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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Test performed according to guideline standard with GLP. Study result has been published in peer-reviewed journal.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):
- Analytical purity: >99.9%
- Impurities (identity and concentrations): Not given
- Supplier: Chevron Chemical, Pittsburgh, USA

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory (Portage, MI, USA)
- Age at study initiation: 60d + 14d
- Weight at study initiation: 213 - 251g
- Fasting period before study: not reported
- Housing: individually
- Diet (e.g. ad libitum): Prolab Certified Rodent Food (Agway, St. Marys, OH, USA)
- Water (e.g. ad libitum): Not specified
- Acclimation period: 14d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2 - 22.8 °C5
- Humidity (%): 50 - 65 %
- Air changes (per hr): 14 per hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4320 L rectangular glass and stainless steel chambers (Wahmann Manufacturing, Timonium, MD, USA)
- Method of holding animals in test chamber: individually
- Source and rate of air: Not reported
- Method of conditioning air: Not reported
- Temperature, humidity, pressure in air chamber: 17.2 - 22.8 °C, 50 - 65 %
- Air flow rate: 900L/min
- Air change rate: 14 per hour
- Treatment of exhaust air: Not reported


TEST ATMOSPHERE
- Brief description of analytical method used: GC/FID
- Samples taken from breathing zone: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations were monitored once every 30 min during each 6h exposure period.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
6h/day
Frequency of treatment:
GD 6-15
Duration of test:
until GD 21
No. of animals per sex per dose:
25
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on preliminary range finding studies conducted in the same laboratory

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 6, 9, 12, 15, 18, and 21


FOOD CONSUMPTION AND COMPOUND INTAKE: Yes


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: gravid uterus, ovaries (incl. corpora lutea), cervix, vagina, abdominal and thoracic cavities, upper and lower respiratory tracts incl. nasal turbinates)


OTHER: liver weights recorded
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late 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: Yes
Statistics:
p level 0.05 (two tailed)
ANOVA and t test, as well as Kruskal-Wallis test + Mann-Whitney U test, when appropriate.
Historical control data:
Not given

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
>= 500 ppm: reduced food consumption;
1200 ppm: reduced body weight gain, perioral wetness and encrustation, increase in rel. liver weight
(see table below)

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 ppm (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 1 200 ppm (nominal)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No statistically significant effects on any gestational parameters, incl. number of corpora lutea, number of total nonviable (early or late resorptions or dead fetusess) or viable implantations, percent pre- or postimplantation los, or sex ratio.
No significant differences in the incidences of any individual malformation, of malformations by category (external, visceral, or skeletal), or of total malformations. Dilated cerebral ventricles (most common obserevd malformation) were spontaneous in nature and occured at similar incidences in treated and exposed groups. No significant increase in incidences of individual external variations by category. Incidences of serveral skeletal and visceral variations were significantly increased. However, they showed no dose-response relationship.

Effect levels (fetuses)

Remarks on result:
other: no effects, see text above

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Results:

Measured parameter

Target Concentration [ppm]

0

100

500

1200

Body weight change in g, GD6-9

12.7+-5.4

9.3+-5.4

8.7+-6.8

2.3+-5.7**

Body weight change in g, GD6-15

49.2+-7.0

48.3+-9.9

48.4+-7.2

38.6+-12.2**

Feed consumption in g/animal day-1, GD6-15

27.2+-2.1

26.9+-2.1

25.3+-2.4*

23.1+-2.5**

Feed consumption, GD15-21

31.1+-2.9

32.4+-3.0

31.6+-2.5

31.1+-2.9

Pregnant/treated rats (n)

23/25

23/25

22/25

25/25

Corpora lutea per dam

17.1+-2.3

16.7+-3.0

16.9+-1.6

17.5+-1.4

Implantations per dam

16.3+-1.7

15.2+-1.8

15.9+-1.4

16.0+-2.3

Live fetuses %

96.4+-5.1

93.4+-9.0

96.5+-3.8

94.5+-5.3

Dead fetuses

0.0+-0.0

0.0+-0.2

0.0+-0.0

0.0+-0.0

Early resorptions

0.5+-0.8

0.9+-1.0

0.5+-0.6

0.8+-0.8

Late resorptions

0.1+-0.3

0.0+-0.0

0.0+-0.0

0.0+-0.2

% live male fetuses per litter

49.7+-10.7

49.5+-12.6

52.9+-12.4

49.5+-12.7

Live fetal body weight (male & female) in g

5.5+-0.2

5.7+-0.2

5.6++-0.3

5.5+-0.3

Live male fetal body weight in g

5.7+-0.2

5.8+-0.3

5.7+-0.3

5.6+-0.3

Live female fetal body weight in g

5.4+-0.2

5.5+-0.2

5.4+-0.3

5.3+-0.3

Means +- standard deviation; 25 dams in each group;

Applicant's summary and conclusion

Conclusions:
Cumene showed no developmental toxicity in rats, as derived in a the test performed according to OECD 414. Thus the NOAEL for developmental toxicity was 1200 ppm, while the NOAEL for maternal toxicity was 100 ppm based on reduced food consumption.
Executive summary:

Groups of 25 rats were exposed on GD 6 -15 to concentrations of 0 (control: filtered air), 100, 500 and 1200 ppm cumene. At 500 ppm and above reduced food consumption was observed. At the highest concentration maternal body weight gain was reduced and relative liver weight was increased. Furthermore, perioral wetness and encrustation were observed. None of the gestational parameters were affected. There were no treatment-related increase in incidences of external, visceral and skeletal malformations.