Di(tetraethylammonium)hexahydroxoplatinate(IV)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study, conducted according to GLP

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2006

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD guideline 421(reproductive/developmental toxicity screening test)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Tetramethylammonium hydroxide

EC Number:

200-882-9

EC Name:

Tetramethylammonium hydroxide

Cas Number:

75-59-2

Molecular formula:

C4H12N.HO

IUPAC Name:

tetramethylazanium hydroxide

Test animals

Species:

rat

Strain:

Sprague-Dawley

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

Doses: 0, 1, 5, 20 mg/kg bw/day

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: until copulation occurred, or two weeks.
- Proof of pregnancy: presence of sperm or a vaginal plug referred to as the day of conception (day 0 of gestation).

Duration of treatment / exposure:

Male: 14 days before mating to the day before scheduled death through mating (total 32 days)
Female: 14 days before mating to 3 days after delivery through mating and gestation periods

Frequency of treatment:

dialy

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

1 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

5 mg/kg bw/day

Doses / concentrations 4

Dose / conc.:

20 mg/kg bw/day

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day

Fetal examinations:

- External examinations: Yes: [all per litter]

Statistics:

Statistical analysis : Bartlett's test, one-way analysis of variance, Dunnett's test, Kruskal-wallis test, chi-square test

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Salivation was observed on the 4th day of administration and later in male and female rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH.
In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter.

Mortality:

mortality observed, treatment-related

Description (incidence):

One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In the female animals and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4) was observed.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

A significant decrease in food consumption was observed at 20 mg/kg bw/day on gestation day (GD) 20 in female animals.

Maternal developmental toxicity

Details on maternal toxic effects:

Salivation was observed on the 4th day of administration and later in maternal rats at 5 mg/kg bw/day and higher. Salivation was considered to be due to strong alkaline property of TMAH, but not due to toxic effects of TMAH. A significant decrease in food consumption was observed at 20 mg/kg bw/day on gestation day (GD) 20 in female animals. In the female animals at 20 mg/kg bw/day, a decrease in locomotor activity, incomplete eyelid opening or eyelid closure, and loss of hair were observed on GD 21 and thereafter, and a significant decrease in body weight on days 0 and 4 after parturition (PND 0 and 4). One female rat at 20 mg/kg bw/day died on GD 22 and another one on GD 23 during parturition. Based on these observations, the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day in rats.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

5 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food efficiency

mortality

Maternal abnormalities

Abnormalities:

not specified

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

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No gross abnormalities were observed during macroscopic external examination of control pups or those from treated dams.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects up to highest dose tested (20 mg/kg bw/day)

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a reproductive/developmental toxicity screening test in rats [OECD TG 421], TMAH was administered by gavage at doses of 0, 1, 5 and 20 mg/kg bw/day. No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.

Executive summary:

In a reproductive/developmental toxicity screening test according to OECD TG 421, Sprague-Dawley rats (10/sex/group) were orally administered TMAH (by gavage) at doses of 0, 1, 5 and 20 mg/kg bw/day.

No effect of TMAH was observed on any reproductive or developmental parameters up to 20 mg/kg bw/day, the highest dose tested, while some toxic effects on parental animals (a decrease in food consumption, a decrease in locomotor activity) were observed at 20 mg/kg bw/day. Thus the NOAEL for parental toxicity was considered to be 5 mg/kg bw/day and the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.