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Toxicological information

Toxicity to reproduction

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Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH


The read-across is an analogue approach based on the hypothesis that the Source substance (Trimethylolpropane (TMP)) and Target substance (Trimethylolethane (TME)) will have similar toxicological and ecotoxicological properties due to their close structural and physicochemical similarities.

The Source substance (which is registered at Annex X) has a comprehensive data set covering the REACH Annex VIII registration band at which the Target substance is being registered. The availability of this data set, along with the Source substances similarity to the Target substance, are considered sufficient for the read-across to be an appropriate adaptation to the standard information requirements of Annex VIII of the REACH regulation for the Target substance in accordance with the provisions of Annex XI, 1.5 of the REACH regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

The Source substance is very pure (>99.6% w/w) while the technical grade of the Target substance as placed on the EU market contains two impurities; bis-TME (Cas No 63603-72-5) and Di-TME (Cas No 34541-79-2). The concentration of these impurities varies between batches and each impurity can be present at up to 4% w/w per batch.

The impurities in the Target substance are considered not to have any impact on toxicological or physico-chemical profile versus the main component. This is discussed further in the Read-Across Assessment Framework Report.


3. ANALOGUE APPROACH JUSTIFICATION

The Source and Target substances both contain the same 1,1,1-trimetholethyl group unit with the only structural difference being the presence of a methyl group (CH3-) for TMP instead of hydrogen (H-) for TME. Both the Source and Target substances have similar molecular weights of 134.17 and 120.15 respectively.

The physicochemical test results between the Source and Target substance are almost identical although water and logPow values are different as is the melting/freezing point. This divergence is not considered to have any significance to the read-across and is discussed further in the Read-Across Framework Report.

Because the structural and physicochemical profiles of the Source and Target substances are so similar, a read-across between the two substances is considered valid, as they are both expected to have similar toxicological and ecotoxicological profiles.

Further discussion of the similarities between the Source and Target substances is discussed in the Read-Across Assessment Framework Report.

4. DATA MATRIX

See Read-Across Assessment Framework Report
Cross-reference
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study and GLP
Reason / purpose for cross-reference:
reference to same study
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: OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test.
GLP compliance:
yes
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
Route of administration:
oral: gavage
Vehicle:
water
Details on 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
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
Remarks:
Doses / Concentrations:
0, 12.5, 50, 200, 800 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
as requested by OECD TG 422
Positive control:
no
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 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
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
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: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
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 of the test substance 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: 4.237g% versus 4.014g% of controls

GROSS PATHOLOGY (PARENTAL ANIMALS)
HISTOPATHOLOGY (PARENTAL ANIMALS)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.


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
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
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.
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
Reproductive effects observed:
not specified
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 be attributable to treatment with the test substance.
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. No signs indicative of reproductive/ developmental toxicity were observed . The NOAEL for reproductive performance and offspring development were both 800 mg/kg bw/day. The NOAEL (general toxicity) was 200 mg/kg bw/day (MHLW 1994).

Data source

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
Ethylidynetrimethanol
EC Number:
201-063-9
EC Name:
Ethylidynetrimethanol
Cas Number:
77-85-0
Molecular formula:
C5H12O3
IUPAC Name:
ethylidynetrimethanol

Results and discussion

Results: P0 (first parental generation)

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:
organ weights and organ / body weight ratios

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

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.

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion