Ethylidynetrimethanol

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study and GLP

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1994

Reference 2

Reference Type:

publication

Title:

Newsletter

Author:

JETOC (Japan Chemical Industry Ecology-Toxicology & Information Center)

Year:

1995

Bibliographic source:

JETOC Information Sheet 18, 8-11

Reference 3

Reference Type:

review article or handbook

Title:

Toxicology Profile of 1,1,1-trimethylolpropane

Author:

BIBRA (The British Industrial Biological Research Association)

Year:

1996

Bibliographic source:

Bibra Toxicology International, Information Departement, Carshalton , Surrey AM54DS, UK

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propylidynetrimethanol

EC Number:

201-074-9

EC Name:

Propylidynetrimethanol

Cas Number:

77-99-6

Molecular formula:

C6H14O3

IUPAC Name:

2-ethyl-2-(hydroxymethyl)propane-1,3-diol

Details on test material:

Purity: 99.9 %; vehicle: distilled water

Test animals

Species:

rat

Strain:

other: Slc:SD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: male: 304-343 g; femalws: 196-226 g
- Housing: pregnant females should be caged individually
- Diet ad libitum
- Water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 50-60
- Photoperiod 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

dosing of both sexes should begin 2 weeks prior to matingm continued through mating period
males: dosing continued up to the day when females are killed
females: dosing continued throughout pregnancy and up to day 4 of lactation

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

data not given

Duration of treatment / exposure:

Male: 45 days
Female: from 14 days before mating to day 3 of lactation

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 12.5, 50, 200, 800 mg/kg/day
Basis:

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Positive control:

no

Examinations

Observations and examinations performed and frequency:

at least once per day:
--behavioural changes, signs of difficult or prolonged parturition, mortality and all signs of toxicity
cage side observations:
changes in skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system fucnction
--food consumption, males and females should be weighed
--duration of gestation, examination of the litter as soon as possible, number and sex of pups, stillbirth, live birth, pup weight, and the presence of gross anomalies
--clinical examinations: hematologym clinical chemistry, urinalysis
--pathology: gross necropsy, histopathology

Sacrifice and pathology:

males day 43
females day 4 of lactation

Other examinations:

as required by the guideline

Statistics:

non parametric analysis

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

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

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

for reproductive toxicity see section 7.8.1

BODY WEIGHT AND WEIGHT GAIN
800 mg/kg bw/day: males and females: lowered during premating period when compared to controls

ORGAN WEIGHTS
males:
800 mg/kg bw/day, significant: absolute mean liver weight: 13.92 g versus 11.55 g of controls
800 mg/kg bw/day, significant. relative mean liver weight: 3.647 g% versus 2.926 g% of controls
females
800 mg/kg bw/day, non-significant: absolute mean liver weight: 11.54 g versus 10.54 g of controls
800 mg/kg bw/day, non-significant. relative mean liver weight: 4.237g% versus 4.014g% of controls

GROSS PATHOLOGY / HISTOPATHOLOGY: NON-NEOPLASTIC
liver:
Necropsy revealed hypertrophy of th liver in 3 male rats receiving 800 mg/kg.
Histopathological examintion revealed no definite morphological lesions.
kidneys:
Slight basophilic alteration of the renal tubular epithelial cells was observed in 
1 female receiving 50 mg/kg, in 2 females receiving 200 mg/kg and in 5 females receiving 800 mg/kg. 
These changes were not unequivocally attributable to the test substance administration, because of their limited distribution and limited degree, 
and because similar lesions were observed in male rats of all groups including the controls.

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

There were no deaths or any abnormal clinical signs attributable to the treatment in male und female rats of any
group throughout the dosing period. The body weights of both
males and females given 800 mg/kg were lower than those of
the control group during the premating period. Food
consumption revealed no differences between the control and
treated groups. There were no observed effects of the test
substance on hematological findings of the treated males.
Blood chemical examination revealed no changes indicating
any specific organ dysfunctions. Absolute and relative liver
weights were elevated significantly in male rats receiving
800 mg/kg and increased but not significantly, in female
rats receiving 800 mg/kg. Necropsy revealed hypertrophy of
the liver in 3 male rats receiving 800 mg/kg.
Histopathological examintion revealed no definite
morphological lesions. Slight basophilic alteration of the
renal tubular epithelial cells was observed in 1 female
receiving 50 mg/kg, in 2 females receiving 200 mg/kg and in
5 females receiving 800 mg/kg. These changes were not
unequivocally attributable to the test substance
administration, because of their limited distribution and
limited degree, and because similar lesions were observed in
male rats of all groups including the controls.

Applicant's summary and conclusion

Executive summary:

Trimethylolpropane was studied for oral toxicity in an OECD TG 422 (combined repeat dose and reproductive/ developmental toxicity screening test) at doses of 0. 12.5, 50, 200, and 800 mg/kg bw/day given by gavage. For repeat dose toxicity the NOAEL was achieved at 200 mg/kg bw/day based on lowered body weight when compared to the controls, and significantly increased absolute and relative liver weights in males and elevated liver weights in females receiving 800 mg/kg bw/day with histopathological changes which could not be unequivocally attributed to treatment (MHLW 1994).