-across strategy and taken into account the maximum content of dihydrogen hexahydroxyplatinate = 1000 mg/kg bw/day / 0.536 (weight %) = 1865 mg/kg bw/day
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- Part of a combined repeated dose study (OECD 422) with reproductive and developmental toxicity screening.
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 30 November 2016 - 6 October 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Study conducted according to GLP
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Justification for study design:
- Not applicable
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 16291C1AES.
- Expiration date of the lot/batch: 01 October 2019.
- Purity test date: 27 October 2016.
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At +10°C to +25°C; under inert gas (argon), in a tightly closed container in a dry place, protected from heat and direct sunlight.
- Stability under test conditions: Stable under prescribed storage conditions.
- Solubility and stability of the test substance in the solvent/vehicle: Satisfactory stability of suspensions of the test material in corn oil for 7 days has been previously demonstrated (LPT Report No. 33687). - Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on species / strain selection:
- The rat is a commonly used rodent species for such studies.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: Yes.
- Age at study initiation: 80 days.
- Weight at study initiation: Males: 404.3 g - 475.3 g / Females: 220.8 g - 279.9 g
- Fasting period before study: No.
- Housing: Housed singly, except during mating period.
- Diet (e.g. ad libitum): Certified commercial diet, provided ad libitum.
- Water (e.g. ad libitum): Tap water provided ad libitum.
- Acclimation period: 5 days.
DETAILS OF FOOD AND WATER QUALITY: Samples of both food and water are analysed periodically for quality; certificates of analysis were provided with the study report.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/- 3°C.
- Humidity (%): 55% +/- 15%.
- Air changes (per hr): 15-20 changes/hour/
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light (150 lux at approximately 1.5m room height).
IN-LIFE DATES: First application 20 December 2016 (aged 80 days). End of in-life period: 21 February 2017. - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item formulations were prepared once weekly and stored in a tightly closed container at room temperature (+10°C to +25°C) until use.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Standard non-aqueous vehicle for formulating suspensions.
- Concentration in vehicle: 20, 60 or 200 mg/mL.
- Amount of vehicle (if gavage): 5 mL/kg bw.
- Lot/batch no. (if required): Batch nos. 16260301 or 15422602, Caesar & Loretz GmbH, 40721 Hilden, Germany
- Purity: not specified. - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: The female was placed with the same male until pregnancy had occurred or 2 weeks had elapsed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of homogeneity and concentration conducted weekly on 3 triplicate samples (total 9 samples), immediately after preparation of the test item-vehicle formulations.
- Duration of treatment / exposure:
- Males: 2 weeks prior to mating (test days 15-29), during the mating period (maximum test days 30-43) and until test day 50.
Females: 2 weeks prior to mating (test days 15-29), during the mating period (maximum test days 30-43) and during the lactation period until test days 64-77 (corresponding to lactation days 13-15). - Frequency of treatment:
- Once daily
- Details on study schedule:
- - Age at mating of the mated animals in the study: 80 days (males and females); F1 animals killed at postnatal day 13
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Vehicle control
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- "low dose"
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- "intermediate dose"
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- "high dose"
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected by the Sponsor based on available toxicological data and a 14-day dose range finding study (LPT Study No. 33687).
In the 14-day dose range finding study, Dihydrogen hexahydroxyplatinate / 2-amino-ethanol (1:2) concentrate was administered orally to male and female rats at dose levels of 500, 750 or 1000 mg/kg b.w./day for 2 weeks. At 750 mg/kg b.w./day a slight reduction in body weight was noted for the female animals (at maximum 6.1% below the value of the control group, statistically not significant). At 1000 mg/kg b.w./day slight reductions in body weight were noted for the male and female animals, statistically significant only for the female animals (6.7% below the value of the control group, p ≤ 0.05). Furthermore, a slight but statistically significant reduction in food consumption was noted for the male animals during the first test week (12.3% below the value of the control group, p ≤ 0.05).
No changes in behavior or the external appearance were noted. No findings were noted during the macroscopic inspection at necropsy. The organ weights of the kidneys, the liver, the testes and / or the ovaries revealed no test item-related differences between the control group and the test itemtreated groups. Based on the data obtained in this dose range finding study, dose levels of 100, 300 and 1000 mg Dihydrogen hexahydroxyplatinate / 2-amino-ethanol (1:2) concentrate/kg b.w./day were selected for the main study (LPT Study No. 33738). - Positive control:
- Not applicable
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily
- Cage side observations checked included skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns. The onset, intensity and duration of any signs observed were recorded.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before first administration and once weekly thereafter.
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 (day 1 post-partum), and on days 4 and 13 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: Not applicable (compound dosed by gavage)
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified
WATER CONSUMPTION AND COMPOUND INTAKE: Drinking water consumption was monitored daily by visual appraisal throughout the study - Oestrous cyclicity (parental animals):
- The oestrus cycle stage of each animal at necropsy was determined from the vaginal smears.
- Sperm parameters (parental animals):
- Parameters examined in male parental (Fo) animals: testis weight, epididymis weight
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: Yes
- 10 pups/litter following a randomisation scheme; excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, runts (pups with body weight < 70% of mean litter weight), postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups
GROSS EXAMINATION OF DEAD PUPS:
Yes, for external gross abnormalities. The external reproductive genitals were examined for signs of altered development.
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: Not examined
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: Not examined
OTHER: The thyroid of 1 male and 1 female pup from each litter was fixed. Thyroid weight were determined after fixation. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were euthanised by carbon dioxide inhalation and exsanguination on test day 48.
- Maternal animals: All surviving animals were euthanised by carbon dioxide inhalation and exsanguination on lactation day 14 or 16.
GROSS NECROPSY
- Gross necropsy consisted of weighing and examination of the organs listed in table 1.
HISTOPATHOLOGY
The tissues indicated in table 2 were prepared for microscopic examination. - Postmortem examinations (offspring):
- SACRIFICE
- All pups were euthanised by carbon dioxide inhalation and exsanguination on post-natal day 13.
- Dead pups and pups sacrificed at day 13 post-partum were carefully examined externally for gross abnormalities. The external reproductive genitals were examined for signs of altered development. - Statistics:
- Parametrical data: Homogeneity of variances and normality of distribution were tested using the BARTLETT’s and SHAPIRO-WILKS test. In case of heterogeneity and/or nonnormality of distribution, stepwise transformation of the values into logarithmic or rank values was performed prior to ANOVA. If the ANOVA yielded a significant effect (p ≤ 0.05), intergroup comparisons with the control group were made by the DUNNETT’s test (p ≤ 0.01 and p ≤ 0.05).
Non-parametrical data: The statistical evaluation of non-parametrical values was done using the FISHER or Chi-Squared test:
FISHERs exact test, n < 100; (p ≤ 0.05 and p ≤ 0.01); or
Chi-Squared test, n ≤ 0.01 (p ≤ 0.05 and p ≤ 0.01) - Reproductive indices:
- - Female fertility index (%) = (Number of pregnant rats/Number of rats used) x 100
- Gestation index (%) = (Number of dams with live pups/Number of pregnant rats) x 100 - Offspring viability indices:
- - Birth index (%) = (Total nymber 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 born (alive + dead)) x 100
- Viability Index (%) = (Number of pups alive on day 4/Number of pups alive on day 0/1) x 100
- Post-implantation Loss (%) = ((Implantations - Living Foetuses)/Implantations) x 100 - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Males
Salivation (slight, incidental (low-dose) or slight-to-pronounced (intermediate- and high-dose)) reported in 1/10, 5/10 and 10/10 animals in the low-, intermediate- and high-dose animals, respectively. No other clinical signs observed in the low-dose group. Piloerection and haemorrhagic nose/snout, and breathing sounds were each observed in 1/10 intermediate-dose animals but considered incidental on the basis of incidence. Incidental haemorrhagic nose/snout was also reported in 1/10 high-dose animals. Breathing sounds were noted in 4/10, and slightly reduced motility in 10/10 high-dose animals.
Females
Slight to pronounced salivation was reported in in 2/10 intermediate-dose and 9/10 high-dose animals. In the high-dose group, slightly reduced motility was reported in 10/10 animals, and breathing sounds were noted in 1/10 animals. No clinical signs were observed in low-dose females. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No premature death was noted in the control group or in the treatment groups.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Males
A slightly-reduced body weight compared to controls was recorded from test day 29 (4.6% below controls, not statistically significant) until sacrifice (test day 51, 8.6% below controls, not statistically significant). Body weight gain for high-dose males was "clearly below" the control group for the whole treatment period (test days 15-51; 3.8% gain for high-dose animals vs. 13.2% in controls). At autopsy, high-dose males had a body weight 9.4% below controls (not statistically significant).
Females
Slight, but statistically not significant, reductions in body weight were reported in high-dose females at the end of gestation and during lactation (6.5% below controls on gestation day 20, 5.8% below controls on lactation day 1 and 5.0% below controls on lactation day 13). At autopsy, high-dose females had a body weight 2.4% below controls (not statistically significant). - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Males
A slight, statistically not significant, reduction in food intake was noted during the first 2 weeks of dosing in the high-dose group (9.0% and 6.0% below controls).
Females
A statistically not significant reduction in food intake was noted in high-dose animals during the first week of dosing (8.1% below controls). A reduction was also seen in the high-dose animals throughout the gestation period (10.5% below controls in the first week (statistically significant), 7.4% below controls in the second week (not statistically significant) and 10.0% below controls in the third week (statistically significant). A slight but statistically significant reduction in food consumption was also noted in intermediate-dose animals during the third week of gestation (8.1% below controls). This was not considered by the study authors as test item-related. - Food efficiency:
- not examined
- Description (incidence and severity):
- No test item-related changes in the consumption of drinking water was noted by visual appraisal for any treated rats.
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No test item-related influence was noted on the haematological parameters of the male and female animals in any of the treatment groups.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No test item related influence was noted for the examined plasma levels of the biochemical parameters in any of the treatment groups.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No observations of abnormal behaviour or test item-related differences in body temperature or the hind-leg splay in comparison to the control group were noted for the male and female animals of all treatment groups. No test item-related influence on the fore- and hindlimb grip strength or in spontaneous motility was noted for the male and female animals in any of the treatment groups.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Males
Test item-related stomach lesions were reported in high-dose animals. Specifically, 3/5 animals examined showed erosions in the glandular mucosa, haemorrhage, inflammation, pigment depositon and ulcers in 1/5, and inflammation of the submucosa of the forestomach in 1/5. However, these findings could be related to the deposition of the test item and were not considered as an adverse effect of the test item.
Females
No test item-related microscopic findings were reported in the 5 high-dose females subjected to examination. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- No test item-related differences in thyroid (T4) hormone levels were noted between the male animals of the control group and the male animals of the treatment groups. Likewise, there were no test-item related differences between T4 levels in control or treated pups. Blood samples taken from treated dams at scheduled sacrifice were not analysed for T4 level.
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- No test item-related influence was noted.
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There was no test item-related influence noted on the fertility index, gestation index, pre-coital time or gestation length of treated animals.
- Dose descriptor:
- NOAEL
- Remarks:
- Fertility and reproductive parameters
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No reproductive effects seen at highest tested dose
- Critical effects observed:
- not specified
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- No test item-related differences were noted between the viability index of the pups from the dams of the control group and the pups from the treated dams.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test item-related difference was noted between the mean body weight of the pups from the dams of the control group and the mean body weight of the pups from the dams of the treatment groups on lactations days 1, 4 and 13.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no test item-related differences in the weight of the thyroid glands of the male and female pups in the controls groups compared to the treatment groups.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No gross abnormalities (e.g. malformations) were noted during the macroscopic external examination of the control pups and the pups from the treated dams.
- Histopathological findings:
- no effects observed
- Description (incidence and severity):
- The microscopic examination of the thyroids of the pups revealed no changes in the pups of the control group and the pups of the treatment groups.
- Other effects:
- no effects observed
- Description (incidence and severity):
- No test item-related differences were noted for the mean number of implantation sites, pups born (alive and dead) and live born pups between the control group and the treatment groups. Correlating the reproductive indices birth index, the live birth index and the percentage of post implantation loss were not influenced by the test item at any tested dose level.
No test item-related differences were noted for the thyroid (T4) hormone levels of the 13 day old pups.
No test item-related difference was noted for the ano-genital distance of the male and the female pups between the control group and the treatment groups. No test item-related difference in the number of nipples was noted between the male pups of the control group and in the male pups of the treatment groups. - Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Dose descriptor:
- NOAEL
- Remarks:
- adverse effects on prenatal development (conceptus to birth)
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects seen at highest tested dose
- Dose descriptor:
- NOAEL
- Remarks:
- adverse effects on postnatal development (pup)
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects seen at highest tested dose
- Critical effects observed:
- not specified
- Reproductive effects observed:
- no
- Conclusions:
- In an OECD Test Guideline 422 combined repeated dose and reproductive/developmental toxicity screening study in rats, dihydrogen hexahydroxyplatinate, compound with 2-aminoethanol was administered by gavage for at least 28 days at doses of 0, 100, 300 or 1000 mg/kg bw/day. No effects on any measured reproductive or fertility parameters were observed. The reproductive NOAEL was the highest tested dose (1000 mg/kg bw/day).
- Executive summary:
In a combined repeated dose toxicity and reproductive/developmental toxicity screening study, conducted according to OECD Test Guideline 422 and to GLP, CD rats (10/sex/group) were orally administered dihydrogen hexahydroxyplatinate, compound with 2-aminoethanol by stomach tube (gavage, in corn oil) at doses of 0, 100, 300 or 1000 mg/kg bw/day. Males were dosed for at least 28 days (14 days pre-mating, as well as during the mating and post-mating periods). Females were dosed for 14 days pre-mating, through mating, gestation (around 22 days) and up to post-natal day 13 (50 -63 days in total). Control animals received vehicle only.
There were no test item-related adverse effects on the measured reproductive or fertility parameters, on the pre-natal (pre- and post-implantation loss, number of pups born, number of stillbirths, birth and live birth indices) or the post-natal (pup body weight, survival index, the endocrine/sexual development (T4 levels, ano-genital distance, male nipples counting), gross abnormalities) developmental of the pups. Consequently, the NOAELs for reproductive toxicity, pre-natal and post-natal development were all set at 1000 mg/kg bw/day, the highest dose tested.
Referenceopen allclose all
Salivation was observed on the 4th day of administration and later in male and female rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH. A significant decrease in food consumption was observed at 20 mg/kg bw/day on Day 3 in male animals and on gestation day (GD) 20 in female animals. In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter, and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4). One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition. Based on these observations, the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day in rats.
In examination of neonates, there was no effect of tetramethylammonium hydroxide on either the numbers of total newborns and live newborns, sex ratio, live birth index, or viability index. No compound-related abnormality was observed either in external features.
Based on these observations, the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
Based on these observations, the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
Salivation was observed on the 4th day of administration and later in male and female rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH. A significant decrease in food consumption was observed at 20 mg/kg bw/day on Day 3 in male animals and on gestation day (GD) 20 in female animals. In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter, and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4). One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition. Based on these observations, the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day in rats.
In examination of neonates, there was no effect of tetramethylammonium hydroxide on either the numbers of total newborns and live newborns, sex ratio, live birth index, or viability index. No compound-related abnormality was observed either in external features.
Based on these observations, the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
Based on these observations, the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No test item-related premature deaths were reported. Two female rats (one from the low-dose group and one from the mid-dose group) died during laboratory examination on test day 15, but their deaths were considered as not test item-related.
There were no changes in behaviour, external appearance, faeces or other clinical signs in any treated group, or the control, at any point during the study.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no test item-related changes in body weight or body weight gain in male rats, in the pre-mating, mating, and post-mating periods, or in females during the pre-mating period, gestation and lactation.FOOD AND WATER CONSUMPTION
No test item-related changes in food consumption were noted between the control groups and any treated rats. There was a statistically significant decrease in food consumption in mid-dose females during the second week of the test; this showed no dose-response relationship and was considered not to be related to treatment.
The consumption of drinking water, assessed by daily visual appraisal, was not altered by treatment.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Not examined (gavage study).
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
Not examined.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Not examined.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no test item-related difference in fertility index in any control or treated rats. Insemination was confirmed in 100% of female rats paired with males; pregnancy was confirmed in 100% of high-dose females, and 91 or 92% of control, low- and mid-dose animals (1 female/group did not conceive). No statistically significant difference in pre-coital time or gestational length was reported.
The mean number of corpora lutea, implantation sites, and relative and absolute pup numbers were not affected by treatment with the test item. In total, six stillbirths were noted, with at least one in each group (including the control). These were considered to be spontaneous. There was no test item-related differences reported in birth index, live birth index, or pre- or post-implantation losses.
ORGAN WEIGHTS (PARENTAL ANIMALS)
No test item-related change in organ weights was reported in any treatment group. A statistically significant decrease in absolute liver weight was noted in low-dose females. This was within the range of the background data for the testing laboratory.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No test item-related changes were observed in macroscopic examination of the internal organs and tissues of all test animals.
HISTOPATHOLOGY (PARENTAL ANIMALS)
No microscopic changes in the examined organs or tissues were seen in any treated animals.
No test item-related premature deaths were reported. Two female rats (one from the low-dose group and one from the mid-dose group) died during laboratory examination on test day 15, but their deaths were considered as not test item-related.
There were no changes in behaviour, external appearance, faeces or other clinical signs in any treated group, or the control, at any point during the study.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no test item-related changes in body weight or body weight gain in male rats, in the pre-mating, mating, and post-mating periods, or in females during the pre-mating period, gestation and lactation.FOOD AND WATER CONSUMPTION
No test item-related changes in food consumption were noted between the control groups and any treated rats. There was a statistically significant decrease in food consumption in mid-dose females during the second week of the test; this showed no dose-response relationship and was considered not to be related to treatment.
The consumption of drinking water, assessed by daily visual appraisal, was not altered by treatment.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Not examined (gavage study).
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
Not examined.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Not examined.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no test item-related difference in fertility index in any control or treated rats. Insemination was confirmed in 100% of female rats paired with males; pregnancy was confirmed in 100% of high-dose females, and 91 or 92% of control, low- and mid-dose animals (1 female/group did not conceive). No statistically significant difference in pre-coital time or gestational length was reported.
The mean number of corpora lutea, implantation sites, and relative and absolute pup numbers were not affected by treatment with the test item. In total, six stillbirths were noted, with at least one in each group (including the control). These were considered to be spontaneous. There was no test item-related differences reported in birth index, live birth index, or pre- or post-implantation losses.
ORGAN WEIGHTS (PARENTAL ANIMALS)
No test item-related change in organ weights was reported in any treatment group. A statistically significant decrease in absolute liver weight was noted in low-dose females. This was within the range of the background data for the testing laboratory.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No test item-related changes were observed in macroscopic examination of the internal organs and tissues of all test animals.
HISTOPATHOLOGY (PARENTAL ANIMALS)
No microscopic changes in the examined organs or tissues were seen in any treated animals.
VIABILITY (OFFSPRING)
No test item-related differences in survival of pups from treated dams or the controls were noted. Survival index in all groups (treated and control) was >98%.
CLINICAL SIGNS (OFFSPRING)
Not examined.
BODY WEIGHT (OFFSPRING)
There was no difference in mean pup body weight or total litter weight between control and treated dams.
SEXUAL MATURATION (OFFSPRING)
Not examined.
ORGAN WEIGHTS (OFFSPRING)
Not examined.
GROSS PATHOLOGY (OFFSPRING)
No gross abnormalities were observed on any pups.
HISTOPATHOLOGY (OFFSPRING)
Not examined.
No test item-related differences in survival of pups from treated dams or the controls were noted. Survival index in all groups (treated and control) was >98%.
CLINICAL SIGNS (OFFSPRING)
Not examined.
BODY WEIGHT (OFFSPRING)
There was no difference in mean pup body weight or total litter weight between control and treated dams.
SEXUAL MATURATION (OFFSPRING)
Not examined.
ORGAN WEIGHTS (OFFSPRING)
Not examined.
GROSS PATHOLOGY (OFFSPRING)
No gross abnormalities were observed on any pups.
HISTOPATHOLOGY (OFFSPRING)
Not examined.
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No test item-related premature deaths were reported. Two female rats (one from the low-dose group and one from the mid-dose group) died during laboratory examination on test day 15, but their deaths were considered as not test item-related.
There were no changes in behaviour, external appearance, faeces or other clinical signs in any treated group, or the control, at any point during the study.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no test item-related changes in body weight or body weight gain in male rats, in the pre-mating, mating, and post-mating periods, or in females during the pre-mating period, gestation and lactation.FOOD AND WATER CONSUMPTION
No test item-related changes in food consumption were noted between the control groups and any treated rats. There was a statistically significant decrease in food consumption in mid-dose females during the second week of the test; this showed no dose-response relationship and was considered not to be related to treatment.
The consumption of drinking water, assessed by daily visual appraisal, was not altered by treatment.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Not examined (gavage study).
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
Not examined.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Not examined.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no test item-related difference in fertility index in any control or treated rats. Insemination was confirmed in 100% of female rats paired with males; pregnancy was confirmed in 100% of high-dose females, and 91 or 92% of control, low- and mid-dose animals (1 female/group did not conceive). No statistically significant difference in pre-coital time or gestational length was reported.
The mean number of corpora lutea, implantation sites, and relative and absolute pup numbers were not affected by treatment with the test item. In total, six stillbirths were noted, with at least one in each group (including the control). These were considered to be spontaneous. There was no test item-related differences reported in birth index, live birth index, or pre- or post-implantation losses.
ORGAN WEIGHTS (PARENTAL ANIMALS)
No test item-related change in organ weights was reported in any treatment group. A statistically significant decrease in absolute liver weight was noted in low-dose females. This was within the range of the background data for the testing laboratory.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No test item-related changes were observed in macroscopic examination of the internal organs and tissues of all test animals.
HISTOPATHOLOGY (PARENTAL ANIMALS)
No microscopic changes in the examined organs or tissues were seen in any treated animals.
No test item-related premature deaths were reported. Two female rats (one from the low-dose group and one from the mid-dose group) died during laboratory examination on test day 15, but their deaths were considered as not test item-related.
There were no changes in behaviour, external appearance, faeces or other clinical signs in any treated group, or the control, at any point during the study.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no test item-related changes in body weight or body weight gain in male rats, in the pre-mating, mating, and post-mating periods, or in females during the pre-mating period, gestation and lactation.FOOD AND WATER CONSUMPTION
No test item-related changes in food consumption were noted between the control groups and any treated rats. There was a statistically significant decrease in food consumption in mid-dose females during the second week of the test; this showed no dose-response relationship and was considered not to be related to treatment.
The consumption of drinking water, assessed by daily visual appraisal, was not altered by treatment.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
Not examined (gavage study).
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
Not examined.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
Not examined.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There was no test item-related difference in fertility index in any control or treated rats. Insemination was confirmed in 100% of female rats paired with males; pregnancy was confirmed in 100% of high-dose females, and 91 or 92% of control, low- and mid-dose animals (1 female/group did not conceive). No statistically significant difference in pre-coital time or gestational length was reported.
The mean number of corpora lutea, implantation sites, and relative and absolute pup numbers were not affected by treatment with the test item. In total, six stillbirths were noted, with at least one in each group (including the control). These were considered to be spontaneous. There was no test item-related differences reported in birth index, live birth index, or pre- or post-implantation losses.
ORGAN WEIGHTS (PARENTAL ANIMALS)
No test item-related change in organ weights was reported in any treatment group. A statistically significant decrease in absolute liver weight was noted in low-dose females. This was within the range of the background data for the testing laboratory.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No test item-related changes were observed in macroscopic examination of the internal organs and tissues of all test animals.
HISTOPATHOLOGY (PARENTAL ANIMALS)
No microscopic changes in the examined organs or tissues were seen in any treated animals.
VIABILITY (OFFSPRING)
No test item-related differences in survival of pups from treated dams or the controls were noted. Survival index in all groups (treated and control) was >98%.
CLINICAL SIGNS (OFFSPRING)
Not examined.
BODY WEIGHT (OFFSPRING)
There was no difference in mean pup body weight or total litter weight between control and treated dams.
SEXUAL MATURATION (OFFSPRING)
Not examined.
ORGAN WEIGHTS (OFFSPRING)
Not examined.
GROSS PATHOLOGY (OFFSPRING)
No gross abnormalities were observed on any pups.
HISTOPATHOLOGY (OFFSPRING)
Not examined.
No test item-related differences in survival of pups from treated dams or the controls were noted. Survival index in all groups (treated and control) was >98%.
CLINICAL SIGNS (OFFSPRING)
Not examined.
BODY WEIGHT (OFFSPRING)
There was no difference in mean pup body weight or total litter weight between control and treated dams.
SEXUAL MATURATION (OFFSPRING)
Not examined.
ORGAN WEIGHTS (OFFSPRING)
Not examined.
GROSS PATHOLOGY (OFFSPRING)
No gross abnormalities were observed on any pups.
HISTOPATHOLOGY (OFFSPRING)
Not examined.
There were no test item-related microscopic changes in the reproductive organs of the male animals. The histopathological examination that was performed on one testicle and one epididymis (with special emphasis on the qualitative stages of spermatogenesis (proliferative, meiotic and spermiogenic phases) and histopathology of the interstitial testicular structure) did not reveal any test item-related effects.
No test item-related microscopic changes could be observed in the reproductive organs for group 4 females that were examined microscopically. The mammary glands of females observed showed prominent mammary development.
No test item-related microscopic changes could be observed in the reproductive organs for group 4 females that were examined microscopically. The mammary glands of females observed showed prominent mammary development.
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 5 mg/kg bw/day
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Information on read-across approach
Selected endpoints for the human health hazard assessment of di(tetraethylammonium)hexahydroxoplatinate (IV) (HHPA-TEAH) are addressed by read-across, using a combination of data on hexahydroxoplatinate (HHPA) and tetraethylammonium hydroxide (TEAH) (or its substance analogue tetramethylammonium hydroxide (TMAH)).This way forward is acceptable, since HHPA-TEAH has a narrow stability and rapidly dissociates to HHPA and TEAH in acidic (e.g. gastric) environment.
The hazard information of HHPA and TEAH (or TMAH) was obtained from existing REACH registration dossiers via a license-to-use obtained by the registrant.
Detailed information justifying this read-across approach and listing/summarising the available toxicity data of HHPA-TEAH, HHPA and TEAH respectively, are reported in the ‘HHPA-TEAH ReadAcross justification’ document attached in IU section 13.2.
Toxicity to reproduction
Since no reproduction/developmental toxicity study with HHPA-TEAH is available, information on its dissociation products HHPA and TEAH will be used for the hazard assessment and the risk characterisation of HHPA-TEAH.
Key reproduction/developmental toxicity information from read-across substances:
NOAEL for systemic reproductive toxicity, from a combined repeated dose and reproduction/developmental toxicity screening in rats: 1000 mg HHPA/kg bw/day.
NOAEL for systemic reproductive toxicity (read-across TMAH, reproductive/developmental toxicity screening):5 mg TEAH/kg bw/day.
Effects on developmental toxicity
Description of key information
No developmental toxicity study with HHPA-TEAH is available, thus the developmental toxicity is addressed with existing data on HHPA and TEAH as detailed in the ‘HHPA-TEAH ReadAcross justification’ document (Section 13.2).
For the purpose of hazard assessment of HHPA-TEAH, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, conducted according to GLP
- Qualifier:
- according to guideline
- Guideline:
- other: OECD guideline 421(reproductive/developmental toxicity screening test)
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Route of administration:
- oral: gavage
- Details on exposure:
- Doses: 0, 1, 5, 20 mg/kg bw/day
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until copulation occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of gestation). - Duration of treatment / exposure:
- Male: 14 days before mating to the day before scheduled death through mating (total 32 days)
Female: 14 days before mating to 3 days after delivery through mating and gestation periods - Frequency of treatment:
- dialy
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 1 mg/kg bw/day
- Dose / conc.:
- 5 mg/kg bw/day
- Dose / conc.:
- 20 mg/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Statistics:
- Statistical analysis : Bartlett's test, one-way analysis of variance, Dunnett's test, Kruskal-wallis test, chi-square test
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Salivation was observed on the 4th day of administration and later in male and female rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH.
In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the female animals and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4) was observed.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A significant decrease in food consumption was observed at 20 mg/kg bw/day on gestation day (GD) 20 in female animals.
- Details on maternal toxic effects:
- Salivation was observed on the 4th day of administration and later in maternal rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH. A significant decrease in food consumption was observed at 20 mg/kg bw/day on gestation day (GD) 20 in female animals. In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter, and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4). One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition. Based on these observations, the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day in rats.
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food efficiency
- mortality
- Abnormalities:
- not specified
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No gross abnormalities were observed during macroscopic external examination of control pups or those from treated dams. - Dose descriptor:
- NOAEL
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects up to highest dose tested (20 mg/kg bw/day)
- Abnormalities:
- no effects observed
- Developmental effects observed:
- not specified
- Conclusions:
- In a reproductive/developmental toxicity screening test in rats [OECD TG 421], TMAH was administered by gavage at doses of 0, 1, 5 and 20 mg/kg bw/day. No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
- Executive summary:
In a reproductive/developmental toxicity screening test according to OECD TG 421, Sprague-Dawley rats (10/sex/group) were orally administered TMAH (by gavage) at doses of 0, 1, 5 and 20 mg/kg bw/day.
No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, conducted according to GLP
- Justification for type of information:
- Information on read-across approach
Selected endpoints for the human health hazard assessment of di(tetraethylammonium)hexahydroxoplatinate (IV) (HHPA-TEAH) are addressed by read-across, using a combination of data on hexahydroxoplatinate (HHPA) and tetraethylammonium hydroxide (TEAH) (or its substance analogue tetramethylammonium hydroxide (TMAH)). This way forward is acceptable, since HHPA-TEAH has a narrow stability and rapidly dissociates to HHPA and TEAH in acidic (e.g. gastric) environment.
The hazard information of HHPA and TEAH (or TMAH) was obtained from existing REACH registration dossiers via a license-to-use obtained by the registrant.
Detailed information justifying this read-across approach and listing/summarising the available toxicity data of HHPA-TEAH, HHPA and TEAH respectively, are reported in the ‘HHPA-TEAH ReadAcross justification’ document attached in IU section 13.2.
For the purpose of hazard assessment of HHPA-TEAH, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. - Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: OECD guideline 421(reproductive/developmental toxicity screening test)
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Route of administration:
- oral: gavage
- Details on exposure:
- Doses: 0, 1, 5, 20 mg/kg bw/day
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until copulation occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of gestation). - Duration of treatment / exposure:
- Male: 14 days before mating to the day before scheduled death through mating (total 32 days)
Female: 14 days before mating to 3 days after delivery through mating and gestation periods - Frequency of treatment:
- dialy
- Dose / conc.:
- 0 mg/kg bw/day
- Dose / conc.:
- 1 mg/kg bw/day
- Dose / conc.:
- 5 mg/kg bw/day
- Dose / conc.:
- 20 mg/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Statistics:
- Statistical analysis : Bartlett's test, one-way analysis of variance, Dunnett's test, Kruskal-wallis test, chi-square test
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Salivation was observed on the 4th day of administration and later in male and female rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH.
In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the female animals and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4) was observed.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A significant decrease in food consumption was observed at 20 mg/kg bw/day on gestation day (GD) 20 in female animals.
- Details on maternal toxic effects:
- Salivation was observed on the 4th day of administration and later in maternal rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH. A significant decrease in food consumption was observed at 20 mg/kg bw/day on gestation day (GD) 20 in female animals. In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter, and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4). One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition. Based on these observations, the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day in rats.
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food efficiency
- mortality
- Abnormalities:
- not specified
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No gross abnormalities were observed during macroscopic external examination of control pups or those from treated dams. - Dose descriptor:
- NOAEL
- Effect level:
- 20 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects up to highest dose tested (20 mg/kg bw/day)
- Abnormalities:
- no effects observed
- Developmental effects observed:
- not specified
- Conclusions:
- In a reproductive/developmental toxicity screening test in rats [OECD TG 421], TMAH was administered by gavage at doses of 0, 1, 5 and 20 mg/kg bw/day. No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
The NOAEL of the structural analogue tetraethylammonium hydroxide (TEAH) is considered to be 5 mg/kg bw/day
The calculated NOAEL for di(tetraethylammonium)hexahydroxoplatinate(IV) based on the read-across strategy and taken into account the maximum content of TEAH = 5 mg/kg bw/day / 0.528 (weight %) = 9.47 mg/kg bw/day - Executive summary:
In a reproductive/developmental toxicity screening test according to OECD TG 421, Sprague-Dawley rats (10/sex/group) were orally administered TMAH (by gavage) at doses of 0, 1, 5 and 20 mg/kg bw/day.
No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.
The most sensitive NOAEL of the structural analogue tetraethylammonium hydroxide (TEAH) is considered to be 5 mg/kg bw/day
The calculated NOAEL for di(tetraethylammonium)hexahydroxoplatinate(IV) based on the read-across strategy and taken into account the maximum content of TEAH = 5 mg/kg bw/day / 0.528 (weight %) = 9.47 mg/kg bw/day
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 September 2014 - 30 June 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, conducted according to GLP.
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 422 (Combined repeated dose and reproduction / developmental screening)
- 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, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany.
- Age at study initiation: 67 days (at first test item administration).
- Weight at study initiation: males: 326.4 - 402.7 g; females: 189.4 - 246.0 g (at first test item administration).
- Fasting period before study: no data.
- Housing: animals were housed singly, except during the mating period.
- Diet (e.g. ad libitum): certified commercial diet, offered ad libitum.
- Water (e.g. ad libitum): tap water, offered ad libitum.
- Acclimation period: 8 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature of 22degC +/- 3degC (maximum range).
- Humidity (%): relative humidity of 55% +/- 15% (maximum range).
- Air changes (per hr): no data.
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light, about 150 lux.
IN-LIFE DATES:
From: July 2014.
To: 23 October 2014 (males); 14 November 2014 (females). - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: test item formulations were prepared once weekly and stored in a tightly closed container at room temperature (+10 to +25 degC) until use.
DIET PREPARATION
- Rate of preparation of diet (frequency): not applicable.
- Mixing appropriate amounts with (Type of food): not applicable.
- Storage temperature of food: not applicable.
VEHICLE
- Justification for use and choice of vehicle (if other than water): the test substance was found to be unstable in water and other aqueous vehicles. Stability for 7 days in corn oil was demonstrated in an identity and stability investigation, and thus corn oil was taken forward as the vehicle for this study.
- Concentration in vehicle: 20, 60 or 200 mg test item/mL vehicle.
- Amount of vehicle (if gavage): 5 mL/kg bw/day.
- Lot/batch no. (if required): Batch nos. 13249003 and 13249006, Caesar & Loretz GmbH, 40721 Hilden, Germany.
- Purity: no data. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of approximately 10 mL were collected once weekly, at the time of preparation of the formulation, and analysed for homogeneity and concentration.
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until pregnancy occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of pregnancy).
- After successful mating each pregnant female was caged (how): except during mating, animals were housed singly. - Duration of treatment / exposure:
- Males were dosed from test days 1-35 (inclusive), including 2 weeks prior to mating, the mating period and approximately 2 weeks post-mating. Females were dosed from test day 1 (2 weeks prior to mating), throughout mating and gestation, until day 3 post-partum or the day before sacrifice (from test day 41 for the first sacrificed females to test day 58 for the last sacrificed female).
- Frequency of treatment:
- Once daily.
- Duration of test:
- Final treatment was administered on test day 58.
- No. of animals per sex per dose:
- 12.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose levels were selected based a 14-day dose range finding study conducted at the same testing laboratory. In the dose range finding study, male and female rats were treated with 1000 mg test item/kg bw/day. No animal died prematurely, there were no test item-related adverse effects, and no test item-related changes noted at necropsy.
- Rationale for animal assignment (if not random): computer-generated randomisation programme.
- Rationale for selecting satellite groups: not applicable.
- Post-exposure recovery period in satellite groups: not applicable.
- Section schedule rationale (if not random): not applicable. - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: before and after dosing and, additionally, regularly throughout the working day (7:00 to 15:45 on Monday to Friday; 7:00 to 11:00 with a final check at 15:00 on Saturday and Sunday).
- Cage side observations included any behavioural changes, signs of illness or reaction to treatment. Skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns were recorded, together with the onset, intensity and duration of any signs observed.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly, once before the first administration and once a week thereafter.
- Signs recorded included: changes in skin, fur, eyes, mucous membranes; occurrence of secretions, excretions and autonomic activity; changes in gait, posture and response to handling; behavioural changes.
BODY WEIGHT: Yes
- Time schedule for examinations: males and females were weighed on the first day of dosing, weekly thereafter, and at termination. During gestations, females were weighed on days 0, 7, 14 and 20, within 24 hours of parturition (day 1 post-partum), and day 4 post-partum.
FOOD AND WATER CONSUMPTION:
- Food consumption for each animal determined: Yes.
- Food intake per animal was determined using the total amount of food given to and left by each animal.
- Drinking water consumption for each animal determined: Yes, by daily visual appraisal throughout the study.
SACRIFCE
Dams with offspring were sacrificed on day 4 post-partum.
GROSS NECROPSY
- Adult animals were examined macroscopically at sacrifice for any abnormalities or pathological changes, with particular attention given to the reproductive organs.
- The number of implantation sites and corpora lutea were recorded.
HISTOPATHOLOGY / ORGAN WEIGHTS
- The mammary glands, ovaries, uterus (including cervix and oviducts), vagina and all organs showing macroscopic lesions of all adult animals were preserved. The weights of the ovaries and uterus (including cervix and oviducts) were recorded before fixation. - Ovaries and uterine content:
- The ovaries and uterine content were examined after termination: Ovaries were examined histopathologically; uterine content not examined as dams only sacrificed post-partum.
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantation sites: Yes
- Number of early/late resorptions: No data; pre- and post-implantation loss were calculated from the number of corpora lutea, implantations and living foetuses. - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data - Statistics:
- Analysis of normal distribution and homogeneity of variances was performed using the Shapiro-Wilks test and the Bartlett test.
One-way analysis of variance was performed using Anova or the Kruskal-Wallis test.
Intergroup comparisons, in the case of significant differences, were made using the Dunnett test.
Statistical analyses of non-parametrical data were performed using Fisher's exact test or the Chi-squared test. - Indices:
- 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:no effects
Details on maternal toxic effects:
There was no test item-related increase in mortality, no clinical signs of toxicity, changes in body weight or food consumption, or altered haematological, clinical chemistry or neurobehavioural parameters. Treatment also had no effect on the measured reproductive or fertility parameters. - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: No developmental toxicity seen at the highest tested dose
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No differences were noted between the control and the treatment groups for the mean body weight of the pups and the mean total litter weight of the dams.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- not examined
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- The external macroscopic examination after sacrifice revealed no test item-related gross abnormalities.
- Skeletal malformations:
- not examined
- Visceral malformations:
- not examined
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No gross abnormalities were observed during macroscopic external examination of control pups or those from treated dams. - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No embryotoxicity/teratogenicity effects seen at the highest tested dose
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- In an OECD Test Guideline 422 combined repeated dose and reproductive/developmental toxicity screening study in rats, involving the gavage administration of dihydrogen hexahydroxyplatinate for at least 35 days (including, for females, throughout mating, gestation and up to post-natal day 3), no signs of developmental toxicity or any adverse effects on pups were observed. The study NOAEL for developmental toxicity/embryotoxicity was the highest tested dose (1000 mg/kg bw/day).
- Executive summary:
In a combined repeated dose toxicity and reproductive/developmental toxicity screening study, conducted according to OECD Test Guideline 422 and to GLP, CD rats (12/sex/group) were orally administered dihydrogen hexahydroxyplatinate by stomach tube (gavage) at doses of 0, 100, 300 or 1000 mg/kg bw/day. Males were dosed for 35 days (2 weeks pre-mating, during the mating period and for approximately 2 weeks post-mating). Females were dosed for 14 days pre-mating, through mating, gestation and up to post-partum day 3 (test day 41-58).
There were no reported clinical signs of toxicity in the dams, and no gross pathological changes to the pups that were attributed to treatment. The study NOAEL for developmental toxicity was the highest tested dose (1000 mg/kg bw/day).
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 18 September 2014 - 30 June 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, conducted according to GLP.
- Justification for type of information:
- Information on read-across approach
Selected endpoints for the human health hazard assessment of di(tetraethylammonium)hexahydroxoplatinate (IV) (HHPA-TEAH) are addressed by read-across, using a combination of data on hexahydroxoplatinate (HHPA) and tetraethylammonium hydroxide (TEAH) (or its substance analogue tetramethylammonium hydroxide (TMAH)). This way forward is acceptable, since HHPA-TEAH has a narrow stability and rapidly dissociates to HHPA and TEAH in acidic (e.g. gastric) environment.
The hazard information of HHPA and TEAH (or TMAH) was obtained from existing REACH registration dossiers via a license-to-use obtained by the registrant.
Detailed information justifying this read-across approach and listing/summarising the available toxicity data of HHPA-TEAH, HHPA and TEAH respectively, are reported in the ‘HHPA-TEAH ReadAcross justification’ document attached in IU section 13.2.
For the purpose of hazard assessment of HHPA-TEAH, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. - Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 422 (Combined repeated dose and reproduction / developmental screening)
- 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, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany.
- Age at study initiation: 67 days (at first test item administration).
- Weight at study initiation: males: 326.4 - 402.7 g; females: 189.4 - 246.0 g (at first test item administration).
- Fasting period before study: no data.
- Housing: animals were housed singly, except during the mating period.
- Diet (e.g. ad libitum): certified commercial diet, offered ad libitum.
- Water (e.g. ad libitum): tap water, offered ad libitum.
- Acclimation period: 8 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature of 22degC +/- 3degC (maximum range).
- Humidity (%): relative humidity of 55% +/- 15% (maximum range).
- Air changes (per hr): no data.
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light, about 150 lux.
IN-LIFE DATES:
From: July 2014.
To: 23 October 2014 (males); 14 November 2014 (females). - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: test item formulations were prepared once weekly and stored in a tightly closed container at room temperature (+10 to +25 degC) until use.
DIET PREPARATION
- Rate of preparation of diet (frequency): not applicable.
- Mixing appropriate amounts with (Type of food): not applicable.
- Storage temperature of food: not applicable.
VEHICLE
- Justification for use and choice of vehicle (if other than water): the test substance was found to be unstable in water and other aqueous vehicles. Stability for 7 days in corn oil was demonstrated in an identity and stability investigation, and thus corn oil was taken forward as the vehicle for this study.
- Concentration in vehicle: 20, 60 or 200 mg test item/mL vehicle.
- Amount of vehicle (if gavage): 5 mL/kg bw/day.
- Lot/batch no. (if required): Batch nos. 13249003 and 13249006, Caesar & Loretz GmbH, 40721 Hilden, Germany.
- Purity: no data. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of approximately 10 mL were collected once weekly, at the time of preparation of the formulation, and analysed for homogeneity and concentration.
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: until pregnancy occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of pregnancy).
- After successful mating each pregnant female was caged (how): except during mating, animals were housed singly. - Duration of treatment / exposure:
- Males were dosed from test days 1-35 (inclusive), including 2 weeks prior to mating, the mating period and approximately 2 weeks post-mating. Females were dosed from test day 1 (2 weeks prior to mating), throughout mating and gestation, until day 3 post-partum or the day before sacrifice (from test day 41 for the first sacrificed females to test day 58 for the last sacrificed female).
- Frequency of treatment:
- Once daily.
- Duration of test:
- Final treatment was administered on test day 58.
- No. of animals per sex per dose:
- 12.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose levels were selected based a 14-day dose range finding study conducted at the same testing laboratory. In the dose range finding study, male and female rats were treated with 1000 mg test item/kg bw/day. No animal died prematurely, there were no test item-related adverse effects, and no test item-related changes noted at necropsy.
- Rationale for animal assignment (if not random): computer-generated randomisation programme.
- Rationale for selecting satellite groups: not applicable.
- Post-exposure recovery period in satellite groups: not applicable.
- Section schedule rationale (if not random): not applicable. - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: before and after dosing and, additionally, regularly throughout the working day (7:00 to 15:45 on Monday to Friday; 7:00 to 11:00 with a final check at 15:00 on Saturday and Sunday).
- Cage side observations included any behavioural changes, signs of illness or reaction to treatment. Skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns were recorded, together with the onset, intensity and duration of any signs observed.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly, once before the first administration and once a week thereafter.
- Signs recorded included: changes in skin, fur, eyes, mucous membranes; occurrence of secretions, excretions and autonomic activity; changes in gait, posture and response to handling; behavioural changes.
BODY WEIGHT: Yes
- Time schedule for examinations: males and females were weighed on the first day of dosing, weekly thereafter, and at termination. During gestations, females were weighed on days 0, 7, 14 and 20, within 24 hours of parturition (day 1 post-partum), and day 4 post-partum.
FOOD AND WATER CONSUMPTION:
- Food consumption for each animal determined: Yes.
- Food intake per animal was determined using the total amount of food given to and left by each animal.
- Drinking water consumption for each animal determined: Yes, by daily visual appraisal throughout the study.
SACRIFCE
Dams with offspring were sacrificed on day 4 post-partum.
GROSS NECROPSY
- Adult animals were examined macroscopically at sacrifice for any abnormalities or pathological changes, with particular attention given to the reproductive organs.
- The number of implantation sites and corpora lutea were recorded.
HISTOPATHOLOGY / ORGAN WEIGHTS
- The mammary glands, ovaries, uterus (including cervix and oviducts), vagina and all organs showing macroscopic lesions of all adult animals were preserved. The weights of the ovaries and uterus (including cervix and oviducts) were recorded before fixation. - Ovaries and uterine content:
- The ovaries and uterine content were examined after termination: Ovaries were examined histopathologically; uterine content not examined as dams only sacrificed post-partum.
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantation sites: Yes
- Number of early/late resorptions: No data; pre- and post-implantation loss were calculated from the number of corpora lutea, implantations and living foetuses. - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data - Statistics:
- Analysis of normal distribution and homogeneity of variances was performed using the Shapiro-Wilks test and the Bartlett test.
One-way analysis of variance was performed using Anova or the Kruskal-Wallis test.
Intergroup comparisons, in the case of significant differences, were made using the Dunnett test.
Statistical analyses of non-parametrical data were performed using Fisher's exact test or the Chi-squared test. - Indices:
- 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:no effects
Details on maternal toxic effects:
There was no test item-related increase in mortality, no clinical signs of toxicity, changes in body weight or food consumption, or altered haematological, clinical chemistry or neurobehavioural parameters. Treatment also had no effect on the measured reproductive or fertility parameters. - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: No developmental toxicity seen at the highest tested dose
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No differences were noted between the control and the treatment groups for the mean body weight of the pups and the mean total litter weight of the dams.
- Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- not examined
- Changes in litter size and weights:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- The external macroscopic examination after sacrifice revealed no test item-related gross abnormalities.
- Skeletal malformations:
- not examined
- Visceral malformations:
- not examined
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No gross abnormalities were observed during macroscopic external examination of control pups or those from treated dams. - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No embryotoxicity/teratogenicity effects seen at the highest tested dose
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- In an OECD Test Guideline 422 combined repeated dose and reproductive/developmental toxicity screening study in rats, involving the gavage administration of dihydrogen hexahydroxyplatinate for at least 35 days (including, for females, throughout mating, gestation and up to post-natal day 3), no signs of developmental toxicity or any adverse effects on pups were observed. The study NOAEL for developmental toxicity/embryotoxicity was the highest tested dose (1000 mg/kg bw/day).
The calculated NOAEL for di(tetraethylammonium)hexahydroxoplatinate(IV) based on the read-across strategy and taken into account the maximum content of dihydrogen hexahydroxyplatinate = 1000 mg/kg bw/day / 0.536 (weight %) = 1865 mg/kg bw/day - Executive summary:
In a combined repeated dose toxicity and reproductive/developmental toxicity screening study, conducted according to OECD Test Guideline 422 and to GLP, CD rats (12/sex/group) were orally administered dihydrogen hexahydroxyplatinate by stomach tube (gavage) at doses of 0, 100, 300 or 1000 mg/kg bw/day. Males were dosed for 35 days (2 weeks pre-mating, during the mating period and for approximately 2 weeks post-mating). Females were dosed for 14 days pre-mating, through mating, gestation and up to post-partum day 3 (test day 41-58).
There were no reported clinical signs of toxicity in the dams, and no gross pathological changes to the pups that were attributed to treatment. The study NOAEL for developmental toxicity was the highest tested dose (1000 mg/kg bw/day).
The calculated NOAEL for di(tetraethylammonium)hexahydroxoplatinate(IV) based on the read-across strategy and taken into account the maximum content of dihydrogen hexahydroxyplatinate = 1000 mg/kg bw/day / 0.536 (weight %) = 1865 mg/kg bw/day
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 30 November 2016 - 6 October 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 422 (Combined repeated dose and reproduction / developmental screening)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item formulations were prepared once weekly and stored in a tightly closed container at room temperature (+10°C to +25°C) until use.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Standard non-aqueous vehicle for formulating suspensions.
- Concentration in vehicle: 20, 60 or 200 mg/mL.
- Amount of vehicle (if gavage): 5 mL/kg bw.
- Lot/batch no. (if required): Batch nos. 16260301 or 15422602, Caesar & Loretz GmbH, 40721 Hilden, Germany
- Purity: not specified. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of homogeneity and concentration conducted weekly on 3 triplicate samples (total 9 samples), immediately after preparation of the test item-vehicle formulations.
- Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: The female was placed with the same male until pregnancy had occurred or 2 weeks had elapsed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually - Duration of treatment / exposure:
- Males: 2 weeks prior to mating (test days 15-29), during the mating period (maximum test days 30-43) and until test day 50.
Females: 2 weeks prior to mating (test days 15-29), during the mating period (maximum test days 30-43) and during the lactation period until test days 64-77 (corresponding to lactation days 13-15). - Frequency of treatment:
- Once daily.
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- vehicle control
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- "low dose"
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- "intermediate dose"
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- "high dose"
- No. of animals per sex per dose:
- 10.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected by the Sponsor based on available toxicological data and a 14-day dose range finding study (LPT Study No. 33687).
In the 14-day dose range finding study, Dihydrogen hexahydroxyplatinate / 2-amino-ethanol (1:2) concentrate was administered orally to male and female rats at dose levels of 500, 750 or 1000 mg/kg b.w./day for 2 weeks. At 750 mg/kg b.w./day a slight reduction in body weight was noted for the female animals (at maximum 6.1% below the value of the control group, statistically not significant). At 1000 mg/kg b.w./day slight reductions in body weight were noted for the male and female animals, statistically significant only for the female animals (6.7% below the value of the control group, p ≤ 0.05). Furthermore, a slight but statistically significant reduction in food consumption was noted for the male animals during the first test week (12.3% below the value of the control group, p ≤ 0.05).
No changes in behavior or the external appearance were noted. No findings were noted during the macroscopic inspection at necropsy. The organ weights of the kidneys, the liver, the testes and / or the ovaries revealed no test item-related differences between the control group and the test itemtreated groups. Based on the data obtained in this dose range finding study, dose levels of 100, 300 and 1000 mg Dihydrogen hexahydroxyplatinate / 2-amino-ethanol (1:2) concentrate/kg b.w./day were selected for the main study (LPT Study No. 33738). - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily
- Cage side observations checked included skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behaviour patterns. The onset, intensity and duration of any signs observed were recorded.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before first administration and once weekly thereafter.
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 (day 1 post-partum), and on days 4 and 13 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: Not applicable (compound dosed by gavage)
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified
WATER CONSUMPTION AND COMPOUND INTAKE: Drinking water consumption was monitored daily by visual appraisal throughout the study - Ovaries and uterine content:
- The ovaries and uterine content were examined after termination: Ovaries were examined histopathologically; uterine content not examined as dams only sacrificed post-partum.
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantation sites: Yes
- Number of early/late resorptions: No data; pre- and post-implantation loss were calculated from the number of corpora lutea, implantations and living foetuses. - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data - Statistics:
- Parametrical data: Homogeneity of variances and normality of distribution were tested using the BARTLETT’s and SHAPIRO-WILKS test. In case of heterogeneity and/or nonnormality of distribution, stepwise transformation of the values into logarithmic or rank values was performed prior to ANOVA. If the ANOVA yielded a significant effect (p ≤ 0.05), intergroup comparisons with the control group were made by the DUNNETT’s test (p ≤ 0.01 and p ≤ 0.05).
Non-parametrical data: The statistical evaluation of non-parametrical values was done using the FISHER or Chi-Squared test:
FISHERs exact test, n < 100; (p ≤ 0.05 and p ≤ 0.01); or
Chi-Squared test, n ≤ 0.01 (p ≤ 0.05 and p ≤ 0.01) - Indices:
- 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
Post-implantation loss [%] = ((implantations - living neonates)/implantations) x 100 - Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:no effects - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: No developmental toxicity seen at the highest tested dose
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No gross abnormalities were observed during macroscopic external examination of control pups or those from treated dams. - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No embryotoxicity/teratogenicity effects seen at the highest tested dose
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- In an OECD Test Guideline 422 combined repeated dose and reproductive/developmental toxicity screening study in rats, involving the gavage administration of dihydrogen hexahydroxyplatinate, compound with 2-aminoethanol, no signs of developmental toxicity or any adverse effects on pups were observed. The study NOAEL for developmental toxicity/embryotoxicity was the highest tested dose (1000 mg/kg bw/day).
- Executive summary:
In a combined repeated dose toxicity and reproductive/developmental toxicity screening study, conducted according to OECD Test Guideline 422 and to GLP, CD rats (10/sex/group) were orally administered dihydrogen hexahydroxyplatinate, compound with 2-aminoethanol by stomach tube (gavage, in corn oil) at doses of 0, 100, 300 or 1000 mg/kg bw/day. Males were dosed for at least 28 days (14 days pre-mating, as well as during the mating and post-mating periods). Females were dosed for 14 days pre-mating, through mating, gestation (around 22 days) and up to post-natal day 13 (50 -63 days in total).Control animals received vehicle only.
There were no reported clinical signs of toxicity in the dams, and no gross pathological changes to the pups that were attributed to treatment. The study NOAEL for developmental toxicity was the highest tested dose (1000 mg/kg bw/day).
Referenceopen allclose all
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 9.47 mg/kg bw/day
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
Information on read-across approach
Selected endpoints for the human health hazard assessment of di(tetraethylammonium)hexahydroxoplatinate (IV) (HHPA-TEAH) are addressed by read-across, using a combination of data on hexahydroxoplatinate (HHPA) and tetraethylammonium hydroxide (TEAH) (or its substance analogue tetramethylammonium hydroxide (TMAH)). This way forward is acceptable, since HHPA-TEAH has a narrow stability and rapidly dissociates to HHPA and TEAH in acidic (e.g. gastric) environment.
The hazard information of HHPA and TEAH (or TMAH) was obtained from existing REACH registration dossiers via a license-to-use obtained by the registrant.
Detailed information justifying this read-across approach and listing/summarising the available toxicity data of HHPA-TEAH, HHPA and TEAH respectively, are reported in the ‘HHPA-TEAH ReadAcross justification’ document attached in IU section 13.2.
For the purpose of hazard assessment of HHPA-TEAH, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation.
Developmental toxicity
Since no reproduction/developmental toxicity study with HHPA-TEAH is available, information on its dissociation products HHPA and TEAH will be used for the hazard assessment and the risk characterisation of HHPA-TEAH.
For the purpose of hazard assessment of HHPA-TEAH, the point of departure for the most sensitive endpoint of each constituent is used for the DNEL derivation.
Key reproduction/developmental toxicity information from read-across substances:
NOAEL for developmental toxicity/embryotoxicity, from a combined repeated dose and reproduction/developmental toxicity screening in rats: 1000 mg HHPA/kg bw/day.
NOAEL for systemic reproductive toxicity (read-across TMAH, reproductive/developmental toxicity screening): 5 mg TEAH/kg bw/day.
Toxicity to reproduction: other studies
Description of key information
No data identified.
Mode of Action Analysis / Human Relevance Framework
No data identified.
Justification for classification or non-classification
Reliable reproductive/developmental toxicity screening studies on HHPA and TEAH illustrated that classification of these substances for reproductive toxicity is not required, according to EU CLP criteria (EC 1272/2008). Therefore, classification of HHPA-TEAH for reproductive toxicity is considered also not required.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
