Di(tetraethylammonium)hexahydroxoplatinate(IV)

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / 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 acording to GLP

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2006

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / 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

Specific details on test material used for the study:

TMAH (Lot No. 40914), Vehicle: water, purity: over 99.9•%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

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

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).

Analytical verification of doses or concentrations:

not specified

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:

daily

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

Positive control:

no

Examinations

Parental animals: Observations and examinations:

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Signs recorded include: changes in salivation, locomotor activity, fur, eyelid opening or closure

BODY WEIGHT: Yes
- Time schedule for examinations: The male animals were weighed on Day 1 and 3 of dosing, and weekly thereafter. The female animals were weighed on Day 1, 3 and 7 of dosing, weekly thereafter until delivery, and PND 0 and 4. Body weights of the live pups were also recorded.

Oestrous cyclicity (parental animals):

no data

Sperm parameters (parental animals):

no data

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, clinical signs, ody weights and weight gain (PND 4). At the termination of the experiment (PND 4), all animals including pups were sacrificed and autopsied.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external gross abnormalities

Postmortem examinations (parental animals):

SACRIFICE
At the termination of the experiment (PND 4) all surviving animal (male, female, pups) were sacrificed

GROSS NECROPSY

HISTOPATHOLOGY / ORGAN WEIGHTS

Postmortem examinations (offspring):

SACRIFICE
At the termination of the experiment (PND 4), all F1 pups were sacrificed and autopsied.

GROSS NECROPSY

HISTOPATHOLOGY / ORGAN WEIGTHS

Statistics:

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

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 Day 3 in male animals and on gestation day (GD) 20 in female animals.

Reproductive function / performance (P0)

Reproductive performance:

no effects observed

Details on results (P0)

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. A significant decrease in food consumption was observed at 20 mg/kg bw/day on Day 3 in male animals and 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 (P0)

Dose descriptor:

NOAEL

Effect level:

5 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

Target system / organ toxicity (P0)

Critical effects observed:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Details on results (F1)

In examination of neonates, there was no effect of tetramethylammonium hydroxide on either the numbers of total newborns and live newborns, sex ratio, live birth index, or viability index. No compound-related abnormality was observed either in external features.
Based on these observations, the NOAEL for reproductive/developmental toxicity was considered to be 20 mg/kg bw/day in rats.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

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

Overall reproductive toxicity

Reproductive 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.