Ruthenium trichloride hydrate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In an OECD Test Guideline 421 reproduction and developmental toxicity screening study, to GLP, parental (F0) rats (12/sex/group) were fed diets containing ruthenium trichloride hydrate at concentrations of 0, 1500, 5000 or 15,000 ppm for at least 29 days. No adverse effects on any measured reproductive or fertility parameters of parent males and females (F0 animals) were observed at any dose. The reproductive NOAEL was the highest tested dose of 15,000 ppm (about 1276 mg/kg bw/day) (Hargitai, 2017).

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6 September - 23 November 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Study conducted according to GLP

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

yes

Remarks:

The temperature range (21.6-27.4°C) was slightly outside that specified by the guideline (19-25°C); the relative humidity (24-67%) was also slightly outside the guideline range (30-70%); these are not considered to influence the validity of the results

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Justification for study design:

Not applicable

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The rat is regarded as a suitable species for toxicology and reproduction studies. Wistar rat was selected due to experience with this strain of rat in toxicity and reproduction toxicity studies and known fertility. Historical control data for the strain of rat used at the Test Facility demonstrated that sexual maturity is attained at 10 weeks of age.

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, D 97633, Sulzfeld, Germany) from SPF colony
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) 12 wks (14 wks at mating)
- Weight at study initiation: (P) Males: 373-472 g; Females: 216-279 g
- Fasting period before study: No data
- Housing: Rodents were group-housed in polycarbonate wire grid bottomed cages with wood chip bedding, with up to 3 animals of the same sex and dose group/cage aside from the mating and gestation/delivery period when they were paired or individually housed (with pups), respectively. Males were caged individually after their mating had been finished. Group housing allowed social interaction, the deep wood sawdust bedding (from GD 10 until the end of the study in case of females) allowed digging and other normal rodent activities. Nest building material was also provided for the animals to allow normal nesting behaviour. Glass hiding tubes were provided to the animals.
- Diet (e.g. ad libitum): Ssniff® SM R/M-Z+H "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH (Address: Ferdinand-Gabriel-Weg 16, D-59494 Soest, Germany) ad libitum.
- Water (e.g. ad libitum): Tap water from municipal supply, as for human consumption, from 500 ml bottle ad libitum.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.6-27.4
- Humidity (%): 24-67
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 6 September 2016 To: 23 November 2016

Route of administration:

oral: feed

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: not applicable

DIET PREPARATION
- Rate of preparation of diet (frequency): A single diet mix batch was prepared before the study.
- Mixing appropriate amounts with (Type of food): Ssniff® SM R/M-Z+H "Autoclavable complete diet for rats and mice – breeding and maintenance". Ruthenium chloride was incorporated into the diet; about 6 minutes for pre-mixing and 4-8 minutes for diet mixing.
- Storage temperature of food: 15-21 °C (storage areas); 22 +/- 3 °C (animal rooms).

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: Up to 15 days (until copulation occurred, this was 5 days for all but one animal; all males mated successfully)
- Proof of pregnancy: vaginal plug or sperm in vaginal smear was evidence of copulation, 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 the diets for homogeneity and concentration of Ruthenium chloride were performed at the Test Site using a validated ICP/AES method to determine the Ruthenium content.

Duration of treatment / exposure:

Males were treated for 29 days (14 days pre-mating and 15 days mating/post-mating period). Females were treated for 14 days pre-mating, for up to 14 days in the mating period, through gestation (22-24 days) and up to and including the day of necropsy (13 days post-partum dosing); non-pregnant females were sacrificed on day 49.

Frequency of treatment:

Constant (dietary)

Details on study schedule:

- Age at mating of the mated animals in the study: 14 weeks

Treatment of both sexes began after the acclimatisation (5 days) plus a pre-exposure period (14 days), then dietary treatment was made for 2 weeks before mating, during the mating, and was continued up to and including the day of necropsy.

Dose / conc.:

0 ppm (nominal)

Remarks:

Control group receiving the basal (control) diet.

Dose / conc.:

100 ppm (nominal)

Remarks:

"Low dose"

Dose / conc.:

300 ppm (nominal)

Remarks:

"Mid dose"

Dose / conc.:

1 000 ppm (nominal)

Remarks:

"High dose"

No. of animals per sex per dose:

12

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: The concentrations of Ruthenium chloride in diet were selected based on the available data and information from a preliminary dose range finding study [CiToxLAB study code 15/266-100PE].
- Rationale for animal assignment (if not random): Randomisation based on body weights.

Positive control:

Not included

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (for morbidity and mortality), at the beginning and the end of the working day. Once daily for general clinical observations, aside from days where more detailed clinical observations were made.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure and then at least weekly (in the morning)
- Signs evaluated included changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. self-mutilation, walking backwards) were also recorded. Special attention was directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. Pertinent behavioural changes, signs of difficult or prolonged parturition and all signs of toxicity including mortality were recorded including onset, degree and duration of signs as applicable.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly; parental females were additionally weighed on GD 0, 3, 7, 10, 14, 17 and 20, and on PPD 4, 7, 10 and 13

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 (Food consumption was determined by re-weighing the non-consumed diet with a precision of 1 g at least weekly (on body weight measurement days or more frequently).
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

Oestrous cyclicity (parental animals):

Oestrus cycles were monitored for each female (15/group) by vaginal smears daily during the pre-exposure period. Any females that failed to show a 4 or 5-day cycle were not included in the study, the first twelve females showing regular oestrus cycles were treated and used for mating. Vaginal smears were also monitored for oestrus cyclicity daily from the beginning of the treatment period until evidence of mating.

Sperm parameters (parental animals):

Parameters examined in parental males: testis weight, epididymis weight, seminal vesicles (with coagulating glands) weight. Special attention was paid to evaluation of the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure.

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, runts, presence of gross abnormalities, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups, blood sampling. Live pups were counted, sexed, weighed individually within 24 hours of parturition (PND 0) and on PND 4 and 13

GROSS EXAMINATION OF DEAD PUPS:
Yes for gross abnormalities; possible cause of death was determined, where possible, for pups born or found dead.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals at the end of the mating period (on day 29)
- Maternal animals: All surviving animals on PPD 13 (or day 49 for non-pregnant females)

GROSS NECROPSY
- Gross necropsy consisted of external examinations; the cranium, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed macroscopically. Special attention was paid to the organs of the reproductive system. The number of implantation sites and corpora lutea were recorded.

HISTOPATHOLOGY / ORGAN WEIGHTS
Detailed histological examination was performed on ovaries, testes and epididymides in the Control and High dose groups, gross lesions of the animal found dead and all macroscopic findings (abnormalities) from all animals, all reproductive organs of two Low and Mid dose groups mating pairs and additional reproductive organs (prostate or uterus and oviduct) for High dose mating pair where no pregnancy was achieved.

Special attention was paid to evaluation of the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. Detailed histological examination of the ovaries covered the follicular, luteal, and interstitial compartments of the ovary, as well as the epithelial capsule and ovarian stroma.

The following organs were weighed: uterus (with cervix), testes, epididymides, prostate, seminal vesicles with coagulating glands, brain, ovaries, thyroids. Relative organ weights were determined.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed on PND 13.
- These animals were subjected to postmortem examinations along with pups found dead.

GROSS NECROPSY
Particular attention was paid to the external reproductive genitals (no signs of altered development was recorded).

HISTOPATHOLOGY / ORGAN WEIGTHS
The thyroid glands of Control and High dose pups were examined microscopically.

Statistics:

Numerical data obtained during the conduct of the study were subjected as appropriate to calculation of group means and standard deviations.

The statistical evaluation of appropriate data was performed with the statistical program package SPSS PC+4.0. The heterogeneity of variance between groups was checked by Bartlett’s test. Where no significant heterogeneity was detected, a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant, Duncan's Multiple Range test was used to assess the significance of inter-group differences. Where significant heterogeneity was found, the normal distribution of data was examined by Kolmogorow-Smirnov test. In the case of non-normal distribution, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was applied. If a positive result was detected, the inter-group comparisons were performed using Mann-Whitney U-test. The Chi-squared test was used for non-continuous data.

Reproductive indices:

Male/female mating and fertility indices, gestation index

Offspring viability indices:

Survival Index, pre-implantation mortality, intrauterine mortality, total mortality, % males

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Red discharge in the left eye for one Low dose male was observed on Days 26-29, but this was not related to the test item treatment. Dark faeces were observed for all High dose males from Day 13-29. However, as the dark colour was ascribed to the presence of test item in the faeces, this test item related effect was considered not to be an adverse effect.

Low dose females showed no clinical signs. In the Mid dose group, piloerection was observed for one female several times during Days 40-43 (from the end of gestation period to until PPD2), though these findings were most probably related to a difficult delivery process. Dark faeces were observed for all High dose females from Day 13 until the end of the study. However, this fact was considered a non-adverse effect.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

One Control female was found dead on Day 36, but no other cases were recorded during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

No significant changes were seen in the body weight gain values of the Low and Mid dose males when compared to the control animals. Decreased growth was recorded in the High dose males at the start of the treatment, the difference was statistically significant (p<0.01). Decreased values when compared to the control were also recorded in the High dose males in other periods, although the difference did not reach statistical significance in those cases. However, the body weight gain data of the High dose males for the complete treatment period (Day 0-29) was significantly lower (p<0.01) than control (by approximately 37%). These facts indicated a test item related effect in the High dose male group.

For females, no statistically significant differences were observed in the growth of the treated groups when compared to the control in any periods or during the entire study. Although some differences were recorded in some individual cases, they did not achieve statistical significance, the observed values were considered as random variation.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

There were no test item related effects in the mean daily food consumption of Low and Mid dose groups (males and females) and High dose females, but the daily food consumption of the High dose males was slightly affected by the treatment.

The mean daily food consumption in the pre-treatment period was similar in the treated males when compared to the Control group. No statistically significant decreases were seen in the treatment period in the Low and Mid dose males (the observed statistically significant increase in the Mid dose males in the second half of the pre-mating period was considered as random variation). However, a statistically significant reduction in food consumption was recorded at the beginning of the treatment in High dose males, considered a slight test item related effect. This transient effect recovered with no significant differences recorded in the mean daily food consumption for the complete treatment period (Day 0-29) in any test item treated male group when compared to the control.

The mean daily food consumption in the pre-treatment period was similar in the treated females compared to the Control group.

During the gestation period, no significant changes were recorded in the Low and Mid dose females when evaluated for the complete period (Day 0-20), although some increases were seen in the second week. The overall food consumption of the High dose females was significantly higher than the control value; similar trends were observed for each week of this period, indicating a non-adverse test item effect.

No statistically significant differences were seen in the daily food consumption of the treated females in the littering period when compared to the controls.

The mean daily food consumption for the complete treatment period (Day 0-PPD13) was significantly higher in all test item treated groups than in the control, but no clear dose response was observed.

Mean test item intakes (males and females combined) were 123.3, 418.5 and 1275.8 mg/kg bw/day at the low, mid and high dose levels, respectively.

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

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related microscopic findings were noted during the detailed histological examination in the testis, epididymis and ovary in High dose animals.

Histopathological evaluation of the male gonads as well as testicular interstitial cell structure; the spermatogenic cells representing different phases of the development and differentiation of the spermatozoons were similar in Control and High dose males. The follicular, luteal and interstitial compartments of the ovary as well as epithelial capsule and stroma had a similar histological structure in both Control and High dose females.

Slight diffuse tubular dilatation of the testes in one High dose male, and minimal spermatocyte degeneration of right testis in another, were incidental or considered to be a common background.

Furthermore, reproductive organs of mating pairs (testes, epididymides, prostate, seminal vesicles with coagulation gland for males; uterus, cervix, ovary, oviduct and vagina for females) of Low, Mid and High dose groups where no pregnancy was achieved were also examined. No test item-related microscopic changes or any specific abnormalities were detected that could be causal for the lack of litters in those cases. Uterine proestrus correlated with necropsy was observed in one female.

The retained thyroid samples of all parental animals were examined. No significant findings were recorded for any examined animals.

Histopathological findings: neoplastic:

not examined

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

Statistically significant decrease (p<0.01) was observed in T4 levels of the Mid and High dose males when compared to the relevant control data, while no significant changes were recorded at the low dose. However, there was no clear dose response, and the group mean values were within the range of the individual values of the of the historical control data. A similar trend was seen in the parental female samples, but the difference did not gain statistical relevance at any dose groups and the mean values were within the historical control data. Thus, no clear test item related effect can be established in this case.

No statistically significant differences were detected in the thyroid-stimulating hormone levels of parental males and females.

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

Only females with regular cyclicity were used for treatment in the study. The cycle length and the days in the different stages of the oestrus cycle were comparable in the treated females to the controls, no statistically significant or biologically relevant changes were observed.

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

Histopathological evaluation of the male gonads as well as testicular interstitial cell structure; the spermatogenic cells representing different phases of the development and differentiation of the spermatozoons were similar in Control and High dose males.

Reproductive performance:

effects observed, non-treatment-related

Description (incidence and severity):

The mating indices were normal in all test item treated groups (92-100%) for both males and females. The fertility indices were also in the normal range (92-100%) for all test item treated males and females. The gestation index was 100% in all test item treated groups. The length of mating did not differ significantly in the test item treated groups when compared to control.

The mean duration of pregnancy was comparable between control and test item treated groups. Delivery lasted more than three hours for one Mid dose female. However, this relatively long parturition was considered to be incidental, and not related to the treatment. There were no significant differences or effects that could be ascribed to treatment on the number of implantation or intrauterine and total mortality values (litter mean and %) in any of the test item treated groups.

Dose descriptor:

NOAEL

Remarks:

Fertility and reproductive parameters

Effect level:

1 276 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects at high dose

Dose descriptor:

NOAEL

Remarks:

Systemic toxicity

Effect level:

419 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOAEL

Remarks:

Systemic toxicity

Effect level:

1 276 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects at high dose

Critical effects observed:

not specified

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

During the external evaluation of the surviving pups, haemorrhage was detected for some pups on the thorax dorsal area, cheek(s), on both snouts, or at several areas in two animals (abdominal / lumbar area, both hind limbs and sacrum; thorax dorsal area, both snouts and both cheeks). These were considered not to be treatment related.

Some pups were cyanotic and/or cold to touch on PND0 (hunched back was also recorded for one animal), but they recovered later and survived the lactation period except for one which was cannibalized on PND4. Two pups were cold on PND1 and found dead on PND2. Cyanosis was also recorded on PND5 for a Low dose pup, but this fact did not affect the survival until termination. These findings are known types of spontaneous events. Based on the low incidence and lack of dose response they were considered unrelated to the test item treatment.

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

The number of viable pups on PNDs 0, 4 and 13, as well as pups’ survival indices and sex ratio at these times, were comparable to control values in all test item treated groups.

There were no relevant changes in the number of viable pups or number of found dead pups in the treated groups on PNDs 0, 4 and 13, when compared to the control value.

Statistically significant decrease in the number of viable pups born was detected in the Mid dose group due to the increased number of still born pups, but due to the lack of dose response this fact was not considered as a treatment related effect.

Statistically increased number of pups cannibalized was seen during the lactation period in the Low and High dose groups compared to the control, but due to the lack of dose response, these facts were considered as animal variability, not treatment related effect.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

There was no effect on the offspring body weight or body weight gain on PNDs 0, 4 or 13 in treated animals, compared to controls. No relevant, statistically significant changes were seen in the litter mean body weight values at these time points in any test item treated groups. There was no effect of the test item on the body weight gain values in the periods of PND 0-4, 4-13 or 0-13.

Significant differences were seen in the body weights when the mean value of all pups in the Low and Mid dose groups were compared to the Control group. However, the litter means are considered to be more appropriate since weights of pups in the same litter are not independent variables. Also, there was no dose response (decreased values were seen in the Low dose group, while increased values were seen in the Mid dose group). The differences in these cases were ascribed to litter differences rather than treatment group. Due to the lack of toxicological relevance, these differences were considered not to be a treatment related effect.

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:

effects observed, non-treatment-related

Description (incidence and severity):

No test item related effect was observed on the thyroid weight of Low and Mid dose pups when compared to control data (combined for male and female pups). A slight statistically significant decrease was seen in the absolute thyroid weight in the High dose group. However, due to the lack of dose response, and the magnitude of the change in the absolute values and as no significant change was detected in the relative thyroid weight in this dose group; this was not considered as a test item effect. A similar trend was seen in case of female data, while no statistically significant changes were detected when the male pup data were evaluated.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related macroscopic changes were seen in the F1 generation in any dose group at termination except of a missing end of tail for a Low dose pup, which was considered as an irrelevant finding.

There was no test item effect on the anogenital distance determined in pups from the treated groups (compared to controls), neither in case when data of all pups were calculated nor in case when results were separated by different sexes. There were no effects on nipple retention in male pups on PND 13.

Histopathological findings:

no effects observed

Description (incidence and severity):

The retained thyroid samples of the Control and High dose pups were examined. No significant findings were recorded for any examined animals.

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

Statistically significant decrease was observed in T4 levels of pups on PND 13 from Mid and High dose animals when compared to the relevant control data, while no significant changes were recorded at the Low dose, or in any groups on PND 4.

The differences between the groups for the hormone data was considered, along with pup weight data, thyroid weights and histopathology; it was concluded that there was no effect of the test item on the thyroids.

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Dose descriptor:

NOAEL

Remarks:

Pre- and post-natal development of pups

Generation:

F1

Effect level:

1 276 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects at high dose

Critical effects observed:

not specified

Reproductive effects observed:

no

Conclusions:

In an OECD Test Guideline 421 reproduction and developmental toxicity screening study, to GLP, parental (F0) rats (12/sex/group) were fed ruthenium trichloride hydrate at dietary concentrations of 0, 1500, 5000 or 15000 ppm for at least 28 days. No adverse effects on any measured reproductive or fertility parameters of parent males and females (F0 animals) or development of offspring (F1 generation) were observed at any dose. The reproductive and developmental NOAEL was the highest tested dose of 15000 ppm (about 1276 mg/kg bw/day). The systemic NOAEL was 5000 ppm (419 mg/kg bw/day), based on reduced growth in males at the highest tested dose.

Executive summary:

In a reproductive and developmental toxicity screening study, conducted according to OECD Test Guideline 421 and to GLP, Wistar rats (12/sex/group) were fed ruthenium trichloride hydrate at concentrations of 0, 1500, 5000 or 15000 ppm. Males were dosed for 29 days (14 days pre-mating and 15 days through the mating and post-mating periods). Females were dosed for 14 days pre-mating, through mating (up to 14 days), gestation (22-24 days) and up to post-partum day 13 (around 8 weeks in total).

There were no reported changes to reproductive parameters (including number of implantations, number of pups, fertility and gestation indices, reproductive performance as well as intrauterine and total mortality). Treatment was not associated with any gross changes, or microscopic findings in the reproductive organs, at up to the highest tested dose. Thyroid hormone analysis was also unaffected by treatment. Systemic toxicity of parental animals was limited to reduced growth in males at the highest tested dose.

There were no adverse effects on the F1 offspring viability, clinical signs or developmental effects. Body and organ weights were also unaffected, while histopathological and hormone evaluation of the thyroid did not reveal any adverse findings.

The reproductive and developmental NOAEL was the highest tested dose of 15000 ppm (1276 mg/kg bw/day); the systemic NOAEL was 5000 ppm (419 mg/kg bw/day).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 276 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

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

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No relevant data in humans were identified.

 

In a reproductive and developmental toxicity screening study, conducted according to OECD Test Guideline 421 and to GLP, Wistar rats (12/sex/group) were fed ruthenium trichloride hydrate at concentrations of 0, 1500, 5000 or 15,000 ppm. Males were dosed for 29 days (14 days pre-mating and 15 days through the mating and post-mating periods). Females were dosed for 14 days pre-mating, through mating (up to 14 days), gestation (22-24 days) and up to post-partum day 13 (around 8 weeks in total). There were no reported changes to reproductive parameters (including number of implantations, number of pups, fertility and gestation indices, reproductive performance as well as intrauterine and total mortality). Test item administration was not associated with any gross changes, or microscopic findings in the reproductive organs, at up to the highest tested dose. Thyroid hormone analysis was also unaffected by treatment. The reproductive NOAEL was the highest tested dose of 15,000 ppm (about 1276 mg/kg bw/day) (Hargitai, 2017).

Effects on developmental toxicity

Description of key information

In an OECD Test Guideline 421 reproduction and developmental toxicity screening study, to GLP, parental (F0) rats (12/sex/group) were fed diets containing ruthenium trichloride hydrate at concentrations of 0, 1500, 5000 or 15,000 ppm for at least 29 days. No adverse effects on development of offspring (F1 generation) were observed at any dose. The developmental NOAEL was the highest tested dose of 15,000 ppm (about 1276 mg/kg bw/day) (Hargitai, 2017).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 276 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

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

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No relevant data in humans were identified.

 

In a reproductive and developmental toxicity screening study, conducted according to OECD Test Guideline 421 and to GLP, Wistar rats (12/sex/group) were fed ruthenium trichloride hydrate at concentrations of 0, 1500, 5000 or 15,000 ppm. Males were dosed for 29 days (14 days pre-mating and 15 days through the mating and post-mating periods). Females were dosed for 14 days pre-mating, through mating (up to 14 days), gestation (22-24 days) and up to post-partum day 13 (around 8 weeks in total). There were no adverse effects on the F1 offspring viability, clinical signs or developmental effects. Body and organ weights were also unaffected, while histopathological and hormone evaluation of the thyroid did not reveal any adverse findings. The developmental NOAEL was the highest tested dose of 15,000 ppm (1276 mg/kg bw/day) (Hargitai, 2017).

Toxicity to reproduction: other studies

Description of key information

No data identified.

Additional information

No data identified.

Mode of Action Analysis / Human Relevance Framework

No data identified.

Justification for classification or non-classification

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