Reaction mass of propylidynetrimethanol and 2-ethylpropane-1,3-diol and 5-ethyl-1,3-dioxane-5-methanol

Toxicity to reproduction

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:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study and GLP compliant

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

Reference 4

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

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

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

Constituent 2

Reference substance name:

TMP

IUPAC Name:

TMP

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 or test system 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)

1

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.

2

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.