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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1986
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report date:
1986

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether
EC Number:
200-076-7
EC Name:
2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether
Cas Number:
51-03-6
Molecular formula:
C19H30O5
IUPAC Name:
2-(2-butoxyethoxy)ethyl 6-propylpiperonyl ether

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Dutchland, Denver, Pennsylvania, USA
- Age at study initiation: 4 months
- Weight at study initiation: 3032 - 4192 g
- Housing: All animals were housed individually in suspended wire cages
- Diet: ad libitum (Purina certified Rabbit Chow #5322)
- Water: ad libitum (Tap water)
- Acclimation period: 29 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 23 °C
- Humidity: 41 - 51 %
- Photoperiod: 12 hrs dark / 12hrs light

IN-LIFE DATES: From: April 2, 1985 (date of arrive in laboratory) To: May 31, 1985 (date of last Cesarean section).

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
Mazola® corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS

The appropriate amount of Piperonyl butoxide (PBO) for each group was weighed into a volumetric flask. PBO is not soluble in water and for this reason a sufficient quantity of the vehicle, Mazola® corn oil, was added to yield 50 mL of prepared test material.
The test article was prepared fresh daily at concentrations to permit the administrstion of dose levels of 50, 100 and 200 mg/kg/day at dosage volume of 0.5 mL/kg.
Details on mating procedure:
- Impregnation procedure: eight proven male rabbits of the same breed and source were selected to serve as donors. Semen was collected using an artificial vagina and gelatinous plug was removed from the ejaculate. The semen was immediately evaluated for motility and was used for insemination only in the motility was 60% or greater. An opportune solution of the ejaculate was introduced into the anterior vagina of the female using an insemination pipette. Immediately after insemination, ovulation was induced by an injection of 1000 U.S.P. units of human chorionic gonadotropin into a marginal ear vein..
An equal number of females from each group was inseminated with semen from a single male.
Insemination procedure were performed on two consecutive days with an equal number of females from each group inseminated per day.
The day of insemination was designed as day 0 of gestation (gd).
Duration of treatment / exposure:
From days 7 to 19 of gestation.
Frequency of treatment:
daily
Duration of test:
29 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (control), 50, 100 and 200 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
16/female/0; 16/female/50; 16/female/100; 16/female/200 mg/kg/day.
Control animals:
yes, concurrent vehicle
Details on study design:
- The selected route of administration was oral since this was considered moist closely equivalent to the typical route of human exposure.
- Dose levels were selected on the basis of a previously conducted range-finding study.
- The test article was administered as a single daily dose on days 7 through 19 of gestation.
- Test article administration was accomplished by intragastric intubation using 5 cc glass syringes and 12 gauge, 16.5 cm long curved stainless steel dosing needles.
- Dosing began to 4-3/4 hours after initiation of the illuminated phase of photoperiod.
- The control group received the vehicle only on a comparable regiment at volume of 0.5 mL/kg

Examinations

Maternal examinations:
APPEARANCE & BEHAVIOUR.
- Throughout the study the females were observed twice daily for mortality and overt changes in appearance and behaviour. They were observed once daily at the time of dosing for clinical signs of toxicity on days 7 through 19 of gestation. The duration of clinical observations was indicates in appropriate time units. Any female showing signs of premature delivery was sacrificed and necropsied on the day such evidence was observed and the delivered pups were sacrificed, necropsied and preserved for subsequent skeletal examination.

BODY WEIGHT
- Individual maternal body weights were recorded on gestation days 0, 7, 13, 20, 24 and 29.

- CESAREAN SECTION OBSERVATIONS
On gestation day 29, all females were sacrificed by an injection of sodium pentobarbital via a marginal ear vein. Immediately following sacrifice, the uterus and ovaries were exposed by an abdominal incision. The number and location of VIABLE and NONVIABLE fetuses, EARLY and LATE RESORPTIONS and the number of total IMPLANTATIONS and CORPOREA LUTEA were recorded.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes

Once the uterus was excised, the fetuses were removed. The abdominal and the thoracic cavities and organs of the does were examined for grossly evident morphological changes and the carcasses discarded. Uteri from females that appeared non-gravid were opened and placed in 10% ammonium sulphide solution for detection of implantations

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:
Fetal examinations:
- External examinations: Yes: all fetuses were individually weighed, tagged and examined for external malformations and variations.
- Each fetuses was dissected, internally sexed and examined for visceral malformations and variations, including the brain by a mid-coronal slice.
- Skeletal examinations: Yes: all fetuses.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: See "Details on maternal toxic effects"

Details on maternal toxic effects:
GENERAL APPEARANCE AND BEHAVIOUR
- Survival was 100 % for the control and all treated groups throughout the study.
- One female in the mid-dose group (100 mg/kg/day) delivered 9 viable fetuses near term on gestation day 29. This was not considered treatment related.
- Decreased defecation was noted in six animals each of the high and the mid dose group.
- Soft stools, hair loss, mucoid material of unknown origin, stained and/or matted hair coat and dental abnormalities, sometimes observed in the control, mid- and high dose groups, were considered inconsequential due either to low incidence or comparable controll group findings.
- No visible abnormalities were observed for any of the low-dose (50 mg/kg/day) females.
- Necropsy incidental lesions found were not considered as result of the treatment.
(See the tables “ANTE MORTEM OBSERVATIONS” and “NECROPSY OBSERVATIONS” attached in “background material”)

BODY WEIGHTS
Slight/moderate body weight losses were incurred by the animals treated at the mid- and high-dose levels during the treatment period (gestation days 7 through 19). Anyway, the weight gain values for these groups during the overall gestation period (days 0 to 29) were comparable to the control value.
No treatment related differences in weight gain were noted between the control and low dose group during the treatment period.
The body weight gains of the treated groups were comparable to that of the control group over the entire gestation period (gestation days 0 to 29).
(See the table “BODY WEIGHT & BODY WEIGHT CHANGES” attached in “background material”)

CESAREAN SECTION OBSERVATIONS
The numbers of viable foetuses, total implantations and corpora lutea per dose in the treated groups were comparable with the control group values.
No meaningful differences were noted between the mean fetal body weight values and fetal sex ratios of the treated groups and those of the control.
(See the table “MATERNAL & FETAL OBSERVATIONS” attached in “background material”)

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: See "Details on embryotoxic / teratogenic effects"

Details on embryotoxic / teratogenic effects:
FETAL MORPHOLICAL OBSERVATIONS
- All malformations observed in the treated groups occurred incidentally and were considered unrelated to the treatment.
(See the table “INCIDENCE OF FETAL MALFORMATIONS” attached in “background material”)
- The number of fetuses having a greater number of full ribs than normal was increased in all treated groups when compared with the control. This variations in development is no considered biological deleterious
(See the table “INCIDENCE OF FETAL DEVELOPMENTAL VARIATIONS” attached in “background material”)

Fetal morphological observations of the treated groups did not indicate the presence of embryotoxic / teratogenic effects at any of the dosage levels tested. (See the tables mentioned above and the table reported in "Any other information on results inccl. tables")

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day
Based on:
act. ingr.
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

The table reported below has been extracted by the full study report N. 542 -002

Effect of Piperonyl Butoxide on Maternal and Fetal Parameters in a Rabbit Teratology Study

 

Observation at dosage level (mg Piperonyl Butoxide/kg/d)

Parameter

0 (Control)

50

100

200

 

Number

%

±SD

Number

%

±SD

Number

%

±SD

Number

%

±SD

Animals on study

16

-

-

16

-

-

16

-

-

16

-

-

Animals that were gravid

16

-

-

16

-

-

14

-

-

16

-

-

Animals that died

0

-

-

0

-

-

0

-

-

0

-

-

Animals that delivered near term

0

-

-

0

-

-

1

-

-

1

-

-

Animals examined at Cesarean section

16

-

-

16

-

-

15

-

-

16

-

-

Nongravid

0

-

-

0

-

-

2

-

-

0

-

-

Gravid

16

-

-

16

-

-

14

-

-

16

-

-

Does with resorption only

0

-

-

0

-

-

0

-

-

1

-

-

Does with viable fetuses

16

-

-

16

-

-

13

-

-

16

-

-

Viable fetuses/doe

8.1

 

2.82

8.1

 

2.43

7.5

 

2.88

8.3

 

2.33

Post implantation loss/doe

 

 

 

 

 

 

 

 

 

 

 

 

Total implantation/doe

 

 

 

 

 

 

 

 

 

 

 

 

Corpora lutea/doe

11.4

 

2.96

11.8

 

2.35

11.2

 

2.28

12.3

 

2.55

Group mean pre implantation loss (%)1)

 

24.7

 

 

25.0

 

 

24.0

 

 

27.41

 

Group mean post implantation loss (%)2)

 

5.8

 

 

8.5

 

 

11.7

 

 

9.5

 

Mean fetal body weight (grams)

38.9

 

6.12

41.2

 

6.09

39.2

 

3.84

39.4

 

5.14

Fetal sex distribution - male

 

58.1

 

 

40.3*

 

 

53.1

 

 

53.0

 

Fetal sex distribution - female

 

41.9

 

 

59.7

 

 

46.9

 

 

47.0

 

1)Value does not include doe with fewer corporea lutea than total implantations

*significantly different from control group (p<0.01)

Applicant's summary and conclusion

Conclusions:
MATERIALS AND METHODS
In a teratogenicity study according to FIFRA 83-3 Guideline, groups of 16 inseminated female New Zealand white SPF rabbits were randomly assigned to receive Piperonyl Butoxide at doses of 0, 50, 100 or 200 mg/kg bw per day orally by gavage on days 7-19 of gestation at a volume of 0.5 mL/kg in corn oil. On day 29 of gestation, the fetuses were removed surgically for evaluation.

RESULTS AND DISCUSSION
All animals survived to the end of treatment. One doe in the mid-dose group delivered before cesarean section.
Maternal weight loss or reduced body weight gain during the treatment period was observed in few animals of the mid- and high-dose groups. No treatment-related effects on fetal development and no teratogenic effects were observed.

CONCLUSION There were no treatment-related effects on fetal development including teratogenicity. Weight loss was noted for high dose and mid dose dams, although no statistical significance levels are given in the report.
The NOEL/NOAEL for maternal toxicity was 50 mg actual Piperonyl Butoxide /kg bw/day.
Although maternal toxicity was apparent in the mid- and high-dose groups, the test article, piperonyl buotxide, elicited neither a fetotoxic nor a teratogenic effect at dosage levels > 200 mg/kg/day (NOEL/NOAEL for mbryotoxic / teratogenic effects).

LO(A)EL maternal toxic effects = 100 mg/kg bw per day , reduced maternal body weight during treatment.
NO(A)EL maternal toxic effects = 50 mg/kg bw per day
LO(A)EL embryotoxic / teratogenic effects = No effects
NO(A)EL embryotoxic / teratogenic effects > 200 mg/kg bw per day

Reliability: 1
Deficiencies: No



Although maternotoxicity was apparent in the mid and high dose groups, the test article, PBO elicited neither a fetotoxic nor a teratogenic effect at dosage levels of 200mg/kg/day or less when administered orally to New Zealand White female rabbits.