Registration Dossier

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Adopted according to OECD SIDS (publicly available peer reviewed source). Original document not available.

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
SIDS Initial Assessment Report For SIAM 20 (Malonic Acid Diesters: Dimethylmalonate, 108-59-8; Diethylmalonate, 105-53-3), April 19-22, 2005 Paris.
Author:
OECD SIDS
Year:
2005
Bibliographic source:
UNEP Publications
Reference Type:
study report
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Purity: 99.8%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Animals: HSDCpb-WU rats
- Age at study initiation: 11-12 weeks
- Weight at study initiation:
males: 377-379 g, females: 210-219 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
Males:
Test groups: 39 days, male recovery group: 39 exposure days, 45 test days.
Females:
Treatment groups: 51 +/- 7 days, recovery group: 39 exposure days, 45 test days.
Frequency of treatment:
once daily, 7 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300, 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
Main group: 10 males, 10 females
Recovery groups: 5 males, 5 females
Control animals:
not specified
Details on study design:
Post-exposure recovery period in satellite groups: 14 days
Treatment:
Male rats: The test item was administered once daily, 7 days per week by gavage for 2 weeks prior to mating, during the mating period and approximately 2 weeks post mating.
Female rats: The test item was administered once daily, 7 days per week by gavage for 2 weeks prior to mating, during the mating period, pregnancy and up to lactation day 4. For the high dose recovery group animals (males and females) the test item was administered once daily, 7 days per week by gavage throughout the treatment period.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
Twice daily: morbidity and mortality. Daily observations for appearance, behaviour, clinical signs and preterminal deaths. Females were observed for signs of difficult and pronlonged parturition.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before exposure and at least once per week thereafter. Signs included were changes in skin, fur, eyes, mucous membranes, occurrence of secretions or excretions and autonomic activity, changes in gait, posture, response to handling, behavioural changes, difficult or prolonged parturition.

BODY WEIGHT: Yes
- Time schedule for examinations:
Body weights were recorded at the beginning of the study, at least weekly thereafter and at termination. All dams were weighed on gestation days 0, 7, 14 and 20 and lactation days 0 and 4.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the pre-mating period and the recovery period
- Anaesthetic used for blood collection:No data
- Animals fasted: No data
- How many animals: 5 randomly selected males and females or each group.
- Standard haematological parameters checked

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the pre-mating period and the recovery period
- Anaesthetic used for blood collection:No data
- Animals fasted: No data
- How many animals: 5 randomly selected males and females or each group.
- Standard clinical chemistry parameters checked

URINALYSIS: No data


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: at the end of the dosing period for males and during the lactation period tor females
- Dose groups that were examined: each group
- Battery of functions tested:
handling observations, open field tests, sensory observations, neuromuscular observations and physiological observations (body temperature)
Sacrifice and pathology:
Pathology: All adult animals and pups were examined for any structural abnormalities and pathological changes.
Histopathology: The following tissues of 5 males and females of the control and high dose group as well as all animals of the recovery and recovery control groups were examined microscopically: all gross lesions, brain, spinal cord, gastrointestinal tract, liver, kidney, adrenals, spleen, heart, thymus, thyroid, trachea, lungs, testes (fixed in Bouins fluid), epididymes (fixed in Bouins fluid), ovaries, uterus, seminal vesioles, coagulating glands, prostate, urinary bladder, axillary lymph nodes, mesenteric lymph nodes, sciatic nerve, femur with marrow, bone marrow smear. Stages of spermatogenesis and interstitial testicular structure in male gonads were determined additionally. Livers of 5 males and females in the mid and low dose groups and testes of 5 males of the mid and low dose groups were also examined.
Other examinations:
LITTER DATA: All pups from each litter were examined for any external deformities, litter size and sex distribution was determined. Pup weights were recorded on day 0 and 4. All pups were examined for malformations and subject to gross pathological examination. Pup survival index up to lactation day 4 was determined.
Organ weights of liver, adrenals, kidneys, thymus spleen, brain and heart were determined of 5 males and females of each group. Testes and epididymis weights of all adult males of each group were also determined.
Statistics:
Dunnett's t-Test: body weight, body weight change, food intake, haematology, clinical chemistry, organ weight, FOB, gestation length, litter size, No. corpora lutea, No. implantation.
Z-Test/Student's t-Test: Mating performance, conception rate, fertility index, gestation index, live birth index, viability index, sex ratio, pup survival data, No. littered, No. dead pups, No. live pups, Pup survival data, Pre- and Post-implantation loss. Histopathological data.
t-Test/ANOVA: dose correlation

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
No test item related clinical signs were observed throughout the test and recovery period in any of the dose groups.

BODY WEIGHT AND WEIGHT GAIN
No treatment related effects on body weight and body weight gain were observed.

FOOD CONSUMPTION
No treatment related effects were observed.

HAEMATOLOGY
No treatment related effects were observed.

CLINICAL CHEMISTRY
No treatment related effects were observed.

NEUROBEHAVIOUR
No treatment related changes were observed.

ORGAN WEIGHTS
No treatment related effects were observed.

GROSS PATHOLOGY
No treatment related effects were observed.

HISTOPATHOLOGY:
1000 mg/kg bw: Livers of males and females showed a significantly increased incidence of hepatocellular hypertrophy. The change was considered reversible as the incidence was not significantly increased in the high dose recovery animals.
300 and 100 mg/kg bw: No treatment related changes of the liver were observed.
All other histopathological findings were not considered treatment related.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment related effects have been observed.
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Significantly increased hepatocellular hypertrophy.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion