2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: peer reviewed published data, NTP study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1979

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: NTP study

Principles of method if other than guideline:

NTP
Dose range finding study for carcinogenicity assay
7 weeks treatment + 1 week observation

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Piperonyl butoxide

IUPAC Name:

Piperonyl butoxide

Details on test material:

PBO technical grade
Lot No 5
piperonyl butoxide, 88.4%
Niagara Chemical Company FMC, Middleport, new York, USA

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Frederick Cancer Research Center
- Age at study initiation: 4 weeks
- Weight at study initiation: 80-105 g
- Fasting period before study: not applicable
- Housing:
- Diet ad libitum
- Water ad libitum
- Acclimation period: 2 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 45-55
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light):12/12

IN-LIFE DATES: From: To: no data

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: with feed

Details on oral exposure:

Test diets containing piperonyl butoxide were prepared fresh each
week in 6- to 12-kilogram batches at appropriate doses. A known
weight of the chemical was first mixed with an equal weight of
autoclaved Wayne® Sterilizable Lab Meal (Allied Mills, Inc.,
Chicago, 111.), using a mortar and pestle. The mixing was
repeated with second and third additions of feed, and final
mixing was performed with the remaining quantity of feed for a
minimum of 15 minutes in a Patterson-Kelly twin-shell blender.
The diets were stored at 7 C in plastic bags during the 1 to
1-1/2 weeks it was used.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

7 weeks + 1 week additional observation

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 1.47%, 2.15%, 3.15%, 4.6%, 6.8%
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 1323, 1935, 2835, 4140, 6120 mg/kg bw/day
Basis:
other: calculated using a factor 0f 0.09 mg/kg bw/d/ ppm

No. of animals per sex per dose:

5

Control animals:

yes, plain diet

Details on study design:

no data

Positive control:

not applicable

Examinations

Observations and examinations performed and frequency:

Daily observation for mortality
Clinicla signs,
body weight: twice per week
Food and water consumption on days 4, 11, 18, 39 for 6 rats per group

Sacrifice and pathology:

organ weights and relative organe weights determined for:
liver, brain, heart, kidney, spleen, lung, testis, prostate, adrenal, thymus, ovary, uterus

Other examinations:

Haematological and clinical chemical examinations
Histological examinations of liver and kidney

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

All animals died at the highest dose level; 4 males and 3 female sdied at the 4.6% dose level, no moratlites at 1.47-3.31%

Mortality:

mortality observed, treatment-related

Description (incidence):

All animals died at the highest dose level; 4 males and 3 female sdied at the 4.6% dose level, no moratlites at 1.47-3.31%

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

No effect at 1.47%, reduced body weight at higher dose levesl.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Effect levels

Dose descriptor:

NOAEL

Effect level:

14 700 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weight, histopathological findings

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Mortality and body weight

Dose	Males	Mean bw at week 7	Females	Mean bw at week 7
%	Mortality	% of control	Mortality	% of control
1.47	0/5	94	0/5	95
2.15	0/5	73	0/5	76
3.15	0/5	60	0/5	68
4.6	4/5	60	3/5	38
6.8	5/5	n/a	5/5	n/a

Applicant's summary and conclusion

Conclusions:

In this dose range finding study the NOAEL.was at lowest dose level at 14700 ppm (corresponding to calculated 1935 mg/kg bw/day).
MTD calculated were 10000 ppm which was employed in a subsequent carcinogenicity study in rats.

Executive summary:

Groups of 5 male and 5 female rats were administered PBO at levels 14700, 21500, 31500, 46000, and 68000 ppm included in the diet. groups of five control animals of each sex were administered a basal diet only. Calculated daily dose levels were 1323, 1935, 2835, 4140, 6120 mg/kg bw/day.

The period of administration of the test chemical was 7 weeks, followed by 1 week of additional observation. Each animal was weighed twice per week At the end of the subchronic studies, all animals were killed by CO₂- inhalation and necropsied. The lowest doses at which clinical and histopathologic findings were observed were 21,500 ppm in the male and female rats thus a NOAEL of 14700 ppm was identified. (1323 mg/kg bw/day).