Antimony, mixed dipentyldithiocarbamate and bis(2-ethylhexyl)dithiocarbamate complexes

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

5 September 2005 to 27 June 27 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:

other: OECD 422

GLP compliance:

yes

Limit test:

no

Test material

Test material information

1

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

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 test animals or test system and environmental conditions:

Sprague-Dawley Crl:CD (SD) IGS BR strain

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.

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

250 mg/kg bw/day (nominal)

Doses / concentrations 4

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

Maternal examinations:

Clinical, behavioral, and functional observations, body weight, food and water consumption, hematology and blood chemistry were evaluated.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

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

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:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Maternal developmental toxicity

Number of abortions:

not examined

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

not examined

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Effect levels (maternal animals)

Key result

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

clinical signs

Maternal abnormalities

Key result

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

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Effect levels (fetuses)

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:

other: clinical signs

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

Necropsy

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

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.