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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20th August 1979 to June 1980
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980
Reference Type:
publication
Title:
The toxicology of glycidol and some glycidyl ethers
Author:
Hine, C.H. et al.
Year:
1956
Bibliographic source:
Arch. Ind. Health 14, 250-264 (1956)

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Method: other
Four groups of 15 albino male rats were exposed to atmospheres containing 0, 40, 130, or 400 ppm glycidol in air (dose concenmtrations selected based on earlier wotk by Hine - see summary of 1956 paper). The exposure period was 6 h per day for five consecutive days. Methylmethane sulphonate was used as the positive control. After treatment, the exposed males were serially cohoused with two virgin females for a period of one week, over a nine week consecutive period. The females were sacrificed on day 15 after the mid point of their cohousing.and examined for pregnancy rate, total number of implants and total of dead implants.
GLP compliance:
yes
Type of assay:
rodent dominant lethal assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Glycidol
- Molecular weight (if other than submission substance): 74.08
- Physical state: odourless, colourless liquid

Test animals

Species:
rat
Strain:
other: Cpb: WU, Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Age at study initiation: Males: approximately 14 weeks old. Females: mated at the age of approximately 14 weeks old.
- Weight at study initiation: Not documented
- Assigned to test groups randomly: no
- Fasting period before study: During the exposures, the animals had no access to food or water.
- Housing: Housed in stainless steel cages which were kept suspended in an open rack during the non-exposure periods.
- Diet (e.g. ad libitum): Stock diet ad libitum after the exposure periods and during the mating period.
- Water (e.g. ad libitum): Unfluoridated tap water ad libitum after the exposure periods and during the mating period.
- Acclimation period: Not documented

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2°C
- Humidity (%): 50-70%
- Air changes (per hr): Not documented
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

IN-LIFE DATES: From: To: Not documented

Administration / exposure

Route of administration:
inhalation
Vehicle:
Glycidol vapour was mixed with filtered compressed air
Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The males were exposed to glycidol vapour in horizontally placed glass exposure cylinders (0.90 x 0.15cm) consisting of 2 Pyrex tube sections with sampling ports at the inlet and at the outlet part of the cylinder. To prevent crowding and minimize filtration of inspired air by the animals' fur, each cylinder was fitted with an interior of peforated stainless steel plate to accomodate the rats separately.
- Method of holding animals in test chamber: Not documented
- Source and rate of air: Not documented
- Method of conditioning air: Glycidol was evaporated by passing a filteredcompressor-generated airflow through a glass evaporator containing the test substance. The glycidol air flow was mixed with filtered air from the compressed air-line to provide the glycidol concentration required.
- System of generating particulates/aerosols: Not documented
- Temperature, humidity, pressure in air chamber: approximately 22°C for the 40ppm and 130ppm and approximately 25°C for the 400ppm.
- Air flow rate: 10L/min
- Air change rate: Not documented
- Method of particle size determination: Not documented
- Treatment of exhaust air: Not documented

TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatograph fitted with a flame ionization detector
- Samples taken from breathing zone: Not documented
Duration of treatment / exposure:
6 hours/day, for 5 consecutive days
Frequency of treatment:
5 days
Post exposure period:
Not documented
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 40, 130, 400 ppm
Basis:
other: nominal level in air.
No. of animals per sex per dose:
15 males per dose
Control animals:
yes
Positive control(s):
methylmethanesulfonate
- Justification for choice of positive control(s): a known mutagen, used as a positive reference compound to demonstrate a dominant lethal effect in the test sytem.
- Route of administration: Intraperitoneal injection
- Doses / concentrations: 25mg methylmethane sulfonate/kg body weight.

Examinations

Tissues and cell types examined:
Male rats: Testicles
Female rats: uterine implants, early and late foetal deaths, living embryos

The general condition and behaviour of all rats was regularly checked and any signs of reaction to treatment recorded

Bodweights were recorded at the beginning and end of exposure and at weekly intervals thereafter. Food intake was measured during the exposure period only.
Details of tissue and slide preparation:
Following necropsy the testes were weighed, preserved in neutral phosphate buffered formaldehyde and examined microscopically after staining with H&E.

Following termination of the females, they were assessed to determine the gravid status, number of uterine implants, number of early and late foetal deaths, number of live embryos and the number of corpora lutea. Females were also examined for any gross lesions that may have affected pregnancy.
Evaluation criteria:
Not documented
Statistics:
Body weights and relative testicle weights were analysed by Student T-test. The numbers of pregnant females/number of mated females and the proportion of females with one or more and two or more dead implants were analysed by the Chi-square test. The mean numbers of corpura lutea/pregnant female and the mean number of total implants/pregnant female were compared with concomitant controls by the Student t-test. The mean number of dead implants/pregnant female was analysed by the Wilcoxon test. Dead implants per total implants were computed for each male and the numbers obtained transformed using the Freeman-Turkey arc-sine transformation. A t-test was used to compare each treatment group with the concomitant control group.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
ambiguous
Toxicity:
no effects
Vehicle controls validity:
not specified
Negative controls validity:
not specified
Positive controls validity:
not specified
Additional information on results:
During the exposure period, males of the 400ppm dose group 2 deaths were reported and surviving animals were found to be sexually inactive for up to 3 days following administration. During the exposure period, the food intake of all males in all the test groups was less than that of the controls. The males of the mid and high dose groups lost body weight during exposure but thereafter body weight gain was comparable with that of the controls. In the high dose groups, fertility index and numbers of uterine implants were significantly decreased in posttreatment weeks 1 to 5 and the numbers of dead implants were significantly increased during posttreatment weeks 1 and 2. Fertility gradually improved thereafter. In the mid and low dose groups, fertility indexes and numbers of uterine impants were fully comparable with control values. Numbers of dead implants in the mid-dose group were slightly higher than in the controls in posttreatment week 3. The numbers of uterine implants in mid and low dose groups were not adversely affected by treatment. The number of corpura lutea were comparable among the various groups, although relatively low numbers occurred in the high-dose group during the first weeks. Pre-implantation loss was relatively high in females in the top-dose group during posttreatment matings 1 to 6. However, this was considered to be a reflection of the decrease in the number of uterine implants in these animals.
Gross pathological findings were observed in the lungs of the 2 animals that died in the top dose group. The lungs did not collapse completely, looked compact and had a dark-red colour. At microscopic examination, the lungs of these animals showed severe hyperaemia in all lobes. Gross findings in females included small ovarian cysts and hydrometra, observed in a few females and equally distributed among test and control groups.

Any other information on results incl. tables

400 ppm glycidol in air for 5 consecutive days induced slight dominant lethal effects in postmeiotic germ cell
stadia and strong, though reversible, antifertility effects during the first 5 weeks after treatment. Lower doses sho-
wed no conclusive results.

On the second day of the exposure period, the concentration of glycidol in the test-atmosphere of the high dose group was reduced due to signs of severe dyspnoea.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): positive
In this dominant lethal assay in male albino rats treated with glycidol by inhalation exposure ambiguous results were obtained. However, from the observations with methylmethane sulfonate, it can be concluded that the test system used was suitable to demonstrate dominant lethal effects.
Executive summary:

In a study conducted by Appelman (1980) the test susbtance, Glycidol, was examined for its ability to cause toxicity when tested on male and female Cpb: WU : Wistar rats. Groups of 15 male rats were exposed to the test susbtance for 6 hours a day for 5 consecutive days at concnetrations of 0, 40, 130 and 400ppm. A positive control group of 6 rats was treated with intraperitoneal injection of 25mg/kg body weigth of methylmethane sulfonate. The rats were exposed via the inhalation route. Following exposure, each of the male rats were mated with 2 female virgin rats per week over a period of nine consecutive weeks. Observations made included general appearance and behaviuor, food intake and growth rate of the animal.

Under the conditions of this dominant lethal assay, the results obtained were ambiguous. However, from the observations with methylmethane sulfonate, it can be concluded that the test system used was suitable to demonstrate dominant lethal effects. Under the conditions of this study, the test substance should be classified as a Category 1B mutagen and have the signal word Danger and the hazard statement H340: May cause genetic defects in accordance with Regulation EC no. 1272/2008. According to Directive 67/548/EEC, the test substance should be classified as a Category 2a mutagen, with the symbol T and the risk phrase R46 associated with it.