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EC number: 279-356-6 | CAS number: 79953-85-8
- Life Cycle description
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- Endpoint summary
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
OECD 422, GLP: NOAEL = 1000 mg/kg bw (ERBC 2022)
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From Nov 2021 to Oct 2022
- 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:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 29 July 2016
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- TEST MATERIAL
Batch no. 0004079400
CAS no. 79953-85-8
Purity 99.4 wt%
Expiry/Retest date 27 August 2022
Appearance Yellow powder
Storage conditions Room temperature - Species:
- rat
- Strain:
- Wistar
- Remarks:
- Wistar Hannover rat
- Details on species / strain selection:
- The Wistar Hannover rat was the species and strain of choice because it is accepted by many regulatory authorities and there are ample experience and background data on this species and strain.
The oral route was selected as it is a possible route of exposure of the test item in man and has been specifically requested by the Regulatory Authorities. - Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Italia S.p.A., Calco (Lecco), Italy
- Females: nulliparous and non-pregnant
- Age at study initiation: 9 - 11 weeks old
- Weight at acquisition: 212-230 g for males and 182-193 g for females
- Housing arrival - mating: animals were housed up to 5 of one sex to a cage, in polysulfone solid bottomed cages measuring 59.5×38×20 cm, nesting material was provided inside suitable bedding bags and changed at least twice a week
- Housing during mating: animals were housed one male to one female in clear polysulfone cages measuring 42.5×26.6×18.5 cm with a stainless steel mesh lid and floor, each cage tray held absorbent material which was inspected and changed daily
- Housing after mating: the males were re-caged as they were before mating, females were transferred to individual solid bottomed cages for the gestation period, birth and lactation, nesting material was provided inside suitable bedding bags, additional suitable nesting material was provided as necessary, nesting material was changed at least twice a week
- Diet: ad libitum, laboratory rodent diet (4 RF 21,Mucedola S.r.l., Via G. Galilei, 4, 20019 SettimoMilanese (MI), Italy)
- Water: ad libitum, via water bottles
- Acclimation period: approx. 2 weeks
DETAILS OF FOOD AND WATER QUALITY:
There was no information available to indicate that any non-nutrient substance likely to influence the effect of the test item was present in the drinking water or the diet.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-60
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 21 Dec 2021 (allocation) To: 17 Feb 2022 (last day of necropsy) - Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5% CMC in water, softened by reverse osmosis
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Concentration in vehicle: 10, 30 and 100 mg/mL
- Dose volume: 10 mL/kg body weight, dose volumes for males and females were adjusted once per week for each animal according to the last recorded body weight, dose volumes for females during the gestation and lactation periods were calculated according to the last recorded body weight
- Dosing preparation: preparations were made daily, preparations were kept under magnetic stirring for at least 16 hours at room temperature and up to completion of dosing - Details on mating procedure:
- - M/F ratio per cage: monogamous (one male to one female)
- Length of cohabitation: female was paired with the same male until positive identification of mating
- Proof of pregnancy: spermidentification, vaginal plug in situ or copulation plugs found in the cage tray, day of successful mating was referred to as day 0 post coitum
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged: females were transferred to individual solid bottomed cages for the gestation period, birth and lactation (measuring 42.5×26.6×18.5 cm), nesting material was provided inside suitable bedding bags, additional suitable nesting material was provided as necessary, nesting material was changed at least twice a week - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analytical method was validated in a separate study in the range from 10 to 100 mg/mL. In the same study, a 28 hour stability at room temperature and a 8-day stability at 2- 8°C were verified in the range from 10 to 100 mg/mL. Samples of the formulations prepared during the current study (the first and the last week of treatment where possible) were analysed to check the concentration and homogeneity. Results of the analyses were within the acceptability limits for suspensions (85-115% for concentration and CV < 10% for homogeneity).
- Duration of treatment / exposure:
- Males were treated for 2 consecutive weeks prior to pairing and during pairing with females until the day before necropsy, for a total of 39 days.
Females were treated for 2 consecutive weeks prior to pairing, during pairing and throughout the gestation and lactation periods until day 13 post partum, for a period comprising from 51 to 55 days. - Frequency of treatment:
- daily
- Details on study schedule:
- - Age at mating of the mated animals (P0 generation) in the study: approx. 13-14 weeks (approx. 11-12 weeks old at start of administration, followed by 2 weeks pre-mating phase)
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Group 1
Control - Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- Group 2
Low-level dose - Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- Group 3
Medium-level dose - Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- Group 4
High-level dose - No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose levels of 100, 300 and 1000 mg/kg/day were selected based on information from a preliminary non-GLP compliant study
- Rationale for animal assignment: rats were allocated to the groups by computerised stratified randomisation to give approximately equal initial group mean body weights., individuals were uniquely identified within the study by sex, tattoo on the hind feet and ear notch and housed 5 of one sex per cage
- Fasting period before blood sampling for clinical biochemistry: yes - Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Mortality: checked twice daily
- Clinical signs: once before commencement of treatment and at least once daily during the study
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before commencement of treatment and at least once a week thereafter
- Observation of changes in gait and posture, reactivity to handling, presence of clonic or tonic movements, stereotypies or bizarre behaviour and effects on the autonomic nervous system (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern), changes in fur, skin, eyes, mucous membranes, occurrences of secretions and excretions (see table No. 1 for observed parameters and evaluation scale)
- Animals were examined in an open arena for a minimum of three minutes
BODY WEIGHT: Yes
- Time schedule for examinations: males were weighed weekly from allocation to termination, females were weighed weekly from allocation to positive identification of mating and on days 0, 7, 14 and 20 post coitum, dams were also weighed on days 1, 4, 7, 13 post partum and just before to necropsy
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- the weight of food consumed by each cage of males and females were recorded weekly (whenever possible) during the pre-mating period starting from day 1 of dosing up to mating
- Individual food consumption for mated females were measured on gestation days 7, 14 and 20 post coitum starting from day 0 post coitum and on day 7 and 13 post partum starting from day 1 post partum
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of treatment period
- Anaesthetic used for blood collection: isoflurane
- Animals fasted: Yes (except for coagulation test in males)
- How many animals: 5 males and 5 females (with viable litters if possible), randomly selected
- Parameters checked in table No. 2 were examined
- Coagulation parameters investigated: prothrombin time and activated partial thromboplastin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of treatment period
- Animals fasted: Yes
- How many animals: 5 males and 5 females (with viable litters if possible), randomly selected
- Parameters checked in table No. 3 were examined
SERUM HORMONES: Yes
- Time of blood sample collection: at termination, timing of the blood collection for thyroid hormone determination was as close as possible between animals and at the same time of the day in case of sampling on different days
- Animals fasted: Yes
- How many animals: all parental animals, each litter (1 sample for males and 1 sample for females, when possible), blood samples from different pups was pooled to obtain the required volume
- Hormones analyzed: serum levels of total thyroxine (total T4) and thyroid stimulating hormone (TSH)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule: once during study towards end of treatment, for males on day 39 and for females (with viable litters) on day 12 post partum
- Number of animals: 5 males and 5 females randomly selected from each dose group
- Studies conducted: grip strength and sensory reactivity to stimuli, motor activity assessment
IMMUNOLOGY: No - Oestrous cyclicity (parental animals):
- - Vaginal smears were taken in the morning from day 1 of dosing up to positive identification of mating
- The vaginal smear data was examined to determine the following:
1. anomalies of the oestrous cycle
2. the pre-coital interval (i.e., the number of nights paired prior to the detection of mating)
- Before despatch to necropsy: vaginal smears were also taken from all females and the oestrous cycle phase recorded - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 4 pups per sex per litter (partial adjustment was possible); excess pups were killed, and at least one culled male and one culled female per litter were selected for hormone determination
- No pups were eliminated when the litter size dropped below the culling target (8 pups per litter in total)
- If there was only one pup available above the culling target, only one pup was eliminated and used for blood collection for possible hormone determination
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
(i) Number and sex of pups
(ii) Stillbirths, live births
(iii) Body weight measured on days 1, 4, 7 and 13 post partum
(iv) Anogenital distance measured on day 1 post partum, AGD was normalized to the cube root of body weight collected on day 1 post partum
(v) Nipple count check examined in male pups on day 13 post partum
(vi) Necropsy
GROSS EXAMINATION OF DEAD PUPS: Yes
- All pups found dead in the cage were examined for external and internal abnormalities
- All culled pups sacrificed at day 4 post partum were subjected to an external examination
- All live pups sacrificed on day 14 post partum were examined for external abnormalities
- Gonads were inspected from all pups in order to confirm the sex previously determined by external examination
- All pups with abnormalities were retained in a 10% neutral buffered formalin
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: No
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: No - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: sacrifice after the mating of all females on day 40 of the study
- Maternal animals: females with live pups were killed on day 14 post partum, females showing no evidence of copulation were killed 25 days after the last day of the mating session
GROSS PATHOLOGY: Yes
- Necropsy: the clinical history of adult animals was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices), changes were noted, the requisite organs weighed and the required tissue samples preserved in fixative and processed for histopathological examination
- All females were examined also for the following: number of visible implantation sites (pregnant animals), number of corpora lutea (pregnant animals)
ORGAN WEIGHTS:
- Parental animals: from all animals completing the scheduled test period, the organs indicated in table No. 4 were dissected free of fat and weighed, the ratios of organ weight to body weight was calculated for each animal
HISTOPATHOLOGY: Yes
- Samples of all tissues (parental animals) required for histopathological examination are listed in table No. 4
- Samples of the tissue were fixed and preserved in 10% neutral buffered formalin (except testes and epididymides which were fixed in Modified Davidson’s fluid and preserved in 70% ethyl alcohol)
- After dehydration and embedding in paraffin wax, sections of the tissues were cut at 5 micrometer thickness and stained with haematoxylin and eosin, in addition, the testes and epididymides were cut at 2-3 micrometer thickness and stained with Periodic Acid Schiff (PAS), the morphological evaluation of the seminiferous epithelium (staging of spermatogenic cycle) was performed
The examination was restricted as detailed below:
(i) Sexual organs (cervix, clitoral gland, ovaries, uterus and vagina) and thyroid glands from all parental females
(ii) Sexual organs (coagulation gland, epididymides, preputial gland, prostate gland, seminal vesicles and testes) and thyroid glands from all parental males
(iii) Tissues specified in section 4.5.7 from 5 males and 5 females randomly selected (animals evaluated for clinical pathology) in the control and high dose group killed at term
(iv) Morphological evaluation of the seminiferous epithelium (staging of the spermatogenic cycle) from all males in control and high dose groups
(v) All abnormalities in all groups - Postmortem examinations (offspring):
- SACRIFICE
- Pups (F1 offspring) that had completed the scheduled test period (days 4 or 14 post partum) were euthanised by intraperitoneal injection of Sodium Thiopenthal
- Pups selected for blood collection for hormone determination were killed on the day of blood sampling
GROSS PATHOLOGY
- All pups found dead in the cage were examined for external and internal abnormalities
- All culled pups sacrificed at day 4 post partum were subjected to an external examination
- All live pups sacrificed on day 14 post partum were examined for external abnormalities
- Gonads were inspected from all pups in order to confirm the sex previously determined by external examination
ORGAN WEIGHTS
- Pups at day 14 post partum: thyroid was weighed from one male and one female pup selected for blood collection and preserved in 10% neutral buffered formalin, the thyroid weight was determined after fixation - Statistics:
- Standard deviations were calculated as appropriate.
For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t-test, depending on the homogeneity of data. The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the nonparametric version of the Williams test. The mean values, standard deviations and statistical analysis were calculated from actual values in the computer without rounding off. - Reproductive indices:
- MALES:
Copulation index (%) = (no. of males with confirmed mating/no. of males cohabitated) X 100
Fertility index (%) = (no. of males which induced pregnancy/ no. of males cohabitated) X 100
MALES AND FEMALES:
Pre coital Interval = the number of nights paired prior to detection of mating
FEMALES:
Copulation index (%) = (no. of females with confirmed mating/no. of females cohabitated) X 100
Fertility index (%) = (no. of pregnant females/ no. of females cohabitated) X 100
Pre-natal loss was calculated as a percentage from the formula:
(no. of visible implantations - live litter size at birth/no. of visible implantations) X 100
Pre-natal loss at day 0 post partum was calculated as a percentage from the formula:
(total litter size - live litter size/total litter size) X 100
Post-natal loss at day 4 post partum (before culling) was calculated as a percentage from the formula:
(live litter size at birth - live litter size at day 4 (before culling)/live litter size at birth) X 100
Post-natal loss at day 13 post partum (after culling) was calculated as a percentage from the formula:
(live litter size on day 4 (before culling) - live litter size at day 13/live litter size on day 4 (before culling)) X 100 - Offspring viability indices:
- Sex ratios was calculated at birth, on day 4 and on day 14 post partum and was presented as the percentage of males per litter.
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One control female was sacrificed for humane reason on Day 22 of gestation phase due to difficulties in parturition.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption was unaffected by treatment in both genders during the study.
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Endocrine findings:
- no effects observed
- Description (incidence and severity):
- The determination of T4 and TSH was performed on
- Samples from all parental males from all groups
- Samples from pups on Day 14 post partum.
No treatment-related changes were recorded. Thyroid stimulating hormone was statistically si
gnificantly lower than controls in parental males (31%). This is due to 2 control animals, which sh
owed values above the range of historical data, therefore the differences observed has no biological/
toxicological significance.
The oestrous cyclicity of the treated females monitored during the pre-mating period, for a total of
14 days, was not affected by treatment. The mean number of oestrous cycles observed in treated
animals and control group was comparable.
No differences were recorded in pre-coital interval and copulation plugs between treated and control
groups. Copulatory index and fertility index did not show any treatment-related differences. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Observation of treated animals at removal from the cage and in an open arena did not reveal significant changes when compared to controls.
No alterations in motor activity, grip strength, landing footsplay and sensory reactivity to stimuli were observed in any treatment group at the examination performed at the end of treatment. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related microscopic observations at the end of the treatment period. There were no test item-related microscopic observations in the testis (stage were evaluation on PAS-stained slides). Any microscopic observations had a comparable incidence in control and treated groups and/or are characteristically seen in untreated rats of the same age and were considered incidental and unrelated to treatment.
- Histopathological findings: neoplastic:
- no effects observed
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- The oestrous cyclicity of the treated females monitored during the pre-mating period, for a total of
14 days, was not affected by treatment. The mean number of oestrous cycles observed in treated
animals and control group was comparable.
No differences were recorded in pre-coital interval and copulation plugs between treated and control
groups. Copulatory index and fertility index did not show any treatment-related differences. - Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Implantation, pre implantation loss, pre-natal loss data and gestation length of females: Mean gestation period was comparable between control and treated animals, being of 22/23 days. Corpora lutea, number of implantations sites and live litter size did not show dose-related or treatment-related differences, compared to controls. Pre-natal loss (percentage) was similar between control and treated groups.
- Dose descriptor:
- NOAEL
- Remarks:
- reproduction toxicity
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Dose descriptor:
- NOAEL
- Remarks:
- systemic toxicity
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No treatment-related clinical signs were observed in pups during the 14-day observation period.
- Body weight and weight changes:
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Anogenital distance (AGD):
- no effects observed
- Nipple retention in male pups:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No differences were observed in the weight of thyroid in treated pups, when compared to controls.
- Histopathological findings:
- not examined
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Critical effects observed:
- no
- Reproductive effects observed:
- no
- Conclusions:
- The oral administration of the test substance by gavage to male and female Wistar rats revealed no signs of reproduction and developmental toxicity up to the highest tested dose level. Therefore, a NOAEL for general systemic toxicity, reproductive performance as well as for developmental toxicity was set to 1000 mg/kg bw/day.
Reference
Tab. 5: Summary of reproduction data (group data)
Observations | 0 | 100 | 300 | 1000 |
No. Dams Inseminated | 10 | 8 | 10 | 10 |
Oestrus cycle (mean number) | 4 | 4 | 3 | 3 |
No. Dams That Conceived | 10 | 6 | 10 | 8 |
Percent Dams Conceived | 100.0 | 60.0 | 100.0 | 80.0 |
Conceiving (1-5 days) | 10 | 6 | 9 | 8 |
Conceiving (6-14 days) | 0 | 0 | 1 | 0 |
No. Dams Died During Study | 1 | 0 | 0 | 0 |
No. Dams with Resorptions only | 0 | 0 | 0 | 0 |
No. of Litters | 9 | 6 | 10 | 8 |
Total No. Implantation | 110 | 66 | 107 | 95 |
Mean No. Implants/Pregnancy | 11.0 | 11.0 | 10.7 | 11.9 |
Pre natal Loss (%) | 11.0 | 17.9 | 10.7 | 22.4 |
Post natal Loss (%) | 0.0 | 1.9 | 0.0 | 0.0 |
Tab. 6: Summary of litter data (group data)
Pairs started (no.) | 10 | 10 | 10 | 10 | |
Dams with live pup at birth (no.) | 9 | 6 | 10 | 8 | |
Dams with live pups at Day 4 pp (no.) | 9 | 6 | 10 | 8 | |
Live litter size at birth (mean) | 9.4 | 8.8 | 9.6 | 9.3 | |
Live litter size at Day 4 (mean) | 9.2 | 8.7 | 9.6 | 9.3 | |
Sex ratio (%) at birth (mean) | 55.1 | 60.4 | 53.7 | 52.4 | |
Sex ratio (%) at Day 4 (mean) | 54.0 | 60.8 | 53.7 | 52.4 | |
Litter weight at Day 1 (mean) | 63.7 | 60.5 | 66.6 | 62.4 | |
Litter weight at Day 4 (mean) | 96.9 | 94.5 | 103.5 | 94.9 | |
Pup weight at Day 1 (mean) | 6.9 | 6.9 | 7.2 | 6.8 | |
Pup weight at Day 4 (mean) Pup weight at the Day of AGD (Day 1pp) |
10.6 | 10.9 | 11.3 | 10.4 | |
Pub weight at the Day of AGD (Day 1pp) mean males | 7.0 | 7.1 | 7.4 | 7.0 | |
Pub weight at the Day of AGD (Day 1pp) mean females | 6.8 | 6.7 | 7.0 | 6.7 | |
Pup AGD normalized (Day 1pp) mean males | 2.4 | 2.5 | 2.5 | 2.5 | |
Pup AGD normalized (Day 1 pp) mean females | 1.5 | 1.4 | 1.5 | 1.4 | |
Male pup nipple present at Day 13 (no.) | 0 | 0 | 0 | 0 | |
Pup weight at Day 13 (mean) | 29.0 | 29.2 | 30.7 | 28.6 | |
PUPS WITH MAJOR ABNORMALITIES AT NECROPSY | |||||
Dams with 0 | 9 | 6 | 10 | 8 | |
Dams with 1 | 0 | 0 | 0 | 0 | |
Dams with>2 | 0 | 0 | 0 | 0 |
Table 7: Sum of pre- and postnatal loss
Observations | 0 | 100 | 300 | 1000 | ||
Pre-natal loss (implantations minus live births)(no.) | ||||||
Females with 0 | 3 | 1 | 3 | 0 | ||
Females with 1 | 2 | 3 | 4 | 3 | ||
Females with 2 | 3 | 1 | 2 | 1 | ||
Females with>3 | 2 | 1 | 1 | 4 | ||
Post-natal loss (live births minus live at Day 1) (no.) | ||||||
Females with 0 | 7 | 5 | 10 | 8 | ||
Females with 1 | 2 | 1 | 0 | 0 | ||
Females with 2 | 0 | 0 | 0 | 0 | ||
Females with>3 | 0 | 0 | 0 | 0 | ||
Post-natal loss (live births at Day 4 after culling minus live Day 13) (no.) | ||||||
Females with 0 | 9 | 6 | 10 | 8 | ||
Females with 1 | 0 | 0 | 0 | 0 | ||
Females with 2 | 0 | 0 | 0 | 0 | ||
Females with>3 | 0 | 0 | 0 | 0 |
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
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
The effects of the test item Pigment Yellow 128, on male and female
reproductive performance, such as gonadal function, mating behaviour,
conception, development of conceptuses, parturition and lactation of the
offspring were investigated, when administered daily by oral gavage to
Wistar Hannover rat. Males were treated for 14 days prior to pairing and
during pairing with females until the day before necropsy, up to a total
of 35/36 days. Females were treated for 14 days prior to pairing, during
pairing and throughout the gestation and lactation periods until Day 13
post partum, up to at least 51 days. No treatment-related mortalities
occurred during the study. One control female was sacrificed for humane
reasons on Day 22 post coitum due to difficulties in parturition. No
treatment-related clinical signs were recorded. No treatment-related
signs of neurotoxicity and no treatment-related differences in body
weight, body weight gain and food consumption were observed in treated
animals, compared to the controls. No treatment-related changes were
observed in haematological and clinical chemistry parameters. No changes
considered treatment-related were observed in thyroid hormone levels in
parental animals or in pups at Days 4 and 14 post partum determinations.
No treatment-related anomalies were noted in the oestrous cycle,
copulatory and fertility indices of the treated females, when compared
to controls. Parturition, lactation, implantation, litter data and sex
ratio did not show any changes which could be considered adverse. No
significant differences in the anogenital distance was recorded in pups
on Day 1 post partum and no nipples were seen between control and
treated groups of male pups. Necropsy findings and thyroid weight in
pups did not reveal any treatment-related effect. No treatment-related
changes were detected at post mortem examination in treated animals,
when compared with controls. There were no test item-related microscopic
observations in the testis (stage aware evaluation on PAS-stained
slides). On the basis of these results the dosage of 1000 mg/kg/day is
considered the NOAEL (No Observed Adverse Effect Level) for systemic
toxicity, fertility and reproduction parameters for F0 males, F0 females
and F1 pups.
Effects on developmental toxicity
Description of key information
No adverse effects on offspring development were observed at the screening level (OECD 422) (ERBC 2022).
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
- Species:
- rat
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Classification, Labelling, and Packaging
Regulation (EC) No. 1272/2008
The available experimental test
data are reliable and suitable for classification purposes under
Regulation 1272/2008. As a result the substance is not considered to be
classified for toxicity to reproduction under Regulation (EC) No.
1272/2008.
Additional information
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