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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
29 August 2017 - 22 February 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH

This read-across is based on the hypothesis that source and target substances have the same type of toxicological effects based on common underlying mechanisms (ECHA, 2015b). All substances have the same organic structural group (colorant) with different compositions of the inorganic group (metallic salt). Read-across is in this case based on the hypothesis that source and target substances have similar toxicological properties because they degrade to the similar chemical substances (ECHA, 2015c). This prediction is supported by physicochemical and toxicological data on the substances.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Details on the chemicals are given in the read-across justification attached to this dossier, details on the source are given in the cross-reference section of this IUCLID endpoint and dratils on the target substance are given in this dossier.

3. ANALOGUE APPROACH JUSTIFICATION

The target substance CAS 67989-22-4 is an organometallic multi-constituent substance. The source substance CAS 101357-19-1 have the same organic constituent (see table above) as the target substance consisting of triphenylmethan and three dimethylamine moieties. The inorganic Part B is very similar between source and target substances, consisting of the elements O, Mo, P and W in different compositions. These differences are expected to behave very similar. The target and source substances are thus considered suitable for the analogue approach based on structural similarity.

4. DATA MATRIX
A data matrix is given in the read-across justification attached to this dossier.
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Justification for study design:
not specified
Specific details on test material used for the study:
Batch number: 982432
Purity: Preparation containing ≥80% UVCB (treat as 100%)
Storage conditions: Stored at ambient conditions in the dark (away from direct light)
Species:
rat
Strain:
Wistar
Details on species / strain selection:
- Source: Charles River Laboratories, France
- Females (if applicable) nulliparous and non-pregnant: no
- Age at study initiation: 10 weeks both male and female
- Weight at study initiation: Males: 331-431 g, Females: 179-245 g
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Housing: Cages with standard, granulated, S8-15 sawdust bedding (J. Rettenmaier & Söhne)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Five days after arrival and before the start of pre-test. After acclimatization period, the animals were subjected to a 15-day pre-test period.
DETAILS OF FOOD AND WATER QUALITY: Pelleted standard Teklad 2014C and 2914C rat/mouse maintenance diet ad libitum (supplied by Envigo RMS, S.L.). Pelleted standard Teklad 2018C rat/mouse maintenance diet (supplied by Envigo RMS, S.L.) ad libitum, for lactating females and pups (until sacrifice).
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 ºC
- Humidity (%): 30 and 70%
- Air changes (per hr): 15-20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light/12 hours dark.
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
For each dose group the order of administration was all males first and then all females. Each day of treatment the starting order was alternated between males and females. Formulations were maintained under agitation between 5 to 24 hours (from start of agitation until the end of administration).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- PREPARATION OF DOSING SOLUTIONS: The required amount of test item was weighed in a disposable container. Approximately 80% of the final volume requested of arachis oil was poured in another disposable container. The test item was transferred to the container with the arachis oil and the mixture poured into an ultra turrax or a homogenizer to achieve a homogeneous suspension. The suspension was
poured into a volumetric flask or test tube. The disposable container that contained the mixture with the remaining amount of vehicle was washed and the contents added to the flask or test tube to make up to the mark. An adjustment volume was first added to the volumetric container and then to the container containing the formulation to reach the final requested volume of the formulation. Finally, the suspension was submitted to magnetic stirring for 5-10 minutes before sampling for dilution.
- VEHICLE
- Lot/batch no. (if required): KMO9422, KM09047
- Purity: not specified
Duration of treatment / exposure:
5-8 weeks
Frequency of treatment:
Once daily
Details on study schedule:
Paired for mating After 2 weeks of treatment.
Male/female ratio 1:1, Duration of pairing 1-4 days,
Daily checks for evidence of mating: Ejected copulation plugs. Sperm within vaginal smear.
Day 0 of gestation When positive evidence of mating detected.
Male/female separation Day when mating evidence detected.
Pre-coital interval Calculated for each female as time between first pairing and evidence of mating.
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: It was considered a suitable dose level range, based on the preliminary results obtained in the previous non-GLP study HJ88HL 14-day Oral (Gavage) Dose-Range Toxicity Study for OECD 422 conducted at Envigo CRS, S.A.U.
- The high dose was selected as no toxicity was observed in the preliminary study at 1000 mg/kg/day and considering it as a limit dose to be tested.
- Intermediate and low dose levels were selected considering approximately a 3-fold interval between doses.
- Rationale for animal assignment (if not random): random
Positive control:
none
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule once a week
BODY WEIGHT: Yes
- Time schedule for examinations: - pre-test: once a week
- treatment: On day 1 and weekly thereafter
- mating: day 1
- post-mating: weekly
- gestation: On days: 0, 7, 14, 20
- Lactation: On days: 1, 4, 9 and 13
FOOD CONSUMPTION:
- Food consumption: Yes weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Yes Isoflurane
- Animals fasted: Yes
- How many animals: Males:
- Group 1: 1, 2, 3, 4 and 5
- Group 2: 13, 14, 15, 16 and 17
- Group 3: 25, 26, 27, 28 and 29
- Group 4: 37, 38, 39, 40 and 41
Females:
- Group 1: 60, 63, 64, 66 and 67
- Group 2: 82, 74, 76, 83 and 79
- Group 3: 84, 85, 86, 87 and 88
- Group 4: 98, 99, 100, 101 and 102
CLINICAL CHEMISTRY: Yes
- Animals fasted: Yes
- How many animals:same as 'haematology'
NEUROBEHAVIOURAL EXAMINATION: Yes
- Dose groups that were examined: all
- Battery of functions tested: sensory activity, grip strength, motor activity,
Thyroid hormone analysis: T4 levels.
Day 4 of age Offspring: 2 females per litter
Day 13 of age Offspring: 2 males and 2 females per litter
Oestrous cyclicity (parental animals):
Dry smears Using inoculation loops during the following phases:
• For 14 days before treatment (all females including spares); animals that failed to exhibit 4-5 day cycles were not allocated to study.
• Daily from the beginning of treatment period until evidence of mating.
• On the day of necropsy
A cotton swab impregnated in physiological saline was used in order to check the evidence of mating during the mating period.
Sperm parameters (parental animals):
Parameters examined: no
Litter observations:
Records Made during Littering Phase
Clinical observations Observed 24 hours after the considered birth and then daily for evidence of ill-health or reaction to maternal treatment
Litter size Daily from Day 1-13 of age
Sex ratio Days 1, 4, 7 and 13 of age
Individual offspring body weights Days 1, 4, 7 and 13 of age
Ano-genital distance Day 1 - all F1 offspring
Nipple/areolae count Day 13 of age - male offspring.
Postmortem examinations (parental animals):
SACRIFICE
All F0 animals: By intraperitoneal injection of sodium pentobarbital. Each animal was subsequently exsanguinated.
Offspring Selected for thyroid hormone sampling: Cardiac puncture. Death was assured with sodium pentobarbital injection.
All other offspring: injection of sodium pentobarbital.

Necropsy
F0 Males After final investigations completed (after 5 weeks of treatment)
F0 Females failing to produce viable litter (not pregnant) Day 25-26 after mating
F0 Females whose litters die before Day 13 On or after day last offspring dies
Females killed at termination Day 14-16 of lactation

HISTOPATHOLOGY / ORGAN WEIGHTS
For bilateral organs, left and right organs were weighed together. Organ weights were recorded for females sacrificed prematurely.
Postmortem examinations (offspring):
SACRIFICE
- Selected for thyroid hormone sampling: Cardiac puncture. Death was assured with sodium pentobarbital injection.
All other offspring: injection of sodium pentobarbital.

GROSS NECROPSY
- F1 Offspring Selected offspring for thyroid hormone analysis – Day 4 of age (two females per litter where possible)
Scheduled sacrifice - Day 13-15 of age
Statistics:
yes
Reproductive indices:
Percentage mating, Conception rate, Fertility index, Gestation length,
Offspring viability indices:
Litter size, Fertility index, Gestation index, Post-implantation survival index, Live birth index, viability index, lactation index.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
All females allocated to the study showed regular 4-day estrous cycle prior to treatment start. During treatment, irregular cycle was observed in one female at 100 mg/kg/day and two females at 300 mg/kg/day. It has was been considered incidental and not test-item-related, as it was not observed at 1000 mg/kg/day.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
In the testes, seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages. There were no cell or stage-specific abnormalities in males treated at 1000 mg/kg.
Reproductive performance:
no effects observed
Description (incidence and severity):
There was no effect of treatment on the pre-coital interval: all animals mated within four days of mating at the first estrus.
Mating performance was 100% for all groups and conception and fertility was 92% (11/12) at 0 mg/kg/day, 75% (9/12) at 100 mg/kg/day, 100% (12/12) at 300 mg/kg/day and 83% (10/12) at 1000 mg/kg/day. These differences cannot be considered test-item-related as there was no dose relation.
Key result
Dose descriptor:
NOEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Critical effects observed:
no
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
not specified
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
sexual maturation
clinical signs
mortality
body weight and weight gain
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
neuropathology
histopathology: non-neoplastic
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
no
Conclusions:
− The No Observed Effect Level (NOEL) for reproductive / developmental toxicity was considered to be 1000 mg/kg/day, taking into account that there was no effect on estrous cycle, pre-coital interval, mating performance, fertility and gestation length or
in the offspring on litter size, survival, sex ratio, clinical signs, body weights, anogenital distances or macropathology.
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:
Guideline study
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
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

PV3 is not classified for reproductive toxicity based on a guideline OECD 422 study

Additional information