Dihydrogen hexahydroxyplatinate, compound with 2-aminoethanol (1:2)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

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) (Hansen, 2017).

Link to relevant study records

Reference

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:

key 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.

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.

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

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

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No relevant data in humans were identified.

 

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 parameters (fertility index, gestation index, precoital time and gestation length). Consequently, the NOAEL for reproductive toxicity was set at 1000 mg/kg bw/day, the highest dose tested (Hansen, 2017).

Effects on developmental toxicity

Description of key information

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 for at least 28 days, no effects on pre- or postnatal development of pups were observed. The pre- and postnatal developmental NOAELs were set at 1000 mg/kg bw/day, the highest tested dose (Hansen, 2017).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

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

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No relevant data in humans were identified.

 

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 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) development of the pups. Consequently, the NOAELs for effects on pre- and postnatal development were set at 1000 mg/kg bw/day, the highest dose tested (Hansen, 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

In a reliable combined repeated dose toxicity study and reproductive/developmental toxicity screening study involving gavage administration of dihydrogen hexahydroxyplatinate, compound with 2-aminoethanol to rats for at least 28 days, no adverse effects on reproductive parameters (sexual function or fertility) or development of offspring were seen at up to 1000 mg/kg bw/day. As such, classification of this substance for reproductive toxicity is not required, according to EU CLP criteria (EC 1272/2008).