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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1980
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1980
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
There was no mortality during the study. No treatment related physical observations were noted. Body weights were comparable between exposed animals and controls, except for the 100 ppm exposure group. However, this difference was not statistically significant. No statistically significant difference in pregnancy rates was noted. Statistically significant differences in the number of corpora lutea were noted, however, since females were not treated this was not considered treatment related. The implantation efficiency of the 100 ppm group at week 2 was significantly decreased as compared to the negative controls. This effect was deemed not to be treatment related as the effect was not seen in the 300 ppm dose group. The gross necropsy findings were unremarkable, as were the histopathological examinations.
Key result
Dose descriptor:
NOAEC
Effect level:
>= 300 ppm
Sex:
male/female
Basis for effect level:
other: 1720 mg/m3
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
The implantation efficiency of the 100 ppm group at week 2 was decreased as compared to the negative controls. However, as the implantation efficiency was within the range of values noted for the pre-treatment mating, this was not considered to be treatment related. The mean number of early fetal deaths was comparable to negative control values. Late fetal deaths could not be evaluated, as there was an insufficient number. Total number of fetal deaths were comparable between treatment and negative controls. The gross necropsy findings were unremarkable, as were the histopathological examinations.
Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
>= 300 ppm
Sex:
male/female
Basis for effect level:
other: 1720 mg/m3
Reproductive effects observed:
not specified

Mean Body Weights (g)

Week

Negative Control

Positive Control

100 ppm

300 ppm

Initial

289

281

283

284

Pre-treatment mating 1

331

325

328

328

Pre-treatment mating 2

365

362

367

363

Treatment 1

413

418

416

407

Treatment 2

438

449

441

428

Treatment 3

452

470

458

443

Treatment 4

470

487

475

459

Treatment 5

480

504

490

470

Treatment 6

484

516

502

479

Treatment 7

496

531

518

487

Treatment 8

504

538

527

500

Post-treatment mating 1

514

508

535

507

Post-treatment mating 2

523

518

544

516

Reproduction Data

Pregnancy Rate (%)

Week

Negative Control

Positive Control

100 ppm

300 ppm

Pre-treatment mating 1

75.0

70.0

70.0

70.0

Pre-treatment mating 2

80.0

85.0

90.0

95.0

Post-treatment mating 1

85.0

75.0

80.0

65.0

Post-treatment mating 2

100.0

80.0

95.0

100.0

Mean Corpora Lutea

Pre-treatment mating 1

12.5

11.8

12.9

14.0

Pre-treatment mating 2

14.1

14.9

13.1

13.5

Post-treatment mating 1

13.1

11.1

13.9

13.4

Post-treatment mating 2

13.4

11.9

14.4

13.1

Mean Implantations

Pre-treatment mating 1

10.1

11.4

12.0

13.0

Pre-treatment mating 2

12.5

14.0

12.1

11.9

Post-treatment mating 1

11.9

8.8

12.6

12.6

Post-treatment mating 2

12.7

4.1

12.8

12.5

Implantation Efficiency

Pre-treatment mating 1

80.9

96.4

92.8

92.9

Pre-treatment mating 2

88.5

94.1

92.3

88.3

Post-treatment mating 1

91.0

79.0

91.0

94.3

Post-treatment mating 2

95.1

34.0

89.4

95.4

Mean Early Fetal Death

Pre-treatment mating 1

0.2

0.4

0.6

0.5

Pre-treatment mating 2

0.6

0.5

0.5

1.0

Post-treatment mating 1

0.8

5.9

0.5

0.8

Post-treatment mating 2

0.5

4.1

0.9

0.5

Mean Late Fetal Death

Pre-treatment mating 1

0.1

0.0

0.0

0.0

Pre-treatment mating 2

0.0

0.0

0.0

0.1

Post-treatment mating 1

0.0

0.1

0.0

0.0

Post-treatment mating 2

0.0

0.0

0.0

0.0

Viable Fetal Swellings

Pre-treatment mating 1

9.9

10.9

11.4

12.5

Pre-treatment mating 2

11.9

13.5

11.6

10.8

Post-treatment mating 1

11.1

2.8

12.1

11.8

Post-treatment mating 2

12.2

0.0

11.9

12.1

Conclusions:
The NOAEC for reproductive and developmental screening is 300 ppm in rats via inhalation.
Executive summary:

This data is being read across from the source study that tested Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) based on analogue read across.

This study was conducted to assess the reproductive and developmental toxicity potential of MRD-78-25 when administered to male rats. Male rats were cohabitated for two weeks with two female rats. Males were exposed for 6 hrs/day, 5 days/week, for 8 weeks. At the end of the 8 week exposure period, the male rats the cohabitated for 7 days with two virgin female rats. After this cohabitation, the males were again cohabitated with two new virgin females for another 7 days. 18 days after the beginning of cohabitation, the females were sacrificed. There were also a negative control group, and a positive control group exposed to triethylenemelamine prior to mating. Animals were examined for mortality, pharmacological observations, toxicological observations, physical observations, body weight, gross necropsy, and histopathology. Males proven fertile were then exposed to 100 or 300 ppm of test substance vapors via inhalation (10 males per concentration). The number of implantation sites, early resorption sites, late resorption sites, and viable fetal swellings were also examined. Pregnancy rates, implantation rate, and implantation efficiency were comparable between exposure groups and negative controls. The NOAEC for reproductive screening is 300 ppm for rats via inhalation.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report date:
1980

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
no
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)
EC Number:
919-446-0
Molecular formula:
None available. Not a single isomer, see remarks.
IUPAC Name:
Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Age at study initiation: males - 10 weeks, females - 9 weeks at initiation of pre-treatment mating period, 8 weeks at initiation of post-treatment mating period
- Weight at study initiation: 281-289 g
- Housing: stainless steel wire mesh cages, animals were housed individually during exposure and at a 2:1 female/male ratio during mating
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum

IN-LIFE DATES: From: August 21, 1978 To Oct. 13, 1978

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: one cubic meter stainless steel and glass chamber
- Method of conditioning air: The MRD-78-25 (300 ppm) was transferred from a 500 ml Erlenmeyer flask using a metering pump, or a 50 cc Tomac glass syringe into a heated flask (100 ppm) and flash evaporated. Clean air was also passed through the flask to pick up vapor. The vapor air mixture was then fed into the chamber inlets and diluted to the desired concentration. The MRD-78-26 was put in fritted bottom gas-washing bottles (400 and 1200 ppm). Air was passed through the bottles, and the vapor air mixture was then fed into the chamber inlets and diluted to the desired concentration.
- Air flow rate: 132 l/min
- Air change rate: complete air change every 7.6 min, with a 99% equilibration time of 35 min.
Details on mating procedure:
Each male cohabitated for two weeks with two females. Females were sacrificed 18 days after beginning cohabitation. Males were then exposed to the test substance for 8 weeks. Two hours after the last exposure, two untreated virgin females were placed in the males cages. These females cohabitated for seven days and replaced with two new females.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Brief description of analytical method used: IR spectrum taken with a Miran IA Ambient Air Analyzer (Wilks Scientific Corp.), analyzed at 3.4 microns.
- Samples taken from breathing zone: yes, at 1, 3, and 5 hrs after exposure began each day
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 8 weeks
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
300 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
10 males, 40 females
Control animals:
yes, concurrent no treatment
Positive control:
triethylenemelamine
- Justification for choice of positive control(s): Triethylenemelamine has been shown to induce dominant-lethal mutations
- Route of administration: intraperitoneally
- Doses / concentrations: 0.5 mg/kg

Examinations

Parental animals: Observations and examinations:
Animals were examined for mortality, pharmacological observations, toxicological observations (twice daily), physical observations, body weight (weekly), gross necropsy, and histopathology (seminal vesicles, epididymis, testes, prostate).
Postmortem examinations (parental animals):
The following organs were examined in males: seminal vesicles, epididymis, testes, prostate.
Statistics:
Comparisons between controls and treatment groups were made using the Chi-square method. Data was compared using the F-test and student's t-test, with the student's t-test modified using Cochran's approximation.
Reproductive indices:
Males were considered fertile if at least one female became pregnant.
Offspring viability indices:
implantation sites, early resorption sites, late resorption sites, viable fetal swellings

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

There was no mortality during the study. No treatment related physical observations were noted. Body weights were comparable between exposed animals and controls, except for the 100 ppm exposure group. However, this difference was not statistically significant. No statistically significant difference in pregnancy rates was noted. Statistically significant differences in the number of corpora lutea were noted, however, since females were not treated this was not considered treatment related. The implantation efficiency of the 100 ppm group at week 2 was significantly decreased as compared to the negative controls. This effect was deemed not to be treatment related as the effect was not seen in the 300 ppm dose group. The gross necropsy findings were unremarkable, as were the histopathological examinations.

Effect levels (P0)

Key result
Dose descriptor:
NOAEC
Effect level:
>= 300 ppm
Sex:
male/female
Basis for effect level:
other: 1720 mg/m3

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

The implantation efficiency of the 100 ppm group at week 2 was decreased as compared to the negative controls. However, as the implantation efficiency was within the range of values noted for the pre-treatment mating, this was not considered to be treatment related. The mean number of early fetal deaths was comparable to negative control values. Late fetal deaths could not be evaluated, as there was an insufficient number. Total number of fetal deaths were comparable between treatment and negative controls. The gross necropsy findings were unremarkable, as were the histopathological examinations.

Effect levels (F1)

Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
>= 300 ppm
Sex:
male/female
Basis for effect level:
other: 1720 mg/m3

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Mean Body Weights (g)

Week

Negative Control

Positive Control

100 ppm

300 ppm

Initial

289

281

283

284

Pre-treatment mating 1

331

325

328

328

Pre-treatment mating 2

365

362

367

363

Treatment 1

413

418

416

407

Treatment 2

438

449

441

428

Treatment 3

452

470

458

443

Treatment 4

470

487

475

459

Treatment 5

480

504

490

470

Treatment 6

484

516

502

479

Treatment 7

496

531

518

487

Treatment 8

504

538

527

500

Post-treatment mating 1

514

508

535

507

Post-treatment mating 2

523

518

544

516

Reproduction Data

Pregnancy Rate (%)

Week

Negative Control

Positive Control

100 ppm

300 ppm

Pre-treatment mating 1

75.0

70.0

70.0

70.0

Pre-treatment mating 2

80.0

85.0

90.0

95.0

Post-treatment mating 1

85.0

75.0

80.0

65.0

Post-treatment mating 2

100.0

80.0

95.0

100.0

Mean Corpora Lutea

Pre-treatment mating 1

12.5

11.8

12.9

14.0

Pre-treatment mating 2

14.1

14.9

13.1

13.5

Post-treatment mating 1

13.1

11.1

13.9

13.4

Post-treatment mating 2

13.4

11.9

14.4

13.1

Mean Implantations

Pre-treatment mating 1

10.1

11.4

12.0

13.0

Pre-treatment mating 2

12.5

14.0

12.1

11.9

Post-treatment mating 1

11.9

8.8

12.6

12.6

Post-treatment mating 2

12.7

4.1

12.8

12.5

Implantation Efficiency

Pre-treatment mating 1

80.9

96.4

92.8

92.9

Pre-treatment mating 2

88.5

94.1

92.3

88.3

Post-treatment mating 1

91.0

79.0

91.0

94.3

Post-treatment mating 2

95.1

34.0

89.4

95.4

Mean Early Fetal Death

Pre-treatment mating 1

0.2

0.4

0.6

0.5

Pre-treatment mating 2

0.6

0.5

0.5

1.0

Post-treatment mating 1

0.8

5.9

0.5

0.8

Post-treatment mating 2

0.5

4.1

0.9

0.5

Mean Late Fetal Death

Pre-treatment mating 1

0.1

0.0

0.0

0.0

Pre-treatment mating 2

0.0

0.0

0.0

0.1

Post-treatment mating 1

0.0

0.1

0.0

0.0

Post-treatment mating 2

0.0

0.0

0.0

0.0

Viable Fetal Swellings

Pre-treatment mating 1

9.9

10.9

11.4

12.5

Pre-treatment mating 2

11.9

13.5

11.6

10.8

Post-treatment mating 1

11.1

2.8

12.1

11.8

Post-treatment mating 2

12.2

0.0

11.9

12.1

Applicant's summary and conclusion

Conclusions:
The NOAEC for reproductive and developmental screening is 300 ppm in rats via inhalation.
Executive summary:

This study was conducted to assess the reproductive and developmental toxicity potential of MRD-78-25 when administered to male rats. Male rats were cohabitated for two weeks with two female rats. Males were exposed for 6 hrs/day, 5 days/week, for 8 weeks. At the end of the 8 week exposure period, the male rats the cohabitated for 7 days with two virgin female rats. After this cohabitation, the males were again cohabitated with two new virgin females for another 7 days. 18 days after the beginning of cohabitation, the females were sacrificed. There were also a negative control group, and a positive control group exposed to triethylenemelamine prior to mating. Animals were examined for mortality, pharmacological observations, toxicological observations, physical observations, body weight, gross necropsy, and histopathology. Males proven fertile were then exposed to 100 or 300 ppm of test substance vapors via inhalation (10 males per concentration). The number of implantation sites, early resorption sites, late resorption sites, and viable fetal swellings were also examined. Pregnancy rates, implantation rate, and implantation efficiency were comparable between exposure groups and negative controls. The NOAEC for reproductive screening is 300 ppm for rats via inhalation.

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