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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
5 September 2005 to 27 June 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
Reaction mass of tris(dipentyldithiocarbamato-S,S')antimony and [bis(2-ethylhexyl)dithiocarbamato-S,S']bis(dipentyldithiocarbamato-S,S')antimony and bis[bis(2-ethylhexyl)dithiocarbamato-S,S'](dipentyldithiocarbamato-S,S')antimony and tris[bis(2-ethylhexyl)dithiocarbamato-S,S']antimony
EC Number:
948-063-1
IUPAC Name:
Reaction mass of tris(dipentyldithiocarbamato-S,S')antimony and [bis(2-ethylhexyl)dithiocarbamato-S,S']bis(dipentyldithiocarbamato-S,S')antimony and bis[bis(2-ethylhexyl)dithiocarbamato-S,S'](dipentyldithiocarbamato-S,S')antimony and tris[bis(2-ethylhexyl)dithiocarbamato-S,S']antimony
Test material form:
liquid: viscous
Specific details on test material used for the study:
- Description: amber coloured paste
- Date received: 05 September 2005
- Storage conditions: room temperature in the dark, under nitrogen from 13 October 2005

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Sprague-Dawley Crl:CD (SD) IGS BR strain
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Approximately six weeks old
- Weight at study initiation: Males weighed 304 to 364g, females weighed 182 to 235g
- Housing: Initially, all animals were housed in groups of five in polypropylene cages with stainless steel grid floors and tops, suspended over polypropylene trays lined with absorbent paper. During the mating phase, animals were transferred to similar cages on a one male: one female basis. Following evidence of successful mating, the males were returned to their original cages. Mated females were housed individually during gestation and lactation, in polypropylene cages with solid floors and stainless steel lids, furnished with softwood flakes.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Fourteen days

DETAILS OF FOOD AND WATER QUALITY:
A pelleted diet was used throughout the treatment period. A certificate of analysis of the batch is given in the study report. Mains drinking water was supplied from polycarbonate bottles attached to the cage. The diet and drinking water were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study.

ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 2 °C
- Humidity: 55 ± 15 %
- Air changes: At least 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
For the purpose of the study, the test material was prepared at the appropriate concentration as a solution in Arachis oil BP. The stability and homogeneity of the test material formulations were determined internally. Initially formulations were prepared daily until stability was confirmed. The formulations were found to be stable at +4°C for at least fourteen days. Formulations were therefore prepared weekly and stored at approximately +4°C in the dark, under nitrogen (as an added precaution). Samples were taken of each test material formulation and were analysed for concentration of the test material internally. The results indicate that the prepared formulations were within acceptable limits for the purpose of the study.
Details on mating procedure:
Pairing of animals within each dose group was undertaken on a one mule: one female basis on Day 15 of the study, to produce litters.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Summary
Concentration of the test material formulations were determined by high performance liquid chromatography (HPLC) using an external standard technique.

Samples
Standard solutions of test material were prepared in acetonitrile at a nominal concentration of 0.1 mg/ml.

Method
HPLC: Agilent Technologies 1050, incorporating autosampler and work station
Column: Luna C18 5µ (250 x 4.6 mm id)
Mobile phase: Eluent A: tetrahydrofuran, Eluent B: 0.1% orthophosphoric acid, 0-6 mins 30% percent Eluent B, 7 mins 100% Eluent A
Flow-rate: 1 ml/min
UV detector wavelength: ~ 261 nm
Injection volume: 5 µl
Retention time: ~ 6.7 mins
Duration of treatment / exposure:
Up to 54 consecutive days
Frequency of treatment:
Once daily
Details on study schedule:
On Day 15, all animals were paired on a 1 male:1 female basis within each dose group for a maximum of fourteen days.
Following evidence of mating, the males were returned to their original cages and females were transferred to individual cages.
On completion of mating (during Week 6), five selected males per dose group were evaluated for functional/sensory responses to various stimuli.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10/sex/group, 4 groups
Control animals:
yes, concurrent vehicle
Details on study design:
Environmental enrichment was provided in the form of wooden chew blocks and cardboard fun tunnels except for mated females during gestation and lactation. Mated females were also given softwood flakes, as bedding, throughout gestation and lactation.

Examinations

Parental animals: Observations and examinations:
Clinical, behavioral, and functional observations, body weight, food and water consumption, hematology and blood chemistry were evaluated.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male treated with 2SO mglkg/day was found dead on Day 33, however this was considered unrelated to treatment
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):
no effects observed
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

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

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):
not examined
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

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

Offspring Development: No treatment-related effects were detected.

 

Litter Observations: No clinically observable signs of test material toxicity was detected in

offspring from treated animals.

 

Necropsy.

Offspring: No treatment-related macroscopic abnormalities were detected for interim death or terminal kill offspring.

There were no overt differences in mating performance or fertility for treated animals in comparison to controls. No intergroup differences were observed for litter size, sex ratio or viability.

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, the No-Observed-Effect Level (NOEL) for systemic toxicity of the test material was considered to be 1000 mg/kg/day. No treatment-related effects on reproduction were evident and the NOEL for reproductive toxicity was considered to be 1000 mg/kg/day.
Executive summary:

A combined repeat dose toxicity study with reproduction/developmental toxicity screening study was performed in accordance to the standardized guideline OECD 422, under GLP conditions. The study is considered to be a key study and has been assigned a Klimisch score of 1.

Species, number and sex of animals, treatment conditions, clinical signs, behavioral assessments, food and water consumption, body weight measurements, hematology and blood chemistry are described. Test substance batch number is included in the study report, but certificate of analysis for test substance is not included in the study report.

Sprague-Dawley rats, 10/sex/group, 4 groups were dosed at 0, 50, 250, or 1000 mg/kg/day in arachis oil, by gavage for up to 54 consecutive days. Dosing formulations were analyzed and confirmed the concentrations using high performance liquid chromatography (HPLC).

Pairing of animals within each dose group was undertaken on a one male: one female basis on Day 15 of the study to produce litters.

Clinical, behavioral, and functional observations, body weight, food and water consumption, hematology and blood chemistry were evaluated. During the lactation phase, clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of developmental landmarks. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

One male in the 250 mg/kg/day group was found dead on Day 33, but this was considered unrelated to treatment. There were no other unscheduled deaths during the study.

No treatment-related effects were noted in clinical, behavioral, and functional observations, sensory reactivity assessment, and hematology and blood chemistry. No adverse effect on bodyweight change, food and water consumption was detected for males throughout the treatment period, or for females during the maturation, gestation or lactation phases of the study.

There were no treatment-related effects in fertility, litter size, sex ratio, offspring viability and development, and little observations.

No treatment-related effects were noted in necropsy, organ weights, and histopathology.

The oral administration of the test material to rat by gavage at a maximum dose level of 1000 mg/kg/day did not result in any treatment-related effects. The No-Observed-Effect Level (NOEL) for systemic toxicity was considered to be 1000 mg/kg/day. No treatment-related effects on reproduction were evident and the NOEL for reproductive toxicity was considered to be 1000 mg/kg/day.