Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented publication which meets basic scientific principles.
Justification for type of information:
Hydrocarbons, C9-C10, aromatics, >1% Naphthalene are a combination of Hydrocarbons, C9 Aromatics and Hydrocarbons, C10-C12 Aromatics. Read across data is available for Hydrocarbons, C9 Aromatics and Hydrocarbons, C10-C12 Aromatics and the worst case scenario for each end point has been presented.
Cross-reference
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented publication which meets basic scientific principles.
Justification for type of information:
Hydrocarbons, C9-C10, aromatics, >1% Naphthalene are a combination of Hydrocarbons, C9 Aromatics and Hydrocarbons, C10-C12 Aromatics. Read across data is available for Hydrocarbons, C9 Aromatics and Hydrocarbons, C10-C12 Aromatics and the worst case scenario for each end point has been presented.
Reason / purpose:
read-across source
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
At the 100 ppm level, weight gain was reduced, but not significantly different from control. No other signs of maternal toxicity were seen. In the 500 ppm group, one animal died due to an unrelated injury, another animal died due to unknown reasons. There was significantly reduced weight gain in this group. No other signs of toxicity were seen. The 1500 ppm group showed severe maternal toxicity. 14 animals at this exposure level died. Other signs of toxicity include abnormal gait, labored breathing, hunched posture, weakness, inadequate grooming, circling, and ataxia.

No differences in organ weights were noted between the groups. The hematological examination showed significant decreases in hematocrit, and mean corpuscular volume in the high exposure groups. Leukocyte count was reduced in the 500 ppm group, but was not dose related.
Key result
Dose descriptor:
NOAEC
Effect level:
100 ppm
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
100 ppm
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
500 ppm
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
500 ppm
Basis for effect level:
other: developmental toxicity
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: Unexplained mortality of one animal, and significantly reduced weight gain.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Number of live fetuses/litter was in the 100 ppm group significantly reduced, however, this effect was not dose related. The 500 ppm group showed significant reduction in fetal body weight. There was no other evidence of developmental toxicity in this group. In the 1500 ppm group there was a significant reduction in the number of live fetuses/litter, and mean fetal body weight. Postimplantation loss was significantly higher, as was the number of fetuses with cleft palate. Ossification, particularly in the skull and sternebrae, was delayed.
Key result
Dose descriptor:
NOAEC
Effect level:
100 ppm
Sex:
male/female
Basis for effect level:
other: Developmental Toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
500 ppm
Sex:
male/female
Basis for effect level:
other: Developmental Toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Control

100 ppm

500 ppm

1500 ppm

Number of maternal deaths

0

0

2

14/32 (two replacement dams added on GD6)

Number of litters with viable fetuses

24

21

23

13 (3 litters resorptions only)

Live fetuses/litter

10.7 ±1.8

8.7 ± 4.6

9.3 ± 3.1

7.9 ± 4.3

Postimplantation loss/dam

0.9 ± 0.9

2.3 ± 4.1

2.0  ± 3.1

4.3 ± 3.7

Fetal body weight (grams)

1.25 ± 0.14

1.24 ± 0.08

1.16 ± 0.11

0.82 ± 0.17

Maternal weight gain

23  ± 2.7

19 ± 8.8

19 ± 5.6

14 ± 6.8

Conclusions:
The maternal and developmental toxicity NOAEC = 100 ppm. The maternal toxicity LOAEC was 500 ppm based on significant reduction in weight gain for the dams.

The development toxicity LOAEC was 500 ppm based on significant reduction in weight gain likely caused by the significant reduction in maternal body weight.
Executive summary:

This data is being read across from the source study that tested Hydrocarbons, C9, aromatics based on analogue read across.

This study was conducted to determine the developmental toxicity of high flash aromatic naphtha. Groups of 30 pregnant female mice were exposed via inhalation to 100, 500, or 1500 ppm of high flash aromatic naphtha for 6 hrs per day during gestation days 6 -15. The mice were sacrificed on gestation day 18, and examined for a variety of fetal developmental parameters including number of viable and nonviable fetuses, number of resorptions, total implantations, and number of corpea lutea. Animals were also examined for maternal toxicity signs including body weight, and changes in appearance and behaviour.

There was a statistically significant reduction in body weight gain in dams and reduced mean body weight for fetuses in the 500 ppm exposure group. Therefore, the maternal and developmental toxicity NOAEC = 100 ppm. The maternal toxicity LOAEC was 500 ppm based on significant reduction in weight gain for the dams. 

The development toxicity LOAEC was 500 ppm based on significant reduction in weight gain likely caused by the significant reduction in maternal body weight.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1990

Materials and methods

Principles of method if other than guideline:
Groups of 30 pregnant female mice were exposed via inhalation to 100, 500, or 1500 ppm of high flash aromatic naphtha for 6 hrs per day during gestation days 6 -15. The mice were sacrificed on gestation day 18, and examined for a variety of fetal developmental parameters including number of viable and nonviable fetuses, number of resorptions, total implantations, and number of corpea lutea. Animals were also examined for maternal toxicity signs including body weight, and changes in appearance and behaviour.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI
- Age at study initiation: 10-11 weeks
- Housing: Inidividually housed in wire mesh cages
- Diet (e.g. ad libitum): Purina Certified Rodent Chow No. 5002 ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2-3 weeks


ENVIRONMENTAL CONDITIONS
Animal husbandry followed standards by the US Department of Health, Education, and Welfare (1985)

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 16 m glass and steel chambers.
- Method of holding animals in test chamber: cages
- Source and rate of air: Air was provided by a separate HVAC system.
- Method of conditioning air: Air was filtered for particulates and temperature and humidity controlled.
- System of generating particulates/aerosols: Test atmosphere was generated by heating nitrogen to 200°C by passing it through a 1 l stainless steel cylinder with a 1500 W band heater. The nitrogen then passed through a glass column 7.6 cm diameter and 30 cm long packed with glass beads. Test material was delivered by a metering pump into Teflon tubing, to the bottom of the column. The liquid test substance vaporized as it went up the column with the nitrogen. The vapor then went into the test chambers where dilution with the chamber ventilation air produced the desired concentrations.
- Temperature, humidity, pressure in air chamber: Air flow rate, temperature and relative humidity were monitored every half-hour during exposure.


TEST ATMOSPHERE
- Brief description of analytical method used: Measurements made hourly using gas-phase IR.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration of the test material in the test chambers was determined by GC analysis.
Details on mating procedure:
- Proof of pregnancy: vaginal plug
Duration of treatment / exposure:
6 hours per day
Frequency of treatment:
gestation day (GD) 6 - 15 and GD 18
Duration of test:
Through GD 18.
No. of animals per sex per dose:
30 pregnant females per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Rationale for animal assignment: random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Check twice daily for viability and changes in appearance and/or behaviour.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: GD 6-15 and GD18

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0 and GD6-18

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #: 18
- Organs examined: Lung, liver, kidney, uteri


OTHER: Blood samples were drawn on GD15 from the control, 500 ppm, and 1500 ppm groups and evaluated for leukocyte, erythrocyte counts, hemoglobin, and hematocrit
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: uterine content was examined
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of viable and non-viable fetuses
Fetal examinations:
- External examinations: Yes: all per litter were examined for weight, sex, malformations, and variations
- Soft tissue examinations: Half of the fetuses were dissected, internally sexed, and examined for internal malformations and variations. Heads were used for soft tissue examination, also hearts were dissected.
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: Heads of half the fetuses were used for soft tissue examination.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
At the 100 ppm level, weight gain was reduced, but not significantly different from control. No other signs of maternal toxicity were seen. In the 500 ppm group, one animal died due to an unrelated injury, another animal died due to unknown reasons. There was significantly reduced weight gain in this group. No other signs of toxicity were seen. The 1500 ppm group showed severe maternal toxicity. 14 animals at this exposure level died. Other signs of toxicity include abnormal gait, labored breathing, hunched posture, weakness, inadequate grooming, circling, and ataxia.

No differences in organ weights were noted between the groups. The hematological examination showed significant decreases in hematocrit, and mean corpuscular volume in the high exposure groups. Leukocyte count was reduced in the 500 ppm group, but was not dose related.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
100 ppm
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
100 ppm
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
500 ppm
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
500 ppm
Basis for effect level:
other: developmental toxicity

Maternal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
other: Unexplained mortality of one animal, and significantly reduced weight gain.

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Number of live fetuses/litter was in the 100 ppm group significantly reduced, however, this effect was not dose related. The 500 ppm group showed significant reduction in fetal body weight. There was no other evidence of developmental toxicity in this group. In the 1500 ppm group there was a significant reduction in the number of live fetuses/litter, and mean fetal body weight. Postimplantation loss was significantly higher, as was the number of fetuses with cleft palate. Ossification, particularly in the skull and sternebrae, was delayed.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
100 ppm
Sex:
male/female
Basis for effect level:
other: Developmental Toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
500 ppm
Sex:
male/female
Basis for effect level:
other: Developmental Toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Control

100 ppm

500 ppm

1500 ppm

Number of maternal deaths

0

0

2

14/32 (two replacement dams added on GD6)

Number of litters with viable fetuses

24

21

23

13 (3 litters resorptions only)

Live fetuses/litter

10.7 ±1.8

8.7 ± 4.6

9.3 ± 3.1

7.9 ± 4.3

Postimplantation loss/dam

0.9 ± 0.9

2.3 ± 4.1

2.0  ± 3.1

4.3 ± 3.7

Fetal body weight (grams)

1.25 ± 0.14

1.24 ± 0.08

1.16 ± 0.11

0.82 ± 0.17

Maternal weight gain

23  ± 2.7

19 ± 8.8

19 ± 5.6

14 ± 6.8

Applicant's summary and conclusion

Conclusions:
The maternal and developmental toxicity NOAEC = 100 ppm. The maternal toxicity LOAEC was 500 ppm based on significant reduction in weight gain for the dams.

The development toxicity LOAEC was 500 ppm based on significant reduction in weight gain likely caused by the significant reduction in maternal body weight.
Executive summary:

This study was conducted to determine the developmental toxicity of high flash aromatic naphtha. Groups of 30 pregnant female mice were exposed via inhalation to 100, 500, or 1500 ppm of high flash aromatic naphtha for 6 hrs per day during gestation days 6 -15. The mice were sacrificed on gestation day 18, and examined for a variety of fetal developmental parameters including number of viable and nonviable fetuses, number of resorptions, total implantations, and number of corpea lutea. Animals were also examined for maternal toxicity signs including body weight, and changes in appearance and behaviour.

There was a statistically significant reduction in body weight gain in dams and reduced mean body weight for fetuses in the 500 ppm exposure group. Therefore, the maternal and developmental toxicity NOAEC = 100 ppm. The maternal toxicity LOAEC was 500 ppm based on significant reduction in weight gain for the dams. 

The development toxicity LOAEC was 500 ppm based on significant reduction in weight gain likely caused by the significant reduction in maternal body weight.