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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In an oral combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats according to OECD Guideline 422 a NOEL of 100 mg/kg bw/d for reproduction/development was determined, taking into account the slight reduction in gestation index, the decrease in offspring body weights and the slightly lower offspring survival index with respect to the control group recorded at 300 and 1000 mg/kg/day.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 August 2017 - 21 February 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 981108
- Purity:Preparation containing ≥90% UVCB (treat as 100%). No correction factor for purity was applied
- Expiration date of the lot/batch: July 2022

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
Stored at ambient conditions in the dark (away from direct light)
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 10 weeks
- Weight at study initiation: Males: 255-323 g, Females: 167-218 g
- Housing: Optimum hygienic conditions behind a barrier system
- Diet: ad libitum

- Water: ad libitum
- Acclimation period:
5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 ºC
- Humidity (%): Relative humidity between 30 and 70%.
- Air changes (per hr): airconditioned with a minimum of 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:

- VEHICLE
- Justification for use and choice of vehicle (if other than water): Compatible with previous toxicity study.
- Concentration in vehicle: 20-200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg/day
- Lot/batch no.: KMO9422
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 1-4 days
- Proof of pregnancy: Ejected copulation plugs. Sperm within vaginal smear.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The formulations prepared at three different concentrations were analyzed twice over the course of the study to verify their correct preparation. Control (vehicle) formulations were taken and analyzed to confirm the absence of test item or other substances at the retention time of the test item. The test item was used as analytical standard.
Duration of treatment / exposure:
5-8 weeks
Frequency of treatment:
Once daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
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 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.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
During mating: Once a week for F0 males and F0 females
During post-mating: Once a week for F0 males
During gestation: Once a week for F0 females
During lactation: Once a week for F0 females
During Littering phase: Observed 24 hours after the considered birth and then daily for evidence of ill-health or reaction to maternal treatment

BODY WEIGHT: Yes
- Time schedule for examinations:
During mating: Weekly for F0 males and F0 females
During post-mating: Weekly for F0 males
During gestation: On days: 0, 7, 14, 20 for F0 females
During lactation: On days: 1, 4, 9 and 13 for F0 females
During Littering phase: Days 1, 4, 7 and 13 of age for individual offspring

Oestrous cyclicity (parental animals):
Dry smears
Using a 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.
Litter observations:
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
- Male animals: F0 Males, After final investigations completed (after 5 weeks of treatment)
- Maternal animals:
F0 Females failing to produce viable litter (not pregnant): Day 26 after mating
F0 Females whose litters die before Day 13: On the day last offspring dies. Female 88 (300 mg/kg/day) was sacrificed 2 days after the last offspring was found dead.
Females killed at termination: Day 14-16 of lactation

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 3 and 4 were prepared for microscopic examination and weighed, respectively.
Statistics:
All statistical analyses (see References) were carried out separately for males and females. Data relating to food consumption were analyzed on a cage basis during Pre-test and Treatment periods. For all other parameters and periods, the analyses were carried out using the individual animal as the basic experimental unit. The following comparisons were performed:
Group 1 vs 2, 3 and 4
For continuous data, a parametric analysis was performed if Bartlett's test for variance homogeneity is not significant at the 1% level. Treated groups were compared to control using Williams' test, unless there is evidence against a monotonic dose-response when Dunnett's test was performed instead.
A non-parametric analysis was performed if Bartlett's test is still significant at the 1% level following both logarithmic and square-root transformations. Treated groups were compared to control using Shirley's test, unless there
Reproductive indices:
Recorded in the study
Offspring viability indices:
Recorded in the study
Clinical signs:
no effects observed
Mortality:
mortality observed, treatment-related
Description (incidence):
One female dosed at 1000 mg/kg/day was found dead on the day 23.
On gestation day 23, one female dosed at 300 mg/kg/day was found dead.
Body weight and weight changes:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, non-treatment-related
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Changes considered related to treatment with the test item were seen in the thymus and
spleen of both sexes, and in the kidneys and adrenal glands of females:
- Minimal, bilateral, diffuse tubular basophilia was observed in the renal cortices of most
examined females given the test item at 1000 mg/kg and in one female receiving
300 mg/kg. One control male showed only minimal isolated foci of basophilic tubules,
within normal background levels.
- In adrenal glands, high incidence of bilateral diffuse cortical hypertrophy in females
treated at 100, 300 or 1000 mg/kg with respect to controls was observed.
- In thymus, a minimal decrease in cortical cellularity was seen in a male treated at 1000
mg/kg. The incidence and severity of decreased cortical cellularity were higher in females
given 300 or 1000 mg/kg when respect to controls.
- Minimally to slightly decreased marginal zone cellularity in spleen was observed in one
male and one female given the test item at 1000 mg/kg.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Analyses of samples for thyroxine (T4) obtained from F0 study male animals and F1
offspring on Day 13 of age did not reveal any differences that could be attributed to
treatment; no evidence of histopathology changes in the adult thyroids or growth effects on
the offspring were apparent, supporting the conclusion that there is no effect on thyroid
function.
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on the slight reduction in gestation index, the decrease in offspring body weights and the slightly lower offspring survival index
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weights in all test item administered male and female offspring tended to be lower than
those recorded in the Control group. Mean values at 100 and 300 mg/kg/day are similar; the
differences with respect to the Control are greater at 1000 mg/kg/day and increase with the
days of lactation.
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:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
There was no effect in the mean ano-genital distance adjusted to body weight in male or
female offspring in the test-item-dosed groups with respect to Control.

No effects in male nipple were recorded.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: the decrease in offspring body weights and the slightly lower offspring survival index
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
yes
Conclusions:
In conclusion, the effects of oral (gavage) administration of Lumière Blue PTM 0154N to Wistar rats receiving 100, 300 or 1000 mg/kg/day for 14 days prior to mating and until sacrifice can be summarized as follows:

Reproductive / developmental toxicity:
- The No Observed Adverse Effect Level (NOAEL) for reproductive / developmental toxicity was considered to be 100 mg/kg/day, based on the slight reduction in gestation index, the decrease in offspring body weights and the slightly lower offspring survival index with respect to the control group recorded at 300 and1000 mg/kg/day.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Guideline study conducted in 2018
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008 

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. 

As a result the substance is not classified for reproductive or developmental toxicity under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.

Additional information