4-methylstyrene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

no

GLP compliance:

not specified

Species:

rat

Strain:

other: Crl:COBSCD(SD) BR

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

404 days

Frequency of treatment:

daily

Details on study schedule:

2-generation reproduction study

Dose / conc.:

25 mg/kg bw/day

Dose / conc.:

200 mg/kg bw/day

Dose / conc.:

500 mg/kg bw/day

Dose / conc.:

600 mg/kg bw/day

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, non-treatment-related

Description (incidence):

in 500 mg/kg/day group.

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

mortality

body weight and weight gain

Behaviour (functional findings):

not examined

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

adults treated with 500 mg/kg/day of the test substance.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not specified

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

body weight and weight gain

Key result

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

500 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

body weight and weight gain

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day

Treatment related:

yes

Relation to other toxic effects:

reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

Therefore, the the parental NOAEL was 500 mg/kg bw/day and the reproductive NOAEL and LOAEL were 200 and 500 mg/kg bw/day, respectively

Executive summary:

A study was conducted to determine the reproductive effects of the test substance administered orally by gavage to Crl:COBSCD(SD) BR rats for two generations according to a method similar to OECD Guideline 416. Dose levels of 25, 200, 500 and 600 mg/kg bw/day were administered daily for 404 d. There were no effects on the viability of pups from dams dosed at 25 or 200 mg/kg bw/day. In addition, there was no effect on mating, fertility, gestation, delivery of pups, or lactation index at these dose levels. Under the study conditions, mortality, reduced weight gain in adults and slight increase in pup mortality (first generation only) was observed at 500 mg/kg bw/day. Therefore, the the parental NOAEL was 500 mg/kg bw/day and the reproductive NOAEL and LOAEL were 200 and 500 mg/kg bw/day, respectively (Argus, 1982).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

chronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A study was conducted to determine the reproductive effects of the test substance administered orally by gavage to Crl:COBSCD(SD) BR rats for two generations according to a method similar to OECD Guideline 416. Dose levels of 25, 200, 500 and 600 mg/kg bw/day were administered daily for 404 d. There were no effects on the viability of pups from dams dosed at 25 or 200 mg/kg bw/day. In addition, there was no effect on mating, fertility, gestation, delivery of pups, or lactation index at these dose levels. Under the study conditions, mortality, reduced weight gain in adults and slight increase in pup mortality (first generation only) was observed at 500 mg/kg bw/day. Therefore, the NOAEL and LOAEL were 200 and 500 mg/kg bw/day, respectively (Argus, 1982).

Effects on developmental toxicity

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From May 27, 1980 to June 20, 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

Choice of dose levels higher than current practice and methodology lacks detail

GLP compliance:

yes

Species:

rat

Strain:

CD-1

Details on test animals or test system and environmental conditions:

Virgin Charles River COBS CD rats were obtained from The Charles River Breeding Laboratory Inc, Michigan, and were 12 weeks of age and weighed between on GD 0. There were acclimatized in the laboratory for 14 days. Rats were house singly in suspended wire cages. Temperature and humidity were controlled (actual ranges not given) and light cycle was 12 hours dark/12 hours light. Purina certified rodent chow no 5002 and tap water were available ad libitum.

Route of administration:

oral: gavage

Vehicle:

olive oil

Remarks:

Dose volume of 5 mL/kg

Details on exposure:

The test substance was administrated orally by gavage as a single daily dose on Days 6 through 19 of gestation. The test substance was prepared at concentrations to permit administration at dosage levels of 50, 300 and 600 mg/kg bw/day at constant volume of 5 ml/kg.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Rats were mated with a single male until a copulatory plug was observed: this was then deemed GD 0.

Duration of treatment / exposure:

GD 6 to 19

Frequency of treatment:

once daily

Duration of test:

Caesarean sections were conducted on GD 20.

Dose / conc.:

50 other: mg/kg/day nominal

Dose / conc.:

300 other: mg/kg/day nominal

Dose / conc.:

600 other: mg/kg/day nominal

No. of animals per sex per dose:

25 females

Control animals:

yes, concurrent vehicle

Details on study design:

One male and one female rat of the same strain and source were placed together for mating. The day that evidence of mating was detected was designated day 0 of gestation and the female was returned to an individual cage.

Maternal examinations:

Maternal observations:
Clinical observations: daily
Body weights: GD 0, 6, 9, 12, 16 and 20
Appearance and behavior
Cesarean section observations
Fetus: morphological observations

Ovaries and uterine content:

Necropsy GD 20: uterus weight, number and location of viable and non-viable fetuses, early and late resorptions, number of total implantations and corpora lutea.

Fetal examinations:

Fetal observations: weight, external abnormalities (incl. palate and eye), sexed. Approximately 50% placed in Bouins fixative for visceral examinations and sectioning as described by Wilson. Remaining 50 % fixed in alcohol, macerated in potassium hydroxide and stained with Alizarin Red S for skeletal examination.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Compared to the control group there was a reduction in maternal weight gain in all treated groups.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Occasional instances of hair loss on the limbs were observed in all test groups and control. Dry or oily haircoat, black or brown matter around the nose, red matter around the eyes, swollen limbs, and soft stool occurred occasionally in the control and treated groups.

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:yes
Details on maternal toxic effects: Compared to the control group there was a reduction in maternal weight gain in all treated groups, this was considered to be test substance related.

Key result

Dose descriptor:

NOEL

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not examined

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

not examined

Visceral malformations:

not examined

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects: Fetal weights in all treated groups were also statistically significantly lower than the controls. However, it was considered that this may have been the results of an unusually high control value for fetal weight, above the normal background range in this laboratory.

Key result

Dose descriptor:

NOEL

Effect level:

600 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

 

Observation	Control	test substance (mg/kg/day)
		50	300	600
Number pregnant	25	23	22	25
Bwt gain GD 0 – 6 (g)	28	27	25	25
Bwt gain GD 6 – 9 (g)	7	7	2	0
Bwt gain GD 0 – 20 (adjusted) (g)	67	60	56	50
Bwt GD 20 (adjusted) (g)	316	305	296	291
Mean fetal bwt (g)	4.2+0.53	3.9 *+0.24	3.9 *+0.32	3.8 **+0.25

 

* = statistically different from control p < 0.05

** = statistically different from control p < 0.01

Conclusions:

Under the study conditions, the NOAEL for teratogenicity was established at 600 mg/kg bw/day. The NOAEL for maternal toxicity was not identified, but the LOAEL was 50 mg/kg bw/day (transient bodyweight changes).

Executive summary:

A study was conducted to determine the teratogenic potential of the test substance in rats according to a method similar to OECD Guideline 414. Groups of 25 pregnant Charles River COBS CD rats were given the test substance by oral gavage, from Gestation Day (GD) 6 to 19 at dose levels of 50, 300 and 600 mg/kg bw/day at a constant volume rate of 5 mL/kg bw. A control group received the vehicle only, olive oil, at a dose volume of 5 mL/kg bw. Caesarean sections were conducted on GD 20. There were no mortalities or clinical signs in the maternal groups. Compared to controls, there was a reduction in maternal weight gain in all treated groups and this was considered to be substance-related. Fetal weights in all treated groups were also significantly lower than the controls. However, this may have been the results of an unusually high control value for fetal weight, above the normal background range of the laboratory. There were no biologically meaningful differences in the mean number of corpora lutea, total implantations, early or late resorptions, post implantation loss, viable fetuses, fetal sex distribution, mean fetal body weight or number of fetuses (and litters) with malformations. Under the study conditions, the NOAEL for teratogenicity was established at 600 mg/kg bw/day. The NOAEL for maternal toxicity was not identified, but the LOAEL was 50 mg/kg bw/day (transient bodyweight changes) (Spicer, 1981).

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

From May 15, 1980 to June 13, 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

Cannot confirm number of pregnant animals of 16, no individual data, report lacking detail

GLP compliance:

yes

Species:

rabbit

Strain:

Dutch

Details on test animals or test system and environmental conditions:

Virgin Dutch Belted rabbits were obtained form Langshaw farms, Michigan) and were 6 months of age and weighed between 2.194 and 2.970 kg on GD 0. There were acclimatized in the laboratory for 49 days. Rabbits were house singly in suspended wire cages. Temperature and humidity were controlled and light cycle was 12 hours dark/12 hours light. Purina certified rabbit chow no 5322 and tap water was available ad libitum.
During the acclimatization period Purina Sulfa was added to the drinking water for 14 days due to coccidosis; treatment was stopped 4 weeks before study initiation and only rabbits negative for cocidiosis were placed on the study. Rabbits were artificially inseminated on GD0.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on exposure:

Test substance administration began on day 6 and continued up to and including day 27 of gestation.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Rabbits were artificially inseminated on GD0.

Duration of treatment / exposure:

GD 6 to 27

Frequency of treatment:

once daily

Duration of test:

necropsy GD 28

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

150 mg/kg bw/day (nominal)

Control animals:

other: distilled water

Details on study design:

50, 100 and 150 mg/kg/day

Maternal examinations:

Maternal observations:
Clinical observations: daily
Body weights: GD 0, 6, 12, 18, 24 and 28
Appearance and behavior
Cesarean section observations
Necropsy (early decedent): tissues preserved in10 % neutral buffered formalin
Fetus: morphological observations

Ovaries and uterine content:

Necropsy GD 28: uterus weight, number and location of viable and non-viable fetuses, early and late resorptions, number of total implantations and corpora lutea.

Fetal examinations:

Fetal observations: weight, external abnormalities (incl. palate and eye), sex, visceral malformations and variations (incl mid-coronal brain slice), heart dissected, Eviseracted fetus fixed in alcohol, macerated in potassium hydroxide and stained with Alizarin Red S for skeletal examination.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

There were no deaths in the control group. In the treated groups there were a number of deaths between GD 9 and 21, the cause of which was described as follows:
50 mg/kg/day: 1 intubation error, 2 pneumonia, (4 deaths)
100 mg/kg/day: 2 intubation error, 2 pneumonia, 1 no cause identified (2 deaths)
150 mg/kg/day: 1 intubation error, 1 pneumonia. (4 deaths)
It is considered that the known volatile and irritant nature of the test substance contributed to those deaths determined as intubation error and pneumonia. Lung congestion was a common feature in all treated groups, but was not apparent in controls.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Matted haircoat, scabbing on the nose, soft stool and reddened conjunctiva each occurred occasionally among the study group animals. Occasional instances of hair loss on the limbs were observed in all test groups.

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects: yes. Remark: mortality, transient body wieght decrease, irritation in the GI tract and lungs.

Key result

Dose descriptor:

NOAEL

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not examined

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

not examined

Visceral malformations:

not examined

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: no effects.

Key result

Dose descriptor:

NOEL

Effect level:

150 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Review of the necropsy findings shows that the early decedents had observations such as severe mucosal hemorrhage of the stomach and fibrinous adhesions, congestions, edema and hemorrhage in the lungs. Even in those animals that were not early decedents changes in the lungs such as multiple pin point red foci and congestion were noted. Based on what is known of the irritant and volatile nature of the test substance it is the view of the author that those deaths described as being due to pneumonia are probably also related to test article administration. There are no recordings of lung changes in the controls. There is also a slight reduction in body weight gain between days 6 and 12 in females given 50 or 100 mg/kg/day, compared to the controls.

Conclusions:

Under the study conditions, treatment with the test substance did not produce a teratogenic response when administrated orally to pregnant Dutch Belted rabbits at a dosage level of 150 mg/kg bw/day or less. The NOAEL for teratogenicity was 150 mg/kg bw/day. The NOAEL for maternal toxicity was not identified, but the LOAEL was 50 mg/kg bw/day (pneumonia)

Executive summary:

A study was conducted to determine the teratogenic potential of the test substance in rabbits according to a method similar to OECD Guideline 414. Groups of 16 pregnant Dutch Belted rabbits were given the substance by oral gavage, from Gestation Day (GD) 6 to 27 at dose levels of 50, 100 and 150 mg/kg bw/day. A control group received distilled water a dose volume of 0.169 ml/kg. Caesarean section was conducted on GD 28. Under the study conditions, there were no deaths in the control group. In the treated groups ten rabbits died prior to scheduled sacrifice, between Days 9 and 21 of gestation. The known volatile and irritant nature of the test substance contributed to those deaths determined as intubation error and pneumonia. There was one death without apparent cause. Lung congestion was a common feature in all treated groups, but was not apparent in controls. There were no biologically meaningful differences in mean maternal body weight in any treated group, nor effects on the mean number of corpora lutea, total implantations, early or late resorptions, post implantation loss, viable fetuses, fetal sex distribution, mean fetal body weight or number of fetuses (and litters) with malformations. Under the study conditions, treatment with the test substance did not produce a teratogenic response when administrated orally to pregnant Dutch Belted rabbits at a dosage level of 150 mg/kg bw/day or less. The NOAEL for teratogenicity was 150 mg/kg bw/day. The NOAEL for maternal toxicity was not identified, but the LOAEL was 50 mg/kg bw/day (pneumonia) (Spicer, 1982).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

A study was conducted to determine the teratogenic potential of the test substance in rats according to a method similar to OECD Guideline 414. Groups of 25 pregnant Charles River COBS CD rats were given the test substance by oral gavage, from Gestation Day (GD) 6 to 19 at dose levels of 50, 300 and 600 mg/kg bw/day at a constant volume rate of 5 mL/kg bw. A control group received the vehicle only, olive oil, at a dose volume of 5 mL/kg bw. Caesarean sections were conducted on GD 20. There were no mortalities or clinical signs in the maternal groups. Compared to controls, there was a reduction in maternal weight gain in all treated groups and this was considered to be substance-related. Fetal weights in all treated groups were also significantly lower than the controls. However, this may have been the results of an unusually high control value for fetal weight, above the normal background range of the laboratory. There were no biologically meaningful differences in the mean number of corpora lutea, total implantations, early or late resorptions, post implantation loss, viable fetuses, fetal sex distribution, mean fetal body weight or number of fetuses (and litters) with malformations. The NOAEL for teratogenicity was established at 600 mg/kg bw/day. The NOAEL for maternal toxicity was not identified, but the LOAEL was 50 mg/kg bw/day (transient bodyweight changes) (Spicer, 1981).

A study was conducted to determine the teratogenic potential of the test substance in rabbits according to a method similar to OECD Guideline 414. Groups of 16 pregnant Dutch Belted rabbits were given the substance by oral gavage, from Gestation Day (GD) 6 to 27 at dose levels of 50, 100 and 150 mg/kg bw/day. A control group received distilled water a dose volume of 0.169 ml/kg. Caesarean section was conducted on GD 28. Under the study conditions, there were no deaths in the control group. In the treated groups ten rabbits died prior to scheduled sacrifice, between Days 9 and 21 of gestation. The known volatile and irritant nature of the test substance contributed to those deaths determined as intubation error and pneumonia. There was one death without apparent cause. Lung congestion was a common feature in all treated groups, but was not apparent in controls. There were no biologically meaningful differences in mean maternal body weight in any treated group, nor effects on the mean number of corpora lutea, total implantations, earlu or late resorptions, post implantation loss, viable fetuses, fetal sex distribution, mean fetal body weight or number of fetuses (and litters) with malformations. Under the study conditions, treatment with the test substance did not produce a teratogenic response when administrated orally to pregnant Dutch Belted rabbits at a dosage level of 150 mg/kg bw/day or less. The NOAEL for teratogenicity was 150 mg/kg bw/day. The NOAEL for maternal toxicity was not identified, but the LOAEL was 50 mg/kg bw/day (pneumonia) (Spicer, 1982).

Justification for classification or non-classification

Based on reproductive and developmental toxicity studies conducted in the rat and the rabbit, the test substance is not considered to warrant classification for this endpoint according to CLP (EC 1272/2008) criteria.