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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
September 1978 - Dezember 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles, acceptable for assessment, limited documentation.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Food and Drug Administration 1966 "Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use", Segment II (Teratology Study).
Deviations:
yes
Remarks:
Administration via inhalation route
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): MRD-78-26
- Physical state: Clear colourless liquid
- Analytical purity: 100% pure commercial product
- Lot/batch No.: SN 03613EC
- Other: Source: Exxon Corporation, Linden, N.J. 07036

Test animals

Species:
rat
Strain:
other: CD (SD)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs, Inc., Wilmington, Mass. 01887
- Age at study initiation: 9 wks
- Fasting period before study: no
- Housing: individually (except during mating)
- Diet (e.g. ad libitum): Standard Laboratory diet (Purina Lab Chow), fresh food presented as needed, except during each 6-hour exposure.
- Water (e.g. ad libitum): Automated water system (Elizabethtown Water Company), except during each 6-hour exposure.
- Acclimation period: 18 days


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 cubic meter exposure chamber
- Method of holding animals in test chamber: no data
- Method of conditioning air:
- Temperature, humidity, pressure in air chamber: room temprature, dried air
- Method of particle size determination: not applicable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
No details given.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: no, males from in-house colony
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
GD6 - 15
Frequency of treatment:
6 hours/day
Duration of test:
until GD21 (all surviving dams), until day 21 postmating (all surviving non-pregnant females)
Doses / concentrations
Remarks:
Doses / Concentrations:
400, 1200 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
20 females
Control animals:
yes, sham-exposed

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: mortality, gross signs of toxicologic or pharmacologic effects


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: GD 0, 6-15, and 21


BODY WEIGHT: Yes (including calculation of Body Weight Change)
- Time schedule for examinations: GD 0, 6-15, and 21


POST-MORTEM EXAMINATIONS: Yes, all females
- Sacrifice on gestation day # 21
- Organs examined: appendix containing the data was missing

OTHER:
Dams showing signs of abortion or premature delivery were sacrificed and fetuses obtained 19 days or later were processed and examined for skeletal anomalies. Only grossly abnormal fetuses obtained earlier than GD19 weresaved for possible future examination.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes (evidence of implantation, but no recognizable fetus)
- Number of late resorptions: Yes (recognizable dead fetus undergoing degeneration)
- Dead fetuses: Yes (dead fetus with no visible degeneration)
- Live fetuses
Fetal examinations:
- External examinations: Yes: all fetuses (weight, crown-rump distance from the parietal-interparietal suture to the base of the tail, malformations, sex based upon anogenital distance)
- Soft tissue examinations: Yes: two-thirds of fetuses (gross dissection and examination of viscera including internal sex determination)
- Skeletal examinations: Yes: two-thirds of fetuses (malformations and ossification variations)
- Head examinations: No data
Statistics:
Comparisons between negative and positive control and between negative control and each test substance-treated group were made where applicable (incidence data) by the chi-square method or by the F-test and Student's t-test (absolute data). When variances differed significantly, Student's t-test was appropriately modified using Cochran's approximation (t'). Mean number of live fetuses, resorptions, implantations and corpora lutea were compared to control by the one-tailed t-test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

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

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
1 200 ppm (nominal)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

A) Maternal data:

Pregnancy rates were comparable between the negative control and the treated groups. No mortality occurred in the negative control and the treated groups. Mean body weight gain during the pre-dosing and the dosing intervals were comparable between negative control and treated groups, during the post-dosing interval mean weight gain was statistical significant higher in the treated groups.

Physical observations:

No indication of a treatment effect. Likewise, the data were generally comparable between the negative and the positive control groups.

Reproduction data:

Mean number of corpora lutea, implantation sites, live fetuses, resorption sites, and the incidence of dams with one or more resorption sites were comparable between the negative control and the treated groups.

Implantation efficiency values were slightly higher in the treated groups than in the negative control, in some instances differences were statistically significant, however, this was not considered indicative of an adverse effect.

In contrast, in the positive control group the mean number of live fetuses was significantly decreased and the mean number of resorption sites significantly increased compared to the negative control. Likewise, the incidence of dams with two or more resorptions was also significantly higher than in the negative control group. The mean number of corpora lutea, implantations, and the implantation efficiency value were comparable between the positive and negative control groups.

Gross postmortem examinations:

Few gross lesions were observed at necropsy of treated females (not further specified), no treatment-related effect was indicated.

B) Fetal data:

Mean fetal weights and mean crown-rump distances of both sexes were comparable for negative control and treated groups, while in the positive control group they were significantly lower. Mean numbers of male and female fetuses were comparable between negative control and treated groups. Likewise, sex ratio data was comparable for these groups. In contrast, the mean numbers of male and female fetuses in the positive control group were significantly lower compared to the negative control, due to lower numbers of fetuses in this group.

Variations in degree of ossification:

These variations may represent delays in the ossification process or slight ossification irregularities. The incidences of fetuses with ossification variations was comparable between negative control and the 400 ppm-treated group. In the 1200 ppm-treated group the incidence of fetuses with at least one ossification variation was significantly higher compared to the negative control. The incidence of litters containing fetuses with ossification variations was comparable between negative and treated groups. Likewise, the types and incidences of ossification variations were generally similar between the negative control and the treated groups.

In contrast, in the positive control group the incidence of fetuses with at least one variation was significantly higher, ossification was retarded.

Teratology data:

No treatment-related external, gross evisceration, soft tissue and skeletal malformations were observed in the fetuses of the treated and the negative control group. One late resorption from one female of the 400 ppm group showed extreme edema, however, no other unusual observations were noted in the other late resorptions of treated and negative control groups. In contrast, in the positive control group, external malformations were noted in 14.4 % of the fetuses, the most common symptom was craniorachischisis with protruding tongue and clubbed forelimbs. The incidences of soft tissue malformations were comparable between the negative control and the treated groups, no treatment-related effect was indicated. In the positive control group, these incidences were significantly higher than in the negative control.

Applicant's summary and conclusion

Conclusions:
Under the design of the study the test substance, hydrocarbons, C7-C9, isoalkanes, produced no negative effects.
Executive summary:

Under the design of the study the test substance, hydrocarbons, C7-C9, isoalkanes, produced no negative effects.