Di(tetraethylammonium)hexahydroxoplatinate(IV)

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

GLP compliance:

no

Remarks:

method comparative to OECD TG 410

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:

TS: tetramethylammonium hydroxide 25%, Vehicle: water

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

The vehicle (distilled water) and test substance formulation was applied to the reservoir of a Hill Top Chamber (Hill Top Biolabs, Inc., Cincinnati, Ohio) which was placed on the animal's shaven back behind the shoulder blades. The chamber was held secure with an elastic cloth band fastened with Velcro.

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

6 h/day, 5 d/wk

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2.5 mg/kg bw (total dose)

Remarks:

female

Doses / concentrations 2

Dose / conc.:

5.5 mg/kg bw (total dose)

Remarks:

male and female

Doses / concentrations 3

Dose / conc.:

10 mg/kg bw (total dose)

Remarks:

female

Doses / concentrations 4

Dose / conc.:

50 mg/kg bw (total dose)

Remarks:

female and male

Doses / concentrations 5

Dose / conc.:

120 mg/kg bw (total dose)

Remarks:

male

Doses / concentrations 6

Dose / conc.:

250 mg/kg bw (total dose)

Remarks:

male

No. of animals per sex per dose:

10 males / 10 females

Control animals:

yes, concurrent vehicle

Details on study design:

The initial target dose levels were 0, 0.55, 5, 12 and 25% w/v. The dosages were administered 6 hours/day, 5 days/week, at a constant volume of 1 ml/kg bw. These dose levels were equivalent to 0, 5.5, 50, 120 and 250 mg/kg bw/day. On the first day of administration, all male rats in the 120 and 250 mg/kg bw groups died within 3 hours after dosing and one male in the 50 mg/kg group died at the end of the day. Therefore, the dose levels to be administered to the female rats were lowered and a total of 7 treatment groups (a vehicle control and 6 dose levels) were evaluated between both sexes.
Because of the early deaths, other design changes were implemented. In an attempt to determine a possible cause of test substance-induced toxicity/moribundity, blood samples were collected via the retroorbital plexus from five male and four female rats in the 5% dose level group for hematology and limited serum chemistry analysis on study Day 4 and 3, respectively. In addition, rats dying spontaneously within the first week of the study were subjected to a gross necropsy and any tissues with grossly observable lesions (excluding application site skin) were collected. After one week of treatment the rats that died (five in the 50 mg/kg dose group) were subjected to a complete necropsy and their tissues were preserved, regardless of gross appearance. At study termination (day29) all surviving rats were euthanized, a gross necropsy performed and all gross lesions were collected and preserved in 10% neutral buffered formalin for possible microscopic evaluation.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

All of the male rats in the 120 and 250 mg/kg bw dose groups died within 3 hours after treatment initiation. Clinical signs noted in a few of the rats in these groups were lethargy followed by convulsions, tremors, and death beginning within one and a half to 2 hours after administration of the first dose of the test substance. One female rat in the 50 mg/kg bw dose group exhibited hyperactivity and labored breathing. No overt clinical signs of toxicity were observed at the lower doses (males; 5.5 mg/kg bw: females; 2.5, 5.5 or 10 mg/kg bw).

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Skin irritation at the application site included erythema, edema and/or scabbing in all groups treated with the test substance. In addition, scabbing (i.e.; possible grooming irritation) was seen in all groups, including the controls, and was considered to be associated with the animal's instinctive grooming behavior occurring when the collars were removed on the weekends.

Mortality:

mortality observed, treatment-related

Description (incidence):

All of the male rats in the 120 and 250 mg/kg bw dose groups died within 3 hours after treatment initiation. The 50 mg/kg bw male and female rats died intermittently throughout the study with the longest survival being approximately 2 weeks. No deaths were observed at the lower doses (males; 5.5 mg/kg bw: females; 2.5, 5.5 or 10 mg/kg bw).

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significant differences were seen in body weights, body weight gain or food consumption, except for a body weight gain reducetion in the 4 surviving high dose females at week 1.

Food consumption and compound intake (if feeding study):

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No overt changes in chemistry were seen, with the possible exception of a moderate increase in alkaline phosphatase noted in the male rats in the 50 mglkg group.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

No gross lesions were noted in any of the dead animals at 120 or 250 mg/kg bw dose. Gross lesions were noted in the rats at 50 mg/kg bw and included red lungs (2 rats), urinary bladder calculus (2 rats), red ovaries (2 rats), dark eye (1 rat) and small seminal vesicles (1 rat). Red ovaries were also observed in all surviving rats at the 10 mg/kg bw (10/10) and 4/10 at the 5.5 mg/kg bw dose levels.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

5.5 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

gross pathology

mortality

2

Key result

Dose descriptor:

NOAEL

Effect level:

2.5 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

gross pathology

mortality

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a repeated dose dermal toxicity study in rats, conducted by a method comparative to OECD TG 410, involving dermal application of tetramethylammonium hydroxide for 4 weeks clinical signs of toxicity and adverse histopathological effects were observed. Based on these findings, the NOAELs for repeated dose dermal toxicity were considered to be 5.5 mg/kg bw/day in male rats and 2.5 mg/kg bw/day in female rats.

Executive summary:

In a repeated dose dermal toxicity study, rats were exposed for 4 weeks (6 hours/day, 5 days/week) to tetramethylammonium hydroxide (TMAH) at doses of 0, 5.5, 50, 120 and 250 mg/kg bw/day in male rats and 0, 2.5, 5.5, 10 and 50 mg/kg bw/day in female rats. In addition to erythema, edema and/or scabbing observed at the application sites in all of the treated animals, red ovaries were observed in female rats at 5.5, 10 and 50 mg/kg bw/day, and red lungs, urinary bladder calculus, dark eye and small seminal vesicles in male and/or female rats at 50 mg/kg bw/day. Based on these findings, the NOAELs for repeated dose dermal toxicity were considered to be 5.5 mg/kg bw/day in male rats and 2.5 mg/kg bw/day in female rats.