Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

ECHA (ECHA-09-FS-05-EN, 15/09/2009) considers registration dossier for substance ≥ 100 t/y as technically complete even if it does not contain the results of a screening study for reproductive/developmental toxicity since the dossier contains the results of a pre-natal developmental toxicity study (see section 7.8.2).

Moreover the 28-day repeated dose toxicity study conducted on the test substance, does not indicate adverse effects on reproductive organs (testes and ovaries) or tissues (Annex IX, Section 8.7.3).

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

- By oral route: NOAEL for maternal and developmental toxicity is 0.8 mL/kg bw/day in mice which corresponds to 748 mg/kg bw/day.

- By inhalation route: NOAEC(6h/d) for developmental toxicity in rats is considered to be higher than the test dose of 600 ppm, ca. 3343 mg/m3.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: Evaluation of the effect of the test material on the development of embryonic rats.
- Short description of test conditions: Mated female rats received test material at the dose levels of 0 or 600 ppm for 6 hours each day on days 6 through 15 of gestation. The rats were exposed in a 66L inhalation chamber with a flow rate of 30L/min and the chamber material concentration was monitored every three minutes via a gas sampling valve connected to a gas chromatograph. Controls were held in a material free inhalation chamber at equivalent time.
- Parameters analysed / observed: All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 20 (gd20) and the fetuses were delivered by caesarean section. The number and placement of fetuses and resorption sites were recorded. Fetuses were removed, weighed, sexed, and examined for external, soft tissue and skeletal abnormalities.
GLP compliance:
no
Remarks:
Pre-GLP
Limit test:
no
Species:
rat
Strain:
Fischer 344
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: not reported
- Weight at study initiation: approx. 172, 175, 173 and 174 g for groups exposed to 0, 250, 500 and 1000 mg/kg bw/d, respectively.
- Fasting period before study: not reported
- Housing: plastic cages containing wood chip bedding
- Diet (e.g. ad libitum): Ralston Purina Co. ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72-76 °F
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12h / 12h

IN-LIFE DATES: From: To: not reported
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
not specified
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 66L inhalation chamber
- Method of holding animals in test chamber: Not specified
- Source and rate of air: Not specified
- Method of conditioning air: Not specified
- System of generating particulates/aerosols: Not specified
- Temperature, humidity, pressure in air chamber: Not specified
- Air flow rate: 30 L / minute
- Air change rate: Not specified
- Method of particle size determination: Not specified
- Treatment of exhaust air: Not specified

TEST ATMOSPHERE
- Brief description of analytical method used: chromatograph
- Samples taken from breathing zone: yes, every 3 minutes via a valve connected to a gas chromatograph
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: The females were placed with fertile males of the same stock overnight and checked for presence of sperm by vaginal wash the next morning.
- Proof of pregnancy: The day on which sperm was found was designated day 0 of pregnancy.
Duration of treatment / exposure:
6 hours per day
Frequency of treatment:
daily, from gd6 to gd15
Duration of test:
until gd20
Dose / conc.:
0 ppm (nominal)
Dose / conc.:
600 ppm (nominal)
No. of animals per sex per dose:
Not reported
Control animals:
yes, concurrent no treatment
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: No data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Measured data were analyzed for statistical significance by the Student's t method and are listed as mean +/- standard deviation (S.D.).
Incidence data were analyzed with Fisher's exact test.
The level of significance chosen for all tests was p < 0.05.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Many animals in the treated group exhibited tremors and a few also had mild convulsions.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Treated rats gained less weight than the controls during the treatment period.
The weight gain following cessation of treatment was not signficantly different from the control.
Early or late resorptions:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
< 600 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: tremors and mild convulsions observed at 600 ppm
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The incidence of malformation was not significantly elevated in the treated group.
The most common major malformation observed was nanoidism. This abnormality occured in the control and treated groups.
Key result
Dose descriptor:
NOAEL
Effect level:
> 600 ppm (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no adverse effects observed at 600 ppm
Key result
Developmental effects observed:
no

Toxicokinetics:

The blood concentration of test substance in pregnant females exposed by inhalation reached a plateau in about 1 hour.

Fetal blood required a longer time period to reach a plateau, at a concentration roughly equivalent to 50 percent of the mean maternal test substance blood level.

Conclusions:
Under this test conditions, the NOAEC(6h/d) for maternal toxicity cannot be determined and the NOAEC(6h/d) for developmental toxicity in rats is considered to be higher than the test dose of 600 ppm, ca. 3343 mg/m3.
Executive summary:

In a pre-natal developmental toxicity study, groups of pregnant rats were exposed to 0 and 600 ppm/6h/day on days 6 through 15 of gestation. All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 20 (gd20) and the fetuses were delivered by caesarean section.

The number and placement of fetuses and resorption sites were recorded. Fetuses were removed, weighed, sexed, and examined for external, soft tissue and skeletal abnormalities.

Many animals in the treated group exhibited tremors and a few also had mild convulsions.

There was a decreased maternal weight gain compared to the controls during the early phase of treatment.

Treatment with test substance had an inconsistent effect on litter parameters such as mean fetal weight, incidence of resorptions and incidence of fetal abnormalities.

There was a statistically significant increase in litters containing resorptions amounting to 25 percent or more of the implants in the high dose group; however, the incidence of resorptions/litter although elevated was not significant.

The incidence of malformation was not significantly elevated for any treatment group.

The blood level data show fetal blood concentrations to be lower than maternal blood test substance concentrations. Thus, the test substance reaches the fetus but the placenta produces a sparing effect with regard to fetal test substance concentration. These blood level data substantiate that a test substance exposure that produces moderate toxicity in gravid rats also produces substantial blood levels in the fetus but with negligible embryotoxicity.

Under this test conditions, the NOAEC(6h/d) for maternal toxicity cannot be determined and the NOAEC(6h/d) for developmental toxicity in rats is considered to be higher than the test dose of 600 ppm, ca. 3343 mg/m3.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: Evaluation of the effect of the test material on the development of embryonic rats.
- Short description of test conditions: Mated female rats received test material by gavage at the dose levels of 0, 250, 500, or 1000 mg/kg bw/day on days 6 through 15 of gestation. The test material was diluted with corn oil and controls received an equivalent volume of corn oil (2.0 ml/kg bw/day).
- Parameters analysed / observed: All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 20 (gd20) and the fetuses were delivered by caesarean section. The number and placement of fetuses and resorption sites were recorded. Fetuses were removed, weighed, sexed, and examined for external, soft tissue and skeletal abnormalities.
GLP compliance:
no
Remarks:
Pre-GLP
Limit test:
no
Species:
rat
Strain:
Fischer 344
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: not reported
- Weight at study initiation: approx. 172, 175, 173 and 174 g for groups exposed to 0, 250, 500 and 1000 mg/kg bw/d, respectively.
- Fasting period before study: not reported
- Housing: plastic cages containing wood chip bedding
- Diet (e.g. ad libitum): Ralston Purina Co. ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72-76 °F
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12h / 12h

IN-LIFE DATES: not reported
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): not reported
- Concentration in vehicle: not reported
- Amount of vehicle (if gavage): Total volume: 2 mL/kg bw/d
- Lot/batch no. (if required): not reported
- Purity: not reported
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: The females were placed with fertile males of the same stock overnight and checked for presence of sperm by vaginal wash the next morning.
- Proof of pregnancy: The day on which sperm was found was designated day 0 of pregnancy.
Duration of treatment / exposure:
by gavage on days 6 through 15 of gestation.
Frequency of treatment:
daily from gd 6 to gd15
Duration of test:
until gd 20
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 1 (Control)
Dose / conc.:
250 mg/kg bw/day (nominal)
Remarks:
Group 2 (Low dose)
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
Group 2 (Mid dose)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
Group 4 (High dose)
No. of animals per sex per dose:
Not reported
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: No data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Measured data were analyzed for statistical significance by the Student's t method and are listed as mean +/- standard deviation (S.D.).
Incidence data were analyzed with Fisher's exact test.
The level of significance chosen for all tests was p < 0.05.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Many animals in the 1000 mg/kg bw/d group exhibited tremors and a few also had mild convulsions.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Treated rats gained less weight than the controls during the treatment period.
The decreased weight gain was dose related with both the 1000 mg/kg and 500 mg/kg orally dosed groups.
The 1000 mg/kg bw/d group also gained significantly less weight during the latter phase of treatment.
The values for total weight gained during gestation and also maternal weight gain (gd20 weight with gravid uterus removed - gd0 weight) were also significantly reduced in the 1000 mg/kg bw/d group.
The weight gain following cessation of treatment was not signficantly different from the control for any group.
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
There was a statistically significant increase in litters containing resorptions amounting to 25 percent or more of the implants in the high dose group; however, the incidence of resorptions / litter although elevated was not significant.
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: tremors and mild convulsions at 1000 mg/kg bw/day
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The 500 mg/kg bw/d dosed group had a significantly reduced fetal weight while the 1000 mg/kg bw/d group did not.
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
There were an increase in embryolethality in the 1000 mg/kg bw/d group but this is probably due to a maternal toxicity (secondary effect).
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The incidence of malformation was not significantly elevated for any treatment group.
The most common major malformation observed in the 2 higher dosed groups was nanoidism. This abnormality did not occur in the control or lowest dose group in this study but has occured in other control litters historically in this laboratory at a rate similar to that observed in the higher treatment group.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The second most common major malformation involved the urinary tract development. The malformation included hydro-nephrosis, dilated ureter, and agenesis of the bladder. It occured in 3 fetuses from 1 litter. Since the substance was observed in the fetuses from only one litter it probably arose spontaneously rather than as a result of the test material treatment. Thus, the incidence of this major malformations at the higher dose does not appear significant.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: effects are due to maternal toxicity at 1000 mg/kg bw/day (increase in embryolethality) and at 500 mg/kg bw/day (decrease in fetal weight)
Key result
Developmental effects observed:
no
Conclusions:
Under the test conditions, the NOAEL for maternal toxicity is 500 mg/kg bw/day and the NOAEL for developmental toxicity is 1000 mg/kg bw/day in rats.
Executive summary:

In a pre-natal developmental toxicity study, test substance was administered by oral route (gavage) to groups of mated female rats at the dose levels of 0, 250, 500, or 1000 mg/kg bw/day on days 6 through 15 of gestation. The test material was diluted with corn oil and controls received an equivalent volume of corn oil (2.0 ml/kg bw/day). All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 20 (gd20) and the fetuses were delivered by caesarean section.

The number and placement of fetuses and resorption sites were recorded. Fetuses were removed, weighed, sexed, and examined for external, soft tissue and skeletal abnormalities.

There was a decreased weight gain in the two higher dose groups and tremors and mild convulsions were observed in the top dose group.

Data concerning nonteratogenic embryotoxicity were ambigous.

There were an increase in embryolethality in the 1000 mg/kg bw/d group and a decrease in fetal weight in the 500 mg/kg bw/d group. These indicators of embryotoxicity were not distributed in a dose-related manner. Most likely they were secondary to maternal toxicity (reduced weight gains, tremors, and convulsions) in the high dosed groups.

Under the test conditions, the NOAEL for maternal toxicity is 500 mg/kg bw/day and the NOAEL for developmental toxicity is 1000 mg/kg bw/day in rats.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to other study
Principles of method if other than guideline:
- Principle of test: Evaluation of the teratogenic effects of the test substance on the ICR mice.
- Short description of test conditions: mated female mice were treated by gavage with test substance at the dose levels of 0, 0.2, 0.4, 0.6 or 0.8 mL/kg bw/day, which corresponds to 0, 187, 374, 561 or 748 mg/kg bw/day, on days 6 through 9 of gestation. The test material was diluted with soybean or mineral oil and controls received soybean or mineral oil.
- Parameters analysed / observed: All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 17 (gd17) and the fetuses were delivered by caesarean section. The number and position of each fetus was recorded, weighed and examined for external, soft tissues and skeletal abnormalities.
GLP compliance:
no
Remarks:
Pre-GLP
Limit test:
no
Species:
mouse
Strain:
ICR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Industries
- Age at study initiation: not reported
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: plastic cages containing wood chip bedding
- Diet (e.g. ad libitum): Purina Mouse Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature: 70-76 °F
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12h / 12h

IN-LIFE DATES: From: To: not reported
Route of administration:
oral: gavage
Vehicle:
other: soybean or mineral oil
Details on exposure:
None reported
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: Four to five females were kept with each male. The females were checked for presence of a vaginal plug early in the morning and again late in the afternoon.
- Proof of pregnancy: The day that a vaginal plug was found was designated day 0 of pregnancy and the females were moved to wire bottomed cages.
Duration of treatment / exposure:
by gavage on days 6 through 9 of gestation
Frequency of treatment:
daily
Duration of test:
until gd17
Dose / conc.:
0 other: mL/kg bw/day
Remarks:
Group 1 (Control)
Dose / conc.:
0.2 other: mL/kg bw/day
Remarks:
Group 2 (Low dose, ca. 187 mg/kg bw/day)
Dose / conc.:
0.4 other: mL/kg bw/day
Remarks:
Group 3 (Mid dose, ca. 374 mg/kg bw/day)
Dose / conc.:
0.6 other: mL/kg bw/day
Remarks:
Group 4 (High dose, ca. 561 mg/kg bw/day)
Dose / conc.:
0.8 other: mL/kg bw/day
Remarks:
Group 5 (High dose, ca. 748 mg/kg bw/day)
No. of animals per sex per dose:
Not reported
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #17
- Organs examined: No data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: two thirds per litter
- Skeletal examinations: Yes: one third per litter
- Head examinations: No data
Statistics:
Measured data were analyzed for statistical significance by the Student's t method and are listed as mean +/- standard deviation (S.D.).
Incidence data were analyzed with Fisher's exact test.
The level of significance chosen for all tests was p = 0.05.
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The increased maternal weight in the 0.2 and 0.4 ml/kg bw/d groups is apparently due to increased fetal weight and the increased maternal weight gain in the 0.8 ml/kg bw/d group is due to slightly larger average litter size.
Key result
Dose descriptor:
NOAEL
Effect level:
0.8 other: mL/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed
Remarks on result:
other: ca. 748 mg/kg bw/day
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There was a difference found in mean fetal weights. At doses of 0.2 and 0.4 ml/kg w/d the mean fetal weight was significantly heavier (p=0.05) than in the controls and there was a corresponding higher mean weight gain in the females in these treatment groups and in the 0.8 ml/kg bw/d group.
The increased fetal weight is not easily explained particularly when no such increase occurred in the groups receiving 0.6 and 0.8 ml/kg bw/d.
Key result
Dose descriptor:
NOAEL
Effect level:
0.8 other: mL/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no adverse effects observed
Remarks on result:
other: ca. 748 mg/kg bw/day
Key result
Developmental effects observed:
no
Conclusions:
Under the test conditions, the test substance is not embryotoxic up to 0.8 mL/kg bw/d (ca. 748 mg/kg bw/d).
Executive summary:

In a pre-natal developmental toxicity study, test substance was administered by oral route (gavage) to groups of mated female mice at the dose levels of 0, 0.2, 0.4, 0.6 or 0.8 mL/kg bw/day which corresponds to 0, 187, 374, 561 or 748 mg/kg bw/day on days 6 through 9 of gestation. The test material was diluted with soybean or mineral oil and controls received soybean or mineral oil. All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 17 (gd17) and the fetuses were delivered by caesarean section. The number and position of each fetus was recorded, weighed and examined for external, soft tissues and skeletal abnormalities.

The following comparisons were made between the control and experimental groups: mean implants/female, mean viable fetuses/litter, mean resorptions/litter, frequency of resorptions, frequency of soft tissue anomaly, and frequency of skeletal anomaly.

In ICR mice the test substance does not cause an increase in fetal malformations. The same result was found by Keller et al. (1981), after exposing Fisher 344 rats to oral doses of 250, 500 and 1000 mg/kg/d and an inhalation dose of 572 ppm for six hours per day (nominal dose of 600 ppm). All groups were exposed on day 6 through 15 of gestation. They did find that rats receiving 1000 mg/kg and the inhalation dose showed tremors and moderate convulsions and a reduction in maternal weight gain. These effects were not observed in mice. Mice are more sensitive to the toxic effects of test substance having a LD50 of 3.9 ml/kg while the LD50 in rats is over 20 ml/kg bw (Kinkead 1979). The concentrations used in the mouse study were higher in proportion to the toxic dose than those in the rat study. Even so there was no increase in the incidence of fetal malformations.

The increased fetal weight in the mouse study is not easily explained particularly when no such increase occurred in the groups receiving 0.6 and 0.8 ml/kg bw/d. The increased maternal weight in the 0.2 and 0.4 ml/kg bw/d groups is apparently due to increased fetal weight and the increased maternal weight gain in the 0.8 ml/kg bw/d group is due to slightly larger average litter size.

Under this test conditions, the NOAEL for maternal and developmental toxicity is 0.8 mL/kg bw/day in mice which corresponds to 748 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
748 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Pre-GLP Key study with Klimisch reliability 2.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
3 343 mg/m³
Study duration:
subacute
Experimental exposure time per week (hours/week):
6
Species:
rat
Quality of whole database:
Pre-GLP Key study with Klimisch reliability 2.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental toxicity study by oral route:

Two studies are available and considered as key studies.

- In a pre-natal developmental toxicity study (Keller, 1981, K, Rel.2), test substance was administered by oral route (gavage) to groups of mated female rats at the dose levels of 0, 250, 500, or 1000 mg/kg bw/day on days 6 through 15 of gestation. The test material was diluted with corn oil and controls received an equivalent volume of corn oil (2.0 ml/kg bw/day). All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 20 (gd20) and the fetuses were delivered by caesarean section.

The number and placement of fetuses and resorption sites were recorded. Fetuses were removed, weighed, sexed, and examined for external, soft tissue and skeletal abnormalities.

There was a decreased weight gain in the two higher dose groups and tremors and mild convulsions were observed in the top dose group.

There were an increase in embryolethality in the 1000 mg/kg bw/d group and a decrease in fetal weight in the 500 mg/kg bw/d group. These indicators of embryotoxicity were not distributed in a dose-related manner. Most likely they were secondary to maternal toxicity (reduced weight gains, tremors, and convulsions) in the high dosed groups.

The NOAEL for maternal toxicity is 500 mg/kg bw/day and the NOAEL for developmental toxicity is 1000 mg/kg bw/day in rats.

- In a pre-natal developmental toxicity study (Killer, 1981, K, Rel.2), test substance was administered by oral route (gavage) to groups of mated female mice at the dose levels of 0, 0.2, 0.4, 0.6 or 0.8 mL/kg bw/day which corresponds to 0, 187, 374, 561 or 748 mg/kg bw/day on days 6 through 9 of gestation. The test material was diluted with soybean or mineral oil and controls received soybean or mineral oil. All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 17 (gd17) and the fetuses were delivered by caesarean section. The number and position of each fetus was recorded, weighed and examined for external, soft tissues and skeletal abnormalities. The following comparisons were made between the control and experimental groups: mean implants/female, mean viable fetuses/litter, mean resorptions/litter, frequency of resorptions, frequency of soft tissue anomaly, and frequency of skeletal anomaly.

In ICR mice the test substance does not cause an increase in fetal malformations. The same result was found by Keller et al. (1981), after exposing Fisher 344 rats to oral doses of 250, 500 and 1000 mg/kg/d and an inhalation dose of 572 ppm for six hours per day (nominal dose of 600 ppm). All groups were exposed on day 6 through 15 of gestation. They did find that rats receiving 1000 mg/kg and the inhalation dose showed tremors and moderate convulsions and a reduction in maternal weight gain. These effects were not observed in mice.

Mice are more sensitive to the toxic effects of test substance having a LD50 of 3.9 ml/kg while the LD50 in rats is over 20 ml/kg bw (Kinkead 1979). The concentrations used in the mouse study were higher in proportion to the toxic dose than those in the rat study. Even so there was no increase in the incidence of fetal malformations.

The increased fetal weight in the mouse study is not easily explained particularly when no such increase occurred in the groups receiving 0.6 and 0.8 ml/kg bw/d. The increased maternal weight in the 0.2 and 0.4 ml/kg bw/d groups is apparently due to increased fetal weight and the increased maternal weight gain in the 0.8 ml/kg bw/d group is due to slightly larger average litter size.

The NOAEL for maternal and developmental toxicity is 0.8 mL/kg bw/day in mice which corresponds to 748 mg/kg bw/day.

Based on the results of these two key studies, mice are more sensitive to the toxic effects of test substance. Therefore, the NOAEL for maternal and developmental toxicity 0.8 mL/kg bw/day in mice which corresponds to 748 mg/kg bw/day was chosen for chemical safety assessment.

Developmental toxicity by Inhalation route:

One study was available and considered as a key study (Keller, 1981, Rel.2, K). In a pre-natal developmental toxicity study, groups of pregnant rats were exposed to 0 and 600 ppm/6h/day on days 6 through 15 of gestation. All animals were weighed and observed daily for clinical signs. The animals were sacrificed at gestational day 20 (gd20) and the fetuses were delivered by caesarean section.

The number and placement of fetuses and resorption sites were recorded. Fetuses were removed, weighed, sexed, and examined for external, soft tissue and skeletal abnormalities.

Many animals in the treated group exhibited tremors and a few also had mild convulsions. There was a decreased maternal weight gain compared to the controls during the early phase of treatment. Treatment with test substance had an inconsistent effect on litter parameters such as mean fetal weight, incidence of resorptions and incidence of fetal abnormalities.

There was a statistically significant increase in litters containing resorptions amounting to 25 percent or more of the implants in the high dose group; however, the incidence of resorptions/litter although elevated was not significant. The incidence of malformation was not significantly elevated for any treatment group.

The blood level data show fetal blood concentrations to be lower than maternal blood test substance concentrations. Thus, the test substance reaches the fetus but the placenta produces a sparing effect with regard to fetal test substance concentration. These blood level data substantiate that a test substance exposure that produces moderate toxicity in gravid rats also produces substantial blood levels in the fetus but with negligible embryotoxicity.

The NOAEC(6h/d) for maternal toxicity cannot be determined and the NOAEC(6h/d) for developmental toxicity in rats is considered to be higher than the test dose of 600 ppm, ca. 3343 mg/m3.

Justification for classification or non-classification

 


Harmonized classification:


The substance has no harmonized classification according to the Regulation (EC) No 1272/2008 including ATP2.


 


Self-classification:


Based on the available data, no additional classification is proposed according to the Regulation (EC) No. 1272/2008 and of UN GHS criteria.

Additional information