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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
other: Read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read Across from a GLP well conducted study on the supporting structural related substance
Justification for type of information:
The justification for the use of the similar substance is detailed in the Read Across document attached in section 13

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Castor oil, sulfated, sodium salt
EC Number:
269-123-7
EC Name:
Castor oil, sulfated, sodium salt
Cas Number:
68187-76-8
Molecular formula:
not applicable
IUPAC Name:
not applicable
Test material form:
liquid
Details on test material:
Test item name: SOLFORICINATO DI SODIO 80V

Test animals

Species:
rat
Strain:
other: Crl:WI(Han) from Charles River Laboratories, Margate, UK.
Details on test animals or test system and environmental conditions:
Age at mating: 9 -11 weeks old and weighing at least 140 g

Mating (overnight at the supplier’s laboratory) will be confirmed by the presence of a vaginal plug in situ, or other evidence of mating if necessary. The day on which mating is confirmed will be designated as Gestation Day 0.
Delivered to Covance by Gestation Day 3, along with the Gestation Day 0 body weight data recorded at the supplier.

Housing Cages: conforming to the 'Code of practice for the housing and care of animals bred, supplied or used for scientific purposes' (Home Office, London, 2014).
Housing density: single housed
Rooms: exclusive to study
Acceptable temperature range: 22°C +/- 3°C
Acceptable humidity range: 40 to 70 %.
Air changes: A minimum of 15 air changes/hour.
Photo-period: 12 hours nominal.
Exceptions Where experimental procedures dictate, they will be documented in the study record.
Diet: Ad libitum access to SDS Rat and Mouse Breeder Diet VRF1.
Water: Ad libitum access to water bottles (mains water supply).
Bedding: Suitable wood bedding (Aspen); changed weekly.
Environmental enrichment: Wooden aspen chew blocks (minimum). Other approved methods of enrichment may be used.
Analysis and certification: Diet and bedding – per batch (reviewed prior to use).
Water – periodic analysis.
Environmental enrichment – as available.
Central records maintained.
Food / water restriction: As required by experimental procedures.
Assessment on arrival All animals: clinical inspection for ill-health.
Acclimatisation: limited to mated status
Animal health assessment: Performed prior to start of dosing.
Method of assigning to treatment groups: Randomisation procedure based on body weight and day of mating (i.e. all animals confirmed as mated on a specific day will be randomly allocated to the treatment groups).
Treatment group positions in the cage battery: Animals will be positioned on batteries to avoid potential for cross contamination, To enable exposure of each cage/battery to similar environmental conditions
Identification of the test system: Subcutaneous electronic transponder. Cages will be identified with study information including study number and animal number/s.
Procedure acclimatisation None.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Route Oral: gavage.
Justification Possible route of human exposure
Frequency of dosing: Once daily from Gestation Days 6 to 20, inclusive.
Dose volume 20 mL/kg. Dose volumes will be calculated from the most recent body weight for each animal.
Storage conditions in the animal facility prior to dose administration
Formulation receipt area: 15 to 25°C
Animal room: 15 to 25°C
Stirred before dosing Yes: continuously from at least 15 minutes before dosing commences (excluding vehicle control group).
NB: stirring longer than half an hour is acceptable
Stirred during dosing Yes: continuously (excluding vehicle control group).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see attached information in section 8

Justification for dose levels selection:
High dose This is the limit dose and, based on the previous OECD 422 study, is considered not to cause any overt toxicity.
Intermediate dose Selected as an appropriate intermediate dose level based on guideline requirements of two to four fold increase in dose level.
Low dose Anticipated to be a no observed effect level (NOEL).
Background information In a previous OECD 422 combined repeat dose and reproduction/developmental toxicity screening test (Will Research Project Number 503342) on this test article was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg/day.
Males were exposed for 29 days and females were exposed for up to 47 days.
Adult males administered 1000 mg/kg/day showed a subtle increase in severity of mononuclear inflammation and in incidence and/or severity of myofiber degeneration in the heart. Increased seminal vesicles weights (absolute and relative) of were also noted at this dose level. In addition, relative kidneys weights were higher for males treated at 300 and 1000 mg/kg/day, although no correlations with blood parameters and histopathological examination were observed, therefore these changes were considered to be of no toxicologically significant.
Adult females administered 1000 mg/kg/day showed an increased incidence of vacuolation of the zona glomerulosa of the adrenal glands. However, this was considered non-adverse. Increased uterus weights (absolute and relative) were noted following 1000 mg/kg/day.
No reproductive toxicity was observed up to 1000 mg/kg/day and no developmental toxicity was observed in the offspring following maternal administration up to 1000 mg/kg/day.
Based on these results, the No Observed Adverse Effect Levels (NOAEL) was derived as 300 mg/kg/day for males and 1000 mg/kg/day for females. A NOAEL for reproductive and offspring development was considered as 1000 mg/kg/day.
Details on mating procedure:
Mating (overnight at the supplier’s laboratory) will be confirmed by the presence of a vaginal plug in situ, or other evidence of mating if necessary. The day on which mating is confirmed will be designated as Gestation Day 0.
Delivered to Covance by Gestation Day 3, along with the Gestation Day 0 body weight data recorded at the supplier.
Duration of treatment / exposure:
15 days
Frequency of treatment:
Once daily from Gestation Days 6 to 20, inclusive.
Doses / concentrationsopen allclose all
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:
20 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Test article administration
Route Oral: gavage.
Justification Possible route of human exposure.
Dose order Group 1, 2, 3 then 4.
Groups may be dosed out of order when dosing is carried out by more than one technician.
Storage conditions in the animal facility prior to dose administration
Formulation receipt area: 15 to 25°C
Animal room: 15 to 25°C
Stirred before dosing Yes: continuously from at least 15 minutes before dosing commences (excluding vehicle control group).
NB: stirring longer than half an hour is acceptable
Stirred during dosing Yes: continuously (excluding vehicle control group).
Other information None.
Method of preparation Formulated based on method supplied by Sponsor. Details of the methodology have been provided in the validation report (Study 153/19/HSII) and are retained in the study record.

Frequency of preparation
Group 1, 2 and 3: at least weekly.
Group 4: Daily and dosed within 8 hours of preparation.

Formulation analysis
Stability data: 2.5 and 22.5 mg/mL stable at ambient (approximately 26°C) for 7 days and 50 mg/mL stable at ambient for 1 day (study 153/19/HSII).
Homogeneity data: Homogeneity determined at concentration of 2.5 to 50 mg/mL (study 153/19/HSII).
Study sampling
Achieved concentration: From formulations prepared for use on the first day of dosing (total 1 occasion). The following samples will be taken: 2 x 1 mL of each dose concentration pipetted in Eppendorf vial for analysis.
Due to the short stability for the 50 mg/mL (high dose), the formulation will be diluted down (1 in 10) to allow for accurate concentration analysis after shipment and result calculated back to the higher dose to confirm the concentration.
Residual samples: Not required in the first instance.
New Test Article batches Stability and homogeneity analyses will be performed for each batch of test article used on the study only if significant differences between the batches are advised by the Sponsor.
Storage container Uniquely labelled Eppendorf vials.
Storage of samples 15 to 25°C.
Sample shipment frequency As soon as is practicable following completion of each sampling occasion.
Sample shipment conditions 15 to 25°.

Method of termination (adults) Cervical dislocation following isoflurane anaesthesia, death confirmed by exsanguination.
If urgent euthanasia of an animal in extremis is necessary the animal may be killed by intraperitoneal injection of sodium pentobarbitone (overdose) and death will be confirmed by cervical dislocation and/or exsanguination.
Method of termination (fetuses) Subcutaneous injection of sodium pentobarbitone followed by confirmation of cessation of circulation.
Food removed No.
Sequence Replicate order, where possible.
Blood sampling See section 6.
Macroscopic examination All lesions will be recorded and retained.
Tissue preservation Retained in relevant fixative.
External peer review Not required.
Additional information Tissue or blood samples remaining after completion of post life procedures of control animals may be taken for purposes unrelated to this investigation.


Examinations

Maternal examinations:
Health monitoring
Observe animal in cage to monitor health status.
Any animal which shows marked signs of ill health or overt toxicity may be isolated and may be killed and subject to the relevant terminal procedures.
Animal cohort/Frequency of observation
All animals/Twice daily: beginning and end (nominal) of the working day.

Clinical examinations
Additional observations may be recorded by exception.
Animal cohort / Frequency of observation
All animals / Daily from the start of dosing until necropsy.

Post dosing observations
Observations related to time of dosing.
Character and timing of reactions to treatment will be recorded.
All observations, including absence of observations, will be recorded.
The start time of all observations will be based on each individual animal/group.
Additional observations may be carried out by technicians; the Study Director should be informed / involved in discussions.
Animal cohort/Frequency of observation
All animals /Daily: at 1 hour postdose.

Body weight
Individual body weight.
Animal cohort/Frequency of observation
All animals/Gestation Days 3, 6, 9, 12, 15, 17, 20 and 21.

Food consumption
Recorded in g; calculated as g/animal/day.
Animal cohort/ Frequency of observation
All animals /Gestation Days 6, 9, 12, 15, 17, 20 and 21.

Tissue Retention Thyroid (in buffered 10% formalin)
Tissues Weight Thyroid (weighed post-fixation)
Additional information #Terminal body weight will be recorded for adjusted gravid uterus weight calculations only and will not be reported.

Histology
Tissue trimming, processing and embedding (E): Groups 1, 2, 3, 4: Thyroid, including decedents.
Microtomy and staining (E):Groups 1, 2, 3, 4: Thyroid, including decedents.

Pathology
Microscopic evaluation (E): Groups 1, 2, 3, 4: Thyroid, including decedents.
Additional information None

Ovaries and uterine content:
All lesions will be recorded and retained.
The following will be recorded as appropriate:
Caesarian data with corpora lutea:
Pregnancy status
Gravid uterine weight
Terminal body weight
Number and status of implantations
Number of corpora lutea
Uterine data:
Fetal status
Uterine horn sequence
Fetal identification
Fetal examination allocation

The uterus of any animal not apparently pregnant will be immersed in 10% ammonium sulphide solution for further examination of implantation sites.
Fetal examinations:
For each viable fetus:
Fetal weight, Placenta weight, Fetal sex, Ano-genital distance
Live fetuses: External examination
Dead fetuses: External examination and fetal sex only and then discarded.
Approximately one half of the fetuses in each litter will be examined for visceral abnormalities by microdissection. They will then be eviscerated and the carcasses will be processed for skeletal examination.
The remaining fetuses will be fixed in Bouin’s fluid and examined.
Fetal skeletal preparations: examined in 50% glycerol; retained in glycerol/propylene glycol. Fetuses fixed for visceral examination retained in relevant fixative.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Gross pathological findings:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
food consumption and compound intake
mortality

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
external malformations
visceral malformations
Remarks on result:
other: preliminary results

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

hystopathology and fetal pathology examination in progress and validation

Applicant's summary and conclusion

Conclusions:
The substance was tested for OECD 414 Prenatal developmental toxicity in rats. Some final evaluations are still ongoing (see atatched study pan and declaration), however based on the information currently available the NOAEL is estabihsed at 1000 mg/kg. bw/day, i.e. 640 mg/kg bw/day (active ingredient, 62-64% wt).