Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: Subchronic inhalation study with detailed investigation of reproductive organs
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study with GLP, detailed investigation of reproductive organs in course of a subchronic inhalation study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 413
Deviations:
no
GLP compliance:
yes
Remarks:
Bushy Run Research Center, Export, Pennsylvania
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Cumene (isopropyl benzene, CAS No. 98-82-8)
- Analytical purity: >=99.94% (as determined by GC/FID)
- Impurities (identity and concentrations): Not given
- Lot/batch No.: from Chevron Chemical Company

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague-Dawley Inc.
- Age at study initiation: 8 wks
- Weight at study initiation: Males: 171.4 g; Females: 140.6 g
- Fasting period before study:
- Housing: individually
- Diet (e.g. ad libitum): ad libitum during nonexposure period, powdered Certified Agway Pro Lab RMH 3200 (Agway, Inc.)
- Water (e.g. ad libitum): ad libitum during nonexposure period, tap water (Municippal Authority of Westmoreland County, Greensburg, PA, USA)
- Acclimation period: 1-2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.9-24.0 °C
- Humidity (%): 47-53 %
- Air changes (per hr): 12.5
- 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: heated glass evaporator
- Method of holding animals in test chamber: stainless steel, wire-mesh cages in a 4300L inhalation chamber
- Source and rate of air: Not reported
- Method of conditioning air: Not reported
- System of generating particulates/aerosols: Not reported
- Temperature, humidity, pressure in air chamber: 21.9-24.0 °C, 47-53 %, normal pressure
- Air flow rate: 900L/min
- Air change rate: 12.5 per hour
- Method of particle size determination: Not reported
- Treatment of exhaust air: Not reported


TEST ATMOSPHERE
- Brief description of analytical method used: GC/FID
- Samples taken from breathing zone: yes
Details on mating procedure:
Not investigated, as study is an OECD Guideline 413 with detailed examination of male reproductive organs.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were analysed once everey 25-30 min during 6 h exposure by GC/FID
Duration of treatment / exposure:
5 day per week per 13 weeks and 2 or 3 days
Frequency of treatment:
6 h
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 500, and 1200 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
21
Control animals:
yes, concurrent no treatment
Positive control:
No

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:


BODY WEIGHT: Yes
- Time schedule for examinations: prior to first exposure and weekly during exposure, and preceding sacrifice


FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: weekly
Oestrous cyclicity (parental animals):
Not investigated, as study is an OECD Guideline 413 with detailed examination of male reproductive organs
Sperm parameters (parental animals):
Parameters examined in males (15 per group): sperm count in epididymides, sperm morphology, in epididymides, spermatid count in testis, stages of spermatogenesis in testis
Litter observations:
Not investigated, as study is an OECD Guideline 413 with detailed examination of male reproductive organs
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals
- Female animals: All surviving animals


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations


HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination and weighed:
Postmortem examinations (offspring):
Not investigated, as study is an OECD Guideline 413 with detailed examination of male reproductive organs
Statistics:
Leven's test, ANOVA, t-test, Fisher exact test
p< 0.05 (two tailed)
Reproductive indices:
Not investigated, as study is an OECD Guideline 413 with detailed examination of male reproductive organs
Offspring viability indices:
Not investigated, as study is an OECD Guideline 413 with detailed examination of male reproductive organs

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
not examined

Details on results (P0)

CLINICAL SIGNS AND MORTALITY
No exposure related deaths. One male rat in 1200 ppm was sacrificed moribund because of a cage accident.

BODY WEIGHT AND FOOD CONSUMPTION
No differences in mean body weights. Increased water intake from week 2 to 13.


REPRODUCTIVE FUNCTION: SPERM MEASURES
No cumene related differences in counts of testicular sperms. Mormal morphology and stages of spermatogenesis except for one 1200 ppm rat with difuse testicular atrophy. Abnormalities of the head/tail/junction regions were observed in all groups including controls, but were attributed to individual aberrations and not exposure related.


ORGAN WEIGHTS
at 500 and 1200 ppm: increases in liver, kidney and adreanal glands
at 100 ppm: no effects

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 1 200 ppm
Sex:
male
Basis for effect level:
other: sperm count, sperm morphology, spermatogenesis
Remarks on result:
other: Generation: only specific investigations within a standard 90d study. Therefore, no P or F1 possible (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
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

Details on results (F1)

Not investigated, as study is an OECD Guideline 413 with detailed examination of male reproductive organs.

Effect levels (F1)

Remarks on result:
other: Not investigated, as study is an OECD Guideline 413 with detailed examination of male reproductive organs.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Morphological evaluations of epidiymal sperm from rats exposed to cumene for 13 weeks

Findings

Control

100 ppm

500 ppm

1200 ppm

No. male animals

15

15

15

15

Total sperm assessed

3026

3118

2832

2644

% normal appearance

98.7

98.5

96.9

98.0

% all anomalies

1.4

1.6

3.4

2.3

% head anomalies

0.5

0.5

1.1

0.7

% tail anomalies

0.5

0.6

1.5

1.0

% junction anomalies

0.4

0.5

0.8

0.6

Applicant's summary and conclusion

Conclusions:
No effects on sperm count, sperm morphology, spermatogenesis has been observed in a 90d study in rats up to a concentration of 1200 ppm.