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Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study and GLP compliant
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1994
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 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
Title:
Consensus Report for Trimethylolpropane.|Scientific Basis for Swedish Occupational Standards XVI.
Author:
Criteria Group for Occupational Standards (ed. Per|Lundberg):
Year:
1995
Bibliographic source:
Arbete Och Haelsa 19, 33-35

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Method: other: OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Trimethylolpropane, purity: 99.9%; vehicle: distilled water

Test animals

Species:
rat
Strain:
other: Slc:SD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: Males: 304-343 g; Females: 196-226 g
- Housing: pregnant females shoud be caged individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days


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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
dosing of both sexes should begin 2 weeks prior to mating, continued though mating period
males: dosing continued up to day when females are killed
females: dosing continued throughout pregnancy and up to day 4 of lactation
Details on mating procedure:
one female to one male until pregnancy occurs:
day 0 of pregnancy is defined as the day sperm is found
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
details not given
Duration of treatment / exposure:
Exposure period: male, 45 days; female, from 14 days before mating to day 3 of lactation
Duration of test: terminal kill: male, day 46; female and pups, day 4 of lactation
Frequency of treatment:
daily
Details on study schedule:
Age at mating of the mated animals 10 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 12.5, 50, 200, 800 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
None
Positive control:
no: not required

Examinations

Parental animals: Observations and examinations:
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 function
- food consumption, males and females should be weighed
- duration of gestation, examination of the litter as soon as possible, number and sex of pups, still birth, live birth, pup weight, and the presence of gross anomaies
- clinical examinations: hematology, clinical chemistry, urinalysis
- pathology: gross necropsy, histopathology
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, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities
Postmortem examinations (parental animals):
pathology: gross necropsy, histopathology
Postmortem examinations (offspring):
external malformation
Statistics:
yes but method not mentioned
Reproductive indices:
number of mated pairs
number of copulated pairs
copulation index
number of pregnant animals
fertility index
pairing days until copulation
implantation index
delivery index
Offspring viability indices:
number of pups born,
number of pups alive
birth index
live birth index
sex ratio
number of pups alive on day 4
viability index
body weight of F1 pups on day 4

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

BODY WEIGHT (PARENTAL ANIMALS)
800 mg/kg bw/day: males and females: lowered during premating period when compared to controls

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No effects on the test substnace on copulation, fertility or estrus cycle of rats, on delivery and on dams during the lactation period

ORGAN WEIGHTS (PARENTAL ANIMALS)
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: 4.237 g% versus 4.014 g% of controls

GROSS PATHOLOGY (PARENTAL ANIMALS)
HISTOPATHOLOGY (PARENTAL ANIMALS)
Necropsy revealed hypertrophy of the liver in 3 male rats receiving 800 mg/kg.
Histopathological examination reveiled no definite morphological lesions.
kidneys:
Slight basophilic alteration of the renal tubular epithelial cells was onserved 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.

OTHER FINDINGS (PARENTAL ANIMALS)

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: based on no signs indicative for reproductive / developmental toxicity up to the highest test dose.
Dose descriptor:
other: NOAEL (general toxicity)
Effect level:
200 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: see section 7.5.1

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
not examined
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

External examination of pups revealed no increase in the incidence of abnormalities. Body weight gain of pups was normal up to day 4 of the lactation period. Stillborn, dead pups and pups killed at day 4 of lactation period showed no abnormal gross lesions be attributable to treatment with the test substance.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
800 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: based on no signs indicative of developmental toxicity up to the highest test dose

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

There were no effects of the test substance on copulation, fertility or estrus cycle of rats, on delivery and on dams during the lactation period. External examination of pups revealed no increase in the incidence of abnormalities. Body weight gain of pups was normal up to Day 4 of the lactation period. Stillborn, dead pups and pups killed at day 4 of lactation period showed no abnormal gross lesions to be attributable to treatment with the test substance.

Applicant's summary and conclusion

Conclusions:
No relevant effects on reproductive toxicity or fertility were seen in this study. The NOAEL for developmental/reproductive toxicity was 800 mg/kg/day.
Executive summary:

The toxicity of trimethylolpropane (TMP) was determined in combined repeated dose toxicity study with reproduction/developmental toxicity screening test; OECD guideline 422. TMP was administered by gavage to male and female Slc:SD rats at doses of 0, 12.5, 50, 200 and 800 mg/kg/day. Male rats were dosed daily for 45 days, female rats were dosed daily for 14 days prior to mating until day 3 of lactation. There were no effects of the test substance on copulation, fertility or oestrus cycle of rats, on delivery and on dams during the lactation period. External examination of pups revealed no increase in the incidence of abnormalities. Body weight gain of pups was normal up to day 4 of the lactation period. Stillborn, dead pups and pups killed at day 4 of lactation period showed no abnormal gross lesions be attributable to treatment with the test substance. The NOAEL for developmental/reproductive toxicity was 800 mg/kg/day.