Tungsten hexachloride

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

publication

Title:

Neurobehavioral effects of sodium tungstate exposure on rats and their progeny

Author:

McInturf S.M. et al.

Year:

2008

Bibliographic source:

Neurotoxicol. Teratol. 30(6), 455-461

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: EPA OPPTS 870.3650 "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Study, OECD 422

Deviations:

yes

Remarks:

The protocol was extended beyond the minimum 54 days of treatment to accomodate evaluation of the development of the offspring through postnatal day 20 as well as their dams following the last dose on day 70.

GLP compliance:

not specified

Remarks:

it was not identified by the authors if the study was GLP compliant

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reference substance 001

EC Number:

600-275-2

Cas Number:

10213-10-2

Specific details on test material used for the study:

- Name of test material (as cited in study report): Sodium tungstate dihydrate
- Source: Fisher Scientific
- Analytical purity: > 98%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories (Wilmington, MA)
- Age at study initiation: 8 weeks
- Housing: The adults (e.g., P1) were singly housed (except during mating)
- Acclimation period: 14 days

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: deionized water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The powder readily dissolved in a deionized water (diH2O) vehicle for the concentrations used in this study at 5 mg/mL and 125 mg/mL. The solution was concentrated to administer a volume of 1 mL/kg body weight not to exceed 2 mL. Fresh solution was made daily and administered via oral gavage

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Concentrations of the tungstate anion were determined using inductively coupled plasma mass spectrometry (ICP-MS).

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: not specified
- Length of cohabitation: 14 days
- Verification of same strain and source of both sexes: not specified
- Proof of pregnancy: vaginal plug referred to as day 1 of pregnancy

Duration of treatment / exposure:

70 days

Frequency of treatment:

daily pre- and postnatal exposure

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

5 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

125 mg/kg bw/day

No. of animals per sex per dose:

40

Control animals:

yes, concurrent vehicle

Details on study design:

In order to ensure a total of 70 days exposure, adults were dosed for any additional days necessary following weaning. Prenatal pup exposure was from sodium tungstate crossing through the placenta and postnatal exposure was indirect via dams' milk.

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Throughout the exposure period, dams and the males used for mating were observed for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: Pregnant dams were weighed on gestation days (GD) 1, 10, 15 and 20, and gestational weight gain and gestation length were recorded.

OTHER: N/A

Ovaries and uterine content:

no data

Fetal examinations:

- External examinations: No data
- Soft tissue examinations: Yes: control and high dose pups
- Skeletal examinations: No data
- Head examinations: Yes

Statistics:

All measures were analyzed using ANOVA. Repeated measures ANOVA were used where appropriate. All animals in the pre-weanling litter were tested for righting reflex and separation distress so the litter was used as the unit of analysis for the ANOVA. The fiducial limit was p< 0.05 and post-hoc comparisons were performed using Tukey's HSD analysis for pair-wise comparisons as appropriate.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects: yes

Details on maternal toxic effects:
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS):
A statistically significant difference was found in the dams, average gestation duration was longer for the 125 mg/kg/day dose group than for the control and 5 mg/kg/day groups. Average gestational weight gain did not differ across treatments.

OTHER EFFECTS
Maternal Retrieval and Watermaze Navigation: No effects of sodium tungstate exposure at either dose were found in the dams for latency of maternal retrieval, or watermaze navigation latency or distance traveled.
Acoustic Startle/Prepulse Inhibition: For acoustic startle/prepulse inhibition, no significant main effects or interactions related to dose were found for any of the dependent measures.
Spontaneous Locomotor Activity: Exposure effects in the dams were detected for some of the measures of spontaneous locomotor activity. Specifically, dams treated with the low dose showed significantly more ambulatory time and distance travelled, as well as decreased time in stereotypies as compared to both controls and the high dose. In contrast, dams in the high dose demonstrated significantly less time resting, and more time in stereotypic movements than the vehicle controls or low dose group.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
There were no differences in average number of pups born.
All pups were inspected for physical birth defects, including missing digits, however, none were found.
The high dose group demonstrated a greater number of ultrasonic distress vocalizations when separated from the dam and littermates.
Righting reflex: For righting reflex, a significant effect of sex was found (p <0.05) where males were faster (9.6±1.3 s) than females (14.5 ± 1.6 s). No significant effects related to dose were found.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The tests were selected to provide a screening-level assessment of a range of neurobehavioral capacities in Sodium tungstate exposed dams and their offspring. The tests evaluated reflexive responding, emotionality and spatial learning and memory. Exposure-related effects were observed both in the dams and developing pups, and for low and high dose exposures. Overall, the results of this study suggest pre- and postnatal oral exposure to Sodium tungstate may produce subtle neurobehavioral effects in offspring related to motor activity and emotionality. The NOAEL for developmental toxicity was deemed to be 125 mg/kg bw/day.

Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Study Sodium tungstate was administered to 40 SD rats/sex/dose by gavage at dose levels of 0, 5, and 125 mg/kg bw/day through mating, gestation, and weaning (PND 0-20). A statistically significant difference was found for one of the treatment groups on measures of reproductive toxicity. In the dams, average gestation duration was longer for the 125 mg/kg/day dose group than for the control and 5 mg/kg/day groups. Average gestational weight gain did not differ across treatments. In the pups, there were no differences in average number of pups born.

The NOAEL for the F1 generation was 125 mg/kg/day based on the lack of significant effects.

The Reproduction/Developmental toxicity study in the rat is classified acceptable but does not completely satisfies the guideline requirements for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rodents, as no detailed examination of soft tissue or skeleton of the fetuses were conducted.